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Veterans and Agent Orange: Update 2014 (2016)

Chapter: 8 Cancers

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Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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8

Cancers

Chapter Overview

Based on new evidence and a review of prior studies, the committee for Update 2014 determined that epidemiologic results concerning an association between exposure to the chemicals of interest (COIs) and bladder cancer had accrued to now constitute limited or suggestive evidence of an association. No other new significant associations between the relevant exposures and particular types of cancer were found. Aside from the conclusion concerning bladder cancer, current evidence supports the findings of earlier updates. Thus the current findings on cancer can be summarized as follows:

  • There is sufficient evidence of an association with the COIs and soft tissue sarcomas and B-cell lymphomas (Hodgkin lymphoma, non-Hodgkin lymphomas, chronic lymphocytic leukemia, hairy cell leukemia).
  • There is limited or suggestive evidence of an association between the COIs and bladder cancer; laryngeal cancer; cancers of the lung, bronchus, or trachea; prostate cancer; multiple myeloma, and amyloid light-chain (AL) amyloidosis.
  • There is inadequate or insufficient evidence to determine whether there is an association between the COIs and any other specific type of cancer.

Cancers are the second-leading cause of death in the United States. However, among men 60–75 years old, the group that includes most Vietnam veterans, the risk of dying from cancer exceeds the risk of dying from heart disease, the leading cause of death in the United States, and it does not fall to second place

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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until after the age of 75 years (Heron et al., 2009). About 589,430 Americans of all ages were expected to die from cancer in 2015—more than 1,500 per day. In the United States, one-fourth of all deaths are from cancer (Siegel et al., 2015).

This chapter summarizes—and presents conclusions about—the strength of the evidence from epidemiologic studies regarding associations between exposure to the COIs—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), picloram, and cacodylic acid—and various types of cancer. The committee also considers studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like chemicals (DLCs) informative if their results were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners of DLCs. However, studies that report TEQs based only on mono-ortho PCBs (which are PCBs 105, 114, 118, 123, 156, 157, 167, and 189) were given very limited consideration because mono-ortho PCBs typically contribute less than 10 percent to total TEQs, based on the World Health Organization (WHO) revised toxicity equivalency factors (TEFs) of 2005 (La Rocca et al., 2008; van den Berg et al., 2006). If a new study reported on only a single type of cancer and did not revisit a previously studied population, then its design information is summarized here with its results; design information on all other new studies can be found in Chapter 6.

The objective of this chapter is to provide an assessment of whether the occurrence of various cancers in Vietnam veterans themselves may be associated with exposure they may have received during military service. Therefore, studies of childhood cancers in relation to parental exposure to the COIs are discussed in Chapter 10, which addresses possible adverse effects in the veterans’ offspring. Studies that consider only childhood exposure are not considered relevant to the committee’s charge.

In an evaluation of a possible connection between herbicide exposure and the risk of cancer, the approach used to assess the exposure of study subjects is of critical importance in determining the overall relevance and usefulness of findings. As noted in Chapters 3 and 6, there is great variation in the detail and the accuracy of exposure assessments among studies. A few studies used biologic markers of exposure, such as the presence of a chemical in serum or tissues; some developed an index of exposure from employment or activity records; and some used other surrogate measures of exposure, such as an individual’s presence in a locale when herbicides were used. As noted in Chapter 2, an inaccurate assessment of exposure, a form of measurement error, can obscure the relationship between exposure and disease.

Each section on a type of cancer opens with background information, including data on its incidence in the general US population and known or suspected risk factors. Cancer-incidence data on the general US population are included in the background material to provide a context for consideration of the cancer risk in Vietnam veterans; the figures presented are estimates of incidence in the entire US population, not predictions for the Vietnam-veteran cohort. The data

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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reported are for 2008–2012 and are from the most recent dataset available (NCI, 2015). Incidence data are given for all races combined and also separately for blacks and whites. The age range of 60–74 years now includes about 80 percent of Vietnam-era veterans, and the incidences are presented for three 5-year age groups: 60–64 years, 65–69 years, and 70–74 years. The data were collected for the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute and are categorized by sex, age, and race, all of which can have profound effects on risk. For example, the incidence of prostate cancer is about 2.6 times as high in men who are 70–74 years old as in men 60–64 years old and about 75 percent higher in blacks 60–64 years old than in whites in the same age group (NCI, 2015). Many other factors can influence cancer incidence, including screening methods, tobacco and alcohol use, diet, genetic predisposition, and medical history. Those factors can make someone more or less likely than the average to contract a given kind of cancer; they also need to be taken into account in epidemiologic studies of the possible contributions of the COIs.

Each section of this chapter pertaining to a specific type of cancer includes a summary of the findings described in the previous Agent Orange1 reports: Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994); Veterans and Agent Orange: Update 1996, referred to as Update 1996 (IOM, 1996); Update 1998 (IOM, 1999); Update 2000 (IOM, 2001); Update 2002 (IOM, 2003); Update 2004 (IOM, 2005); Update 2006 (IOM, 2007); Update 2008 (IOM, 2009); Update 2010 (IOM, 2011a); and Update 2012 (IOM, 2014). That is followed by a discussion of the most recent scientific literature, a discussion of biologic plausibility, and a synthesis of the material reviewed. When it is appropriate, the literature is discussed by exposure type (service in Vietnam, occupational exposure, or environmental exposure). Each section ends with the committee’s conclusion regarding the strength of the evidence from epidemiologic studies. The categories of association and the committee’s approach to categorizing the health outcomes are discussed in Chapters 1 and 2.

Biologic plausibility corresponds to the third element of the committee’s congressionally mandated statement of task. In fact, the degree of biologic plausibility itself influences whether the committee perceives positive findings to be indicative of an association or the product of statistical fluctuations (chance) or bias.

Information on biologic mechanisms by which exposure to TCDD could contribute to the generic (rather than tissue-specific or organ-specific) carcinogenic potential of the other COIs is summarized in Chapter 4. It distills toxicologic

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1Despite loose usage of “Agent Orange” by many people, in numerous publications, and even in the title of this series, this committee uses “herbicides” to refer to the full range of herbicide exposures experienced in Vietnam, while “Agent Orange” is reserved for a specific one of the mixtures sprayed in Vietnam.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

information concerning the mechanisms by which TCDD affects the basic process of carcinogenesis; such information, of course, applies to all the cancer sites discussed individually in this chapter. When biologic plausibility is discussed in this chapter’s sections on particular cancer types, the generic information is implicit, and only experimental data peculiar to carcinogenesis at the site in question are presented. A large literature indicates that carcinogenesis is a process that involves not only genetic changes but also epigenetic changes, which modify DNA and its expression without altering its sequence of bases (Johnstone and Baylin, 2010). There is increasing evidence that TCDD and the COIs may disturb cellular processes through epigenetic mechanisms (see Chapter 4), and reference to this evidence, as it applies to cancers, is included where it exists, by cancer site.

Considerable uncertainty remains about the magnitude of the risk posed by exposure to the COIs. Many of the veteran, occupational, and environmental studies reviewed by the committee did not control fully for important confounders. There is not enough information about the exposure experience of individual Vietnam veterans to permit combining exposure estimates for them with any potency estimates that might be derived from scientific research studies to quantify risk. The committee therefore cannot accurately estimate the risk to Vietnam veterans that is attributable to exposure to the COIs. The (at least currently) insurmountable problems in deriving useful quantitative estimates of the risks of various health outcomes in Vietnam veterans are explained in Chapter 1 and in the summary of this report, but the point is not reiterated for every health outcome addressed.

ORGANIZATION OF CANCER GROUPS

For Update 2006, the committee developed a system for addressing cancer types to clarify how specific cancer diagnoses had been grouped for evaluation by the committee and to ensure that the full array of cancer types would be considered. The organization of cancer groups follows the major and minor categories of cause of death related to cancer sites established by the National Institute for Occupational Safety and Health (NIOSH). The NIOSH groups map the full range of International Classification of Diseases, 9th Revision (ICD-9) codes for malignant neoplasms (140–208). The ICD system is used by physicians and researchers to group related diseases and procedures in a standard form for statistical evaluation. Revision 10 (ICD-10) came into use in 1999 and represents a marked change from the previous four revisions that evolved into ICD-9. ICD-9 was in effect from 1979 to 1998; because ICD-9 is the version most prominent in the research reviewed in this series, it is used when codes are given for a specific health outcome. Appendix C describes the correspondence between the NIOSH cause-of-death groupings and ICD-9 codes (see Table C-1); the groupings for mortality are largely congruent with those of the SEER program for cancer incidence (see

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Table C-2, which presents equivalences between the ICD-9 and ICD-10 systems). For the present update, the committee gave more attention to the WHO’s classification of lymphohematopoietic neoplasms (WHO, 2008), which stresses partitioning of the disorders first according to the lymphoid or myeloid lineage of the transformed cells rather than into lymphomas and leukemias.

The system of organization used by the committee simplifies the process for locating a particular cancer for readers and facilitated the committee’s identification of ICD codes for malignancies that had not been explicitly addressed in previous updates. The VAO reports’ default category for any health outcome on which no epidemiologic research findings have been recovered has always been “inadequate evidence” of association with exposure to the COIs, which in principle is applicable to specific cancers. A failure to review a specific cancer or other condition separately reflects the paucity of information, so there is indeed inadequate or insufficient information to categorize an association with such a disease outcome.

BIOLOGIC PLAUSIBILITY

The studies considered by the committee that speak to the biologic plausibility of associations between exposure to the COIs and human cancers have been performed primarily in laboratory animals (rats, mice, hamsters, and monkeys) or in cultured cells.

Concerning 2,4-D, 2,4,5-T, and picloram, several studies have been performed in laboratory animals. In general, the results were negative although some would not meet current standards of cancer bioassays; for instance, there is a question whether the highest doses (generally 30–50 mg/kg) in some of the studies reached a maximum tolerated dose. It is not possible to have absolute confidence that these chemicals have no carcinogenic potential. Further evidence of a lack of carcinogenic potential is provided, however, by negative findings on genotoxic effects in assays conducted primarily in vitro. The results of such studies indicate that 2,4-D and 2,4,5-T are genotoxic only at very high concentrations.

There is evidence that cacodylic acid is carcinogenic. Studies performed in laboratory animals have shown that it can induce neoplasms of the kidney (Yamamoto et al., 1995), bladder (Arnold et al., 2006; Cohen et al., 2007b; Wang et al., 2009; Wei et al., 2002; Yamamoto et al., 1995), liver, and thyroid gland (Yamamoto et al., 1995). Treatment with cacodylic acid induced the formation of neoplasms of the lung when administered to mouse strains that are genetically susceptible to developing these tumors (Hayashi et al., 1998; Yamanaka et al., 2009). Other studies have used the two-stage model of carcinogenesis in which animals are exposed first to a known genotoxic agent and then to a suspected tumor-promoting agent; with this model, cacodylic acid has been shown to act

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

as a tumor-promoter with respect to lung cancer (Yamanaka et al., 1996). These studies are further discussed in Chapter 4.

Collectively, the evidence obtained from studies of TCDD indicates that a connection between human exposure to this chemical and cancers is biologically plausible, as will be discussed more fully in a generic sense below and more specifically in the biologic plausibility sections on individual cancers. Recent reviews have affirmed the well-established mechanistic roles of the aryl hydrocarbon receptor (AHR) in TCDD-induced cancers (Androutsopoulos et al., 2009; Barouki and Coumoul, 2010; Dietrich and Kaina, 2010; Murray et al., 2014; Ray and Swanson, 2009; Rysavy et al., 2013; Tsay et al., 2013). On the basis of these data, the biologic plausibility of an association between TCDD exposure and cancer has been firmly established in a mechanistic sense, and TCDD is considered a nongenotoxic carcinogen, as reviewed by Hernández et al. (2009). TCDD can disrupt circadian rhythms via the AHR, and chronic disruption of circadian rhythms is associated with an increased incidence of cancer, suggesting a potential additional pathway by which TCDD increases cancer risk (Wang C et al., 2014; Xu et al., 2013).

Studies in laboratory animals in which only TCDD has been administered have shown that it can increase the incidence of a number of neoplasms, most notably of the liver, lungs, thyroid, and oral mucosa (Kociba et al., 1978; NTP, 2006). Some studies have used the two-stage model of carcinogenesis and shown that TCDD can act as a tumor promoter and increases the incidence of ovarian cancer (Davis et al., 2000), liver cancer (Beebe et al., 1995), and skin cancers (Wyde et al., 2004). In exerting its carcinogenic effects, TCDD is thought to act primarily as a tumor promoter. In many of the animal studies reviewed, treatment with TCDD has resulted in hyperplasia or metaplasia of epithelial tissues. Work with a mouse lung cancer model suggests that in addition to increasing cell division, the tumor-promoting activity of TCDD includes decreasing apoptosis (Chen et al., 2014a). In addition, in both laboratory animals and cultured cells, TCDD has been shown to exhibit a wide array of effects on growth regulation, hormone systems, and other factors associated with the regulation of cellular processes that involve growth, maturation, and differentiation, in most cases via its interaction with AHR (Murray et al., 2014; Rysavy et al., 2013). Thus, it may be that TCDD increases the incidence or progression of human cancers through the interplay of multiple cellular mechanisms. Tissue-specific protective cellular mechanisms may also be important to the response to TCDD and may complicate our understanding of its site-specific carcinogenic effects.

As shown with long-term bioassays in both sexes of several strains of rats, mice, hamsters, and fish, there is adequate evidence that TCDD is a carcinogen in laboratory animals because it increases the incidence of tumors, including tumors at sites distant from the site of treatment, at doses well below the maximum tolerated dose (Rysavy et al., 2013). TCDD has frequently been characterized as a nongenotoxic carcinogen. TCDD is non-mutagenic because it does not produce

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

changes in DNA sequences, but because of the oxidative stress it produces, TCDD does have some genotoxic potential. This may contribute to its recognized activity as a potent tumor promoter and a weak initiator in two-stage initiation–promotion models for liver, skin, and lung. Early studies demonstrated that TCDD is two orders of magnitude more potent than the “classic” promoter tetradecanoyl phorbol acetate (TPA) and that its skin-tumor promotion depends on the AHR.

A number of potential pathways for TCDD carcinogenesis have been proposed. TCDD may contribute to tumor progression by inhibiting p53 regulation (phosphorylation and acetylation) triggered by genotoxic agents through the increased expression of the metastasis marker AGR2 (Ambolet-Camoit et al., 2010) and through a functional interaction between the AHR and FHL2—the “four and a half LIM protein 2,” in which the LIM domain is a highly conserved protein structure (Kollara and Brown, 2009). Borlak and Jenke (2008) demonstrated that the AHR is a major regulator of c-Raf and proposed that there is cross-talk between the AHR and the mitogen-activated protein kinase signaling pathway in chemically induced hepatocarcinogenesis. TCDD inhibits ultraviolet-C radiation-induced apoptosis in primary rat hepatocytes and Huh-7 human hepatoma cells, and this finding supports the hypothesis that TCDD acts as a tumor promoter by preventing initiated cells from undergoing apoptosis (Chen et al., 2014b; Chopra et al., 2009). AHR activation by TCDD in human breast and endocervical cell lines induces sustained high concentrations of the cytokine interleukin-6, which has tumor-promoting effects in numerous tissues—including breast, prostate, and ovary—and opens up the possibility that TCDD would promote carcinogenesis in these and possibly other tissues (Hollingshead et al., 2008). In rat liver, TCDD downregulates reduced folate carrier (Rfc1) mRNA and protein, whose normal levels are essential in maintaining folate homeostasis (Halwachs et al., 2010). Reduced Rfc1 activity and a functional folate deficiency may contribute to the risk of carcinogenesis posed by TCDD exposure, perhaps via an epigenetic effect of interfering with DNA methylation levels (Davis and Uthus, 2004; Williams, 2012). Recent work has shown an interaction between the AHR and the ADM (adrenomedullin) oncogene in cell lines and lung tissue (Portal-Nunez et al., 2012), and AHR repression experiments in gastric and head and neck cancers suggest that AHR expression leads to increased cancer cell growth and invasion (DiNatale et al., 2012; Yin et al., 2013)

Additional in vitro work with mouse hepatoma cells has shown that activation of the AHR results in increased concentrations of 8-hydroxy-2′-deoxyguanosine (8-OHdG), a product of DNA-base oxidation and a marker of DNA damage. The induction of cytochrome P4501A1 (CYP1A1) in these cells by TCDD or indolo(3,2-b)carbazole is associated with oxidative DNA damage (Park et al., 1996). In vivo experiments in mice corroborated those findings by showing that TCDD caused a sustained oxidative stress, as determined by measurements of urinary 8-OHdG (Shertzer et al., 2002) and involves AHR-dependent uncoupling of mitochondrial respiration (Senft et al., 2002). Mitochondrial reactive-oxygen

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

production depends on the AHR. Other than these observations of 8-OHdG formation and oxidative stress, there is little evidence that TCDD is genotoxic, and it appears likely that some of its mechanisms of action may involve epigenetic modifications of the genome.

Electronics-dismantling workers who experienced complex exposures, including exposure to polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs and PCDFs), had increased concentrations of urinary 8-OHdG, indicative of oxidative stress and genotoxicity; this cannot, however, be ascribed directly to these compounds (Wen et al., 2008). Clastogenic genetic disturbances arising as a consequence of confirmed exposure to herbicides were determined by analyzing sister-chromatid exchanges (SCEs) in lymphocytes from a group of 24 New Zealand Vietnam War veterans and 23 control volunteers (Rowland et al., 2007). The results showed a highly significant difference (p < 0.001) in mean SCE frequency between the group of veterans and the control group. These Vietnam War veterans also had a much higher proportion of cells with SCE frequencies above the 95th percentile than the controls (11.0 percent and 0.07 percent, respectively). A study of SCE frequencies in blood samples taken from Vietnamese women from high and moderate TCDD-sprayed areas also showed increased SCE frequencies of 2.40 per cell and 2.19 per cell, respectively, for these women compared with Vietnamese women from unexposed areas (1.48 per cell, p < 0.001) (Suzuki et al., 2014).

The weight of evidence that TCDD and dioxin-like PCBs make up a group of chemicals with carcinogenic potential includes unequivocal animal carcinogenesis and biologic plausibility based on mechanistic mode-of-action data. Although the specific mechanisms by which dioxin causes cancer remain to be definitively established, the intracellular factors and mechanistic pathways involved in dioxin’s cancer-promoting activity all have parallels in both animals and humans. No qualitative differences have been reported to indicate that humans should be considered as fundamentally different from the multiple animal species in which bioassays have demonstrated dioxin-induced neoplasia. The International Agency on Cancer Research (IARC) has classified TCDD in group 1 as carcinogenic to humans and found the strongest evidence for carcinogenicity for all cancers combined and a positive association between exposure to TCDD and soft-tissue sarcomas, non-Hodgkin lymphomas, and lung cancer (IARC, 2012b). The combination of a positive association with TCDD exposure for these specific cancer sites no doubt contributes to the association with all cancers combined being the strongest, as reports of increased risks for several other cancers in TCDD-exposed workers and in the TCDD-exposed population in Seveso were only sporadic and not fully consistent.

Thus, the toxicologic evidence indicates that a connection of TCDD and perhaps cacodylic acid with cancer in humans is, in general, biologically plausible, but (as discussed in The Committee’s View of “General” Human Carcinogens, below) it must be determined case by case whether such carcinogenic potential

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

contributes to an individual type of cancer. Experiments with 2,4-D, 2,4,5-T, and picloram in animals and cells have not provided a strong biologic basis for the presence or absence of carcinogenic effects.

THE COMMITTEE’S VIEW OF “GENERAL”
HUMAN CARCINOGENS

To address its charge, the committee weighed the scientific evidence linking the COIs to specific individual cancer sites. That was appropriate given the different susceptibilities of various tissues and organs to cancer and the various genetic and environmental factors that can influence the occurrence of a particular type of cancer. Before considering each site in turn, however, it is important to address the concept that cancers share some characteristics among organ sites and to clarify the committee’s view regarding the implications of a chemical being a “general” human carcinogen. All cancers share phenotypic characteristics: uncontrolled cell proliferation, increased cell survival, invasion outside normal tissue boundaries, and eventually metastasis. The current understanding of cancer development holds that a cell or group of cells must acquire a series of sufficient genetic mutations to progress and that particular epigenetic events must occur to accelerate the mutational process and provide growth advantages for the more aggressive clones of cells. Both genetic (mutational) and epigenetic (non-mutational) activities of carcinogenic agents can stimulate the process of cancer development.

In classic experiments based on the induction of cancer in mouse skin that were conducted more than 40 years ago, carcinogens were categorized as initiators, those capable of causing an initial genetic insult to the target tissue, and promoters, those capable of promoting the growth of initiated tumor cells, generally through non-mutational events. Some carcinogens, such as those found in tobacco smoke, were considered “whole carcinogens” or “complete carcinogens”—that is, they were capable of both initiation and promotion. Today, cancer researchers recognize that the acquisition of important mutations is a continuing process in tumors and that promoters, or epigenetic processes that favor cancer growth, enhance the accumulation of genotoxic damage, which traditionally would be regarded as initiating activity.

As discussed above and in Chapter 4, 2,4-D, 2,4,5-T, and picloram have shown little evidence of genotoxicity in laboratory studies, except at very high doses, and little ability to facilitate cancer growth in laboratory animals. However, cacodylic acid and TCDD have shown the capacity to increase cancer development in animal experiments, particularly as promoters rather than as pure genotoxic agents. Extrapolating organ-specific results from animal experiments to humans is problematic because of important differences between species in the overall susceptibility of various organs to cancer development and in organ-specific responses to particular putative carcinogens. Therefore, judgments

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

about the “general” carcinogenicity of a chemical in humans are based heavily on the results of epidemiologic studies, especially on the issue of whether there is evidence of an excess cancer risk at multiple organ sites. As the evaluations of specific types of cancer in the remainder of this chapter indicate, the committee finds that TCDD appears to be a multisite carcinogen. That finding is in agreement with IARC, which has determined that TCDD is a category 1 “known human carcinogen” (Baan et al., 2009; IARC, 2012b); with the US Environmental Protection Agency (EPA), which has concluded that TCDD is “likely to be carcinogenic to humans”2; and with the National Toxicology Program (NTP), which regards TCDD as “known to be a human carcinogen” (NTP, 2011). It is important to emphasize that the goals and methods of IARC and EPA in making their determinations were different from those of the present committee: Those organizations focus on anticipating hazards in order to minimize future exposure, whereas this committee focuses on risk after exposure. Furthermore, the recognition that TCDD and cacodylic acid are multisite carcinogens does not imply that they cause human cancer at every organ site.

The distinction between general carcinogen and site-specific carcinogen is more difficult to grasp in light of the common practice of beginning analyses of epidemiologic cohorts with a category of “all malignant neoplasms,” which is a routine first screen for any unusual cancer activity in the study population rather than a test of a biologically based hypothesis. When the distribution of cancers among anatomic sites is not provided in the report of a cohort study, a statistical test for an increase in all cancers is not meaningless, but it is usually less scientifically supportable than analyses based on specific sites, for which more substantial biologically based hypotheses can often be developed. The size of a cohort and the length of the observation period often constrain the number of cancer cases that are observed and which specific types of cancer have enough observed cases to permit analysis. For instance, an analysis of the cumulative results on diabetes and cancers in the prospective Air Force Health Study (Michalek and Pavuk, 2008) produced important information summarizing previous findings on the fairly common condition of diabetes, but the cancer analysis does not go beyond “all cancers.” The committee does not accept the cancer findings as an indication that exposure to herbicides increases the risk of every variety of cancer, but rather as an indication that the agent is carcinogenic to humans. The committee acknowledges that the results of the highly stratified analyses conducted suggest that the incidence of some cancers did increase in the Ranch Hand subjects, but it views the “all cancers” results as a conglomeration of information on specific cancers—most important, melanoma and prostate cancer, for which elevated results have been published (Akhtar et al., 2004; Pavuk et al., 2006)—and as meriting individual longitudinal analysis to resolve outstanding questions.

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2See http://www.epa.gov/ttn/atw/hlthef/dioxin.html, updated January 2000, accessed September 21, 2013.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

The literature search for this update identified several publications on populations with relevant exposures that included risk statistics for overall cancer incidence (McBride et al., 2013; Yi and Ohrr, 2014) or mortality (Kang et al., 2014; Lin et al., 2012; Wang et al., 2013), which were all somewhat elevated, although not necessarily significantly so. The most substantial elevation (standardized mortality ratio [SMR] = 1.70, 95% confidence interval [CI] 1.35–2.13) was seen among workers at a Chinese automobile foundry factory, where TCDD was only one of several toxic agents, but there was no consistent indication of elevated cancer risk associated with exposure to the VAO COIs specifically (Wang et al., 2013).

The committee notes that current information on overall mortality in US Vietnam veterans themselves has been elusive. Considerable confusion and alarm has arisen from Internet attribution of all of the approximately 800,000 deaths among all 9.2 million US Vietnam-era veterans to the 2.7 million who served in Vietnam (Brady, 2011; Gelman, 2013). The most recent reliable information was obtained in the 30-year update of mortality through 2000 of the deployed and era veterans in the Vietnam Experience Study (Boehmer et al., 2004), which found that mortality among the deployed veterans slightly exceeded that of their non-deployed counterparts, but was only about 9 percent. A follow-up study (O’Toole et al., 2010) of a random sample of 1,000 Australian Vietnam veterans selected from Australia’s comprehensive roster of 57,643 service members deployed to Vietnam may provide a somewhat newer estimate of mortality through 2004; that study found mortality among Vietnam veterans to be 11.7 percent, which may be fairly comparable with that of their American fellows. The recent update on mortality among female US Vietnam veterans (Kang et al., 2014) stated that at the end of 2010, 20.2 percent of the deployed women in the cohort had died compared to 24.6 percent of those who remained in the United States. Because of considerable differences in mortality profiles for men and women, however, this does not provide a particularly accurate estimate for the large majority of American Vietnam veterans who are male.

The remainder of this chapter deals with the committee’s review of the evidence on each individual cancer site in accordance with its charge to evaluate the statistical association between exposure and cancer occurrence, the biologic plausibility and potential causal nature of the association, and the relevance to US veterans of the Vietnam War.

A number of studies of populations that received potentially relevant exposures were identified in the literature search for this review but did not characterize exposure with sufficient specificity for their results to meet the committee’s criteria for inclusion in the evidentiary database. For instance, the British Pesticide Users Health Study has followed almost 60,000 men and 4,000 women who were certified for agricultural pesticide use in Great Britain since 1987. Frost et al. (2011) reported cancer incidence and mortality in this cohort up to 2004 for the full array of anatomic sites, but exposure was defined only as being

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

a member of this cohort. Therefore, the cancer-specific findings of Frost et al. (2011) will not be repeatedly noted in the individual sections below. That is also the case for the mortality follow-up of Japanese Americans in the Honolulu Heart Program reported by Charles et al. (2010). Technically, this rubric would apply to the mortality and morbidity results reported by Waggoner et al. (2011) and Koutros et al. (2010a); however, because of the context provided by the extensive pesticide-specific results that have been published on individual cancers in the Agricultural Health Study (AHS) and the knowledge that 2,4-D was one of the most frequently used pesticides in this large prospective cohort, those results are presented below, but not given full evidentiary weight. Numerous cancer studies of the case-control design addressing particular cancers had exposure characterizations that were no more specific than job titles, farm residence, or pesticide exposure; therefore, their results are not regarded as fully relevant for the purpose of this review, and such studies are mentioned only in passing in a discussion of the cancer investigated.

ORAL, NASAL, AND PHARYNGEAL CANCERS

Oral, nasal, and pharyngeal cancers are found in many anatomic sites: the structures of the mouth (inside lining of the lips, cheeks, gums, tongue, and hard and soft palate—ICD-9 codes 140–145), oropharynx (ICD-9 146), nasopharynx (ICD-9 147), hypopharynx (ICD-9 148), other buccal cavity and pharynx (ICD-9 149), and nasal cavity and paranasal sinuses (ICD-9 160). Although the above cancers are classified together in the same category, the epidemiological risk factors for cancers that occur in the oral cavity and pharynx are very different from the risk factors for cancer of the nasopharynx. We now recognize that, in addition to cigarette smoking and alcohol consumption, infection with human papilloma virus (HPV), particularly alpha HPV16, is an important risk factor for squamous-cell carcinoma of the head and neck, and risk estimates are highest for cancers of the base of the tongue, tonsils, and oropharynx (collectively classified as oropharyngeal cancers) (Gillison et al. 2000; Marur et al., 2010; Oliveira et al., 2012).

The American Cancer Society (ACS) estimated that about 45,780 men and women would receive diagnoses of oral cavity or pharyngeal cancers in the United States in 2015 and that 8,650 men and women would die from these cancers (Siegel et al., 2015). Almost 90 percent of those cancers originate in the oral cavity or oropharynx. Most oral, nasal, and pharyngeal cancers are squamous-cell carcinomas. Nasopharyngeal carcinoma (NPC) is the most common malignant epithelial tumor of the nasopharynx but is relatively rare in the United States. There are three types of NPC: keratinizing squamous-cell carcinoma, nonkeratinizing carcinoma, and undifferentiated carcinoma. The average annual incidence rates reported in Table 8-1 show that men are at greater risk than women to be diagnosed with these cancers and that the incidence rates increase with age. However, because of the small number of cases, incidence rates should

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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TABLE 8-1 Average Annual Incidence (per 100,000) of Nasal, Oral Cavity, and Pharyngeal Cancers in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Nose, Nasal Cavity, and Middle Ear:
Men 2.3 2.3 2.2 2.8 2.8 2.2 3.8 3.8 3.8
Women 1.3 1.3 0.8 1.5 1.5 1.3 2.1 2.2 0.9
Oral Cavity and Pharynx:
Men 53.5 55.9 52.3 59.8 62.2 59.4 61.5 64.5 53.6
Women 15.9 16.7 13.5 19.8 21.0 16.4 24.2 25.7 18.0

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

be interpreted with caution. Tobacco and alcohol use are well-established risk factors and also contribute synergistically to the incidence of oral cavity and pharyngeal cancers, and, as mentioned above, infection with HPV is a major risk factor for oropharygeal cancers (Hashibe et al., 2007, 2009; Kreimer et al., 2013; Michaud et al., 2014; Oliveira et al., 2012). Ecological studies in the United States have shown that between 2001 and 2010 the incidence rates for cancers of the oral cavity went down (possibly because of decreasing prevalence of smoking), whereas incidence rates for oropharyngeal cancers have increased annually by 2.9 percent, which has been attributed to HPV infection (Chaturvedi et al., 2011).

Reported risk factors for nasal cancer include occupational exposure to nickel and chromium compounds (d’Errico et al., 2009; Feron et al., 2001; Grimsrud and Peto, 2006), wood dust (d’Errico et al., 2009), leather dust (Bonneterre et al., 2007), and high doses of formaldehyde (Nielsen and Wolkoff, 2010), as well as infection with Epstein–Barr virus.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COI and oral cavity, nasal, and pharyngeal cancers. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, Update 2010, and Update 2012 did not change that conclusion.

In Update 2006, at the request of the Department of Veterans Affairs (VA), the committee attempted to evaluate tonsil cancer cases separately, but it was able to identify only three cohort studies that provided the number of tonsil cancer cases in their study populations and concluded that the studies did not provide sufficient evidence to determine whether an association existed between exposure

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

to the COIs and tonsil cancer. No new published studies have offered any important additional insight into this specific question. The committee responsible for Update 2006 recommended that VA evaluate the possibility of studying health outcomes, including tonsil cancer, in Vietnam-era veterans by using existing administrative and health-services databases. Anecdotal evidence provided to that committee suggested a potential association between the exposures in Vietnam and tonsil cancer. Increasing evidence indicating that some cancers of the oropharynx and oral cavity can have a viral (HPV) etiology is consistent with the potential mechanistic hypothesis explaining an excess of these cancers in Vietnam veterans: Immune alterations associated with herbicide exposure may have increased susceptibility to HPV infection in the oral cavity and tonsils of Vietnam veterans, thereby making them more prone to the development of squamous-cell carcinomas of these tissues. The present committee strongly reiterates the 2006, 2008, 2010, and 2012 recommendation that VA develop a strategy that uses existing databases to evaluate tonsil cancer in Vietnam-era veterans.

In Update 2010, Cypel and Kang (2010) reported on a follow-up study of Vietnam-era Army Chemical Corps (ACC) veterans, comparing mortality through 2005 in ACC veterans by Vietnam service. They reported a non-significant increase in oral cavity and pharyngeal cancers in the deployed cohort compared with cases in the non-deployed cohort—a result that is consistent with a prior report on mortality through 1991 (Dalager and Kang, 1997). McBride et al. (2009a) reported on mortality through 2004 in the New Zealand cohort of 1,599 workers who had been employed in manufacturing phenoxy herbicides from trichlorophenol (TCP); picloram was also produced in the plant. They reported a non-significant excess in mortality from buccal cavity and pharyngeal cancers, but there were no deaths from nasopharyngeal cancers in either group.

In Update 2012, several occupational cohort studies reported on cancers of the oral cavity or pharynx, but the evidence was inconsistent. Studies of workers at Dow’s plant in Midland, Michigan, and in the NIOSH pentachlorophenol (PCP) cohort reported no increases in incidence (Burns CJ et al., 2011) or mortality (Ruder and Yiin, 2011) from oral cavity and pharyngeal cancers. By contrast, Manuwald et al. (2012) reported significantly increased mortality from cancers of the lip, oral cavity, or pharynx (SMR = 2.17, 95% CI 1.08–3.87) in a cohort of male and female chemical plant workers versus Hamburg’s general population.

The existing evidence from all published studies conducted among Vietnam veterans or various occupational cohorts reporting on the incidence of or mortality from cancers of the nose, oral cavity, or pharynx is largely inconclusive. The majority of these studies have reported no association or non-significant modest excesses in risk, while not characterizing exposure as specifically as needed for the committee’s decision making. In addition, the small numbers of oral, nasal, or pharyngeal cancer cases reported, in combination with a general lack of information on the smoking and drinking habits or HPV exposure status of the study participants, limit the interpretation of the data.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Studies evaluated previously and in the present report are summarized in Table 8-2.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

There have been no studies of US Vietnam veterans evaluating exposure to the COIs and oral, nasal, or pharyngeal cancers since Update 2012. However, two recent cohort studies of Vietnam War veterans (a majority of them males) from New Zealand and Korea reported on cancer incidence and mortality for cancers of the oral cavity, nasal cavity, and pharynx.

McBride and colleagues (2013) followed 2,783 male veterans from New Zealand who served in Vietnam from 1964 through 1972 for cancer incidence and mortality from 1988 through 2008 and compared them with the general population of New Zealand. With regard to incident head and neck cancers (n = 19), which by their definition excluded cancers of the larynx and esophagus, there was a modestly increased risk, albeit not a statistically significant one (standardized incidence ratio [SIR] = 1.34, 95% CI 0.81–2.09). A similar increase (SIR = 1.32, 95% CI 0.78–2.08) was observed when the analysis was restricted to cancers of the oral cavity, pharynx, and larynx (excluding cancers of lip, sinus cavities, or salivary glands) (n = 18). There were five incident cases and two deaths from laryngeal cancer in this cohort. Using the same groupings for cancer mortality, McBride et al. (2013) reported substantial and significant increased risks of death from head and neck cancers (SMR = 2.20, 95% CI 1.09–3.93) and from cancers of the oral cavity, pharynx, and larynx (SMR = 2.13, 95% CI 1.06–3.81) among the New Zealand Vietnam veterans based on 11 deaths in each grouping. McBride et al. (2013) did not report on nasal cancer separately.

Although the follow-up of the cohort of New Zealand Vietnam veterans was relatively long (20 years), the study did not have information on cancer incidence and mortality in the time period immediately after the service. In addition, information on potential confounding factors including smoking, drinking habits, and HPV status was not available, which limits the interpretation of the data, particularly regarding incident cancers. However, the greater than two-fold excess risks of mortality from head and neck cancers as well as from cancers of the oral cavity, pharynx, and larynx cannot be completely attributed to confounding by smoking, because excess risks were not found in this cohort for deaths from other smoking-related diseases such as lung cancer, chronic obstructive pulmonary disease (COPD), or coronary heart disease. Finally, because of the small sample size, the study did not report on tonsillar cancers specifically.

Several recent publications examined incidence (Yi, 2013; Yi and Ohrr, 2014) and mortality (Yi et al., 2014b) for cancers of the oral cavity, nasal cavity, and pharynx in the Korean Veterans Health Study, a large prospective cohort of

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-2 Selected Epidemiologic Studies—Oral, Nasal, and Pharyngeal Cancers (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans      
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)   All COIs Akhtar et al., 2004
Incidence      
Ranch Hand veterans (n = 1,189) 6 0.9 (0.4–1.9)  
With tours between 1966–1970 6 1.1 (0.5–2.3)  
SEA comparison veterans (n = 1,776) 5 0.6 (0.2–1.2)  
With tours between 1966–1970 4 0.6 (0.2–1.4)  
Mortality      
Through 1999—White subjects vs national rates      
Ranch Hand veterans (n = 1,189) 0 0.0 (nr)  
SEA comparison veterans (n = 1,776) 1 0.5 (nr)  
US VA Cohort of Army Chemical Corps   All COIs  
Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 non-deployed) serving during Vietnam era (July 1, 1965–March 28, 1973)      
Mortality—Oral cavity and pharyngeal cancer      
Through 2005     Cypel and Kang, 2010
Deployed (2,872) vs non-deployed (2,737) 6 vs 2 1.7 (0.3–8.7)
Army Chemical Corps vs US men      
Vietnam cohort 6 1.5 (0.6–3.3)  
Non-Vietnam cohort 2 0.8 (0.1–2.8)  
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Mortality      
1965–2000 (ICD-9 140–149) 6 nr Boehmer et al., 2004
US CDC Selected Cancers Study—Case-control study of incidence (Dec 1, 1984–Nov 30, 1989) among US males born 1929–1953   All COIs CDC, 1990a
89 nasopharyngeal carcinomas      
Vietnam service 3 0.5 (0.2–1.8)  
62 nasal carcinomas      
Vietnam service 2 0.7 (0.2–2.9)  
State Studies of US Vietnam Veterans      
Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs non-deployed (lip, oral cavity, pharynx) 12 1.0 (0.5–1.8) Visintainer et al., 1995
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
International Vietnam-Veterans Studies      
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence      
All branches, 1982–2000 (head and neck) 247 1.5 (1.3–1.6) ADVA, 2005b
Navy 56 1.6 (1.1–2.0)  
Army 174 1.6 (1.3–1.8)  
Air Force 17 0.9 (0.5–1.5)  
Mortality      
All branches, return–2001     ADVA, 2005a
Head and neck 101 1.4 (1.2–1.7)  
Navy 22 1.5 (0.9–2.1)  
Army 69 1.5 (1.1–1.8)  
Air Force 9 1.1 (0.5–2.0)  
Nasal 3 0.8 (0.2–2.2)  
1980–1994     CDVA, 1997a
Lip (ICD-9 140) 0 nr  
Nasopharyngeal cancer (ICD-9 147) 2 0.5 (0.1–1.7)  
Nasal cavities (ICD-9 160) 2 1.2 (0.1–4.1)  
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence      
1982–2000     ADVA, 2005c
Head and neck 44 2.0 (1.2–3.4)  
Mortality      
1966–2001     ADVA, 2005c
Head and neck 16 1.8 (0.8–4.3)  
Nasal 0 0.0 (0.0–48.2)  
1982–1994     CDVA, 1997b
Nasopharyngeal cancer (ICD-9 147) 1 1.3 (0.0– > 10)  
Nasal cavities (ICD-9 160) 0 0.0 (0.0– > 10)  
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008)      
Head and neck 19 1.3 (0.8–2.1)  
Oral cavity, pharynx and larynx 18 1.3 (0.8–2.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality (1988–2008)      
Head and neck 11 2.2 (1.1–3.9)  
Oral cavity, pharynx and larynx 11 2.1 (1.1–3.8)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)     Yi and Ohrr, 2014
Lip (C00) 1 vs 2 1.4 (0.1–26.2)
Tongue (C01–C02) 17 vs 14 1.0 (0.5–2.2)  
Mouth (C03–C06) 23 vs 9 2.5 (1.1–5.7)  
Salivary gland (C07–C08) 13 vs 2 7.0 (1.5–32.3)  
Tonsil (C09) 10 vs 12 0.9 (0.4–2.2)  
Other oropharynx (C10) 6 vs 3 2.0 (0.5–8.2)  
Nasopharynx (C11) 21vs 29 0.7 (0.4–1.2)  
Hypopharynx (C12–C13) 18 vs 12 1.0 (0.5–2.2)  
Nose, sinuses, etc. (C30–C31) 11 vs 8 1.8 (0.7–4.7)  
Mortality (1992–2005)     Yi et al., 2014b
Oral cavity cancer (C00–C14)      
Categorized high vs low 45 vs 37 1.1 (0.7–1.7)  
HR per unit of log EOI (n = 180,639) 82 1.1 (0.9–1.2)  
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Mortality 1939–1992     Kogevinas et al., 1997
Oral cavity, pharynx cancer (ICD-9 140–149) 26 1.1 (0.7–1.6)
13,831 exposed to highly chlorinated PCDDs 22 1.3 (0.8–2.0)  
7,553 not exposed to highly chlorinated PCDDs 3 0.5 (0.1–1.3)  
Nasal, nasal sinus cancer (ICD-9 160) 3 1.6 (0.3–4.7)  
13,831 exposed to highly chlorinated PCDDs 0 0.0 (0.0–3.5)  
7,553 not exposed to highly chlorinated PCDDs 3 3.8 (0.8–11.1)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort     Saracci et al., 1991
Bucal cavity, pharynx (ICD-8 140–149) 11 1.2 (0.6–2.1)  
Nose, nasal cavities (ICD-8 160) 3 2.9 (0.6–8.5)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)   MCPA  
Mortality through 1983     Coggon et al., 1986
Lip (ICD-9 140) 0 nr
Tongue (ICD-9 141) 1 1.1 (0.0–6.2)  
Pharynx (ICD-9 146–149) 1 0.5 (0.0–3.0)  
Nose (ICD-9 160) 3 4.9 (1.0–14.4)  
Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)   Dioxins, 2,4,5-T, 2,4,5-TCP  
Mortality 1955–1991 (lip, oral cavity, pharynx)     Hooiveld et al., 1998
All working anytime in 1955–1985 1 2.3 (0.1–12.4)
Cleaned up 1963 explosion 1 7.1 (0.2–39.6)  
German Production Workers—2,479 workers at 4 plants (in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
All for plants—Buccal cavity, pharynx (ICD-9 140–149) 9 3.0 (1.4–5.6) Becher et al., 1996
Tongue 3 nr  
Floor of mouth 2 nr  
Tonsil 2 nr  
Pharynx 2 nr  
German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 mo in 1951–1976) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4, 5-TCP  
Mortality 1951–1992 0 Becher et al., 1996
German Production Workers at Bayer Plant in Dormagen (520 men working > 1 mo in 1965–1989) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Mortality 1965–1989 0 Becher et al., 1996
German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 mo in 1957–1987) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Mortality 1956–1989 6 8.2 (3.0–17.9) Becher et al., 1996
BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)   Focus on TCDD  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality      
Through 1987   90% CI Zober et al., 1990
Buccal cavity, pharynx 1 4.8 (0.3–22.9)
Squamous-cell carcinoma of tonsil 1 nr  
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)   Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP  
Mortality 1952–2007 (ICD-9 140–149) 11 2.2 (1.1–3.9) Manuwald et al., 2012
Men 9 2.0 (0.9–3.8)
Women 2 3.4 (0.4–12.5)  
Mortalilty 1952–1989 3 1.8 (0.4–5.2) Becher et al., 1996
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004 (buccal cavity and pharynx)     McBride et al., 2009a
Ever-exposed workers 3 2.6 (0.5–7.6)
Never-exposed workers 0 0.0 (0.0–11.5)  
Production Workers— Mortality 1969–2000      
713 men and 100 women worked > 1 month in 1969–1984 (ICD-9)     ’t Mannetje et al., 2005
2 2.8 (0.3–9.9)
Lip (140) 0 nr  
Mouth (141–145) 2 5.4 (0.7–20.0)  
Oropharynx (146) 0 nr  
Nasopharynx (147) 0 0.0 (0.0–41.8)  
Hypopharynx, other (148–149) 0 nr  
Phenoxy herbicide sprayers (> 99% men) 1 1.0 (0.0–5.7) ’t Mannetje et al., 2005
Lip (140) 0 nr
Mouth (141–145) 0 0.0 (0.0–7.5)  
Oropharynx (146) 0 nr  
Nasopharynx (147) 1 8.3 (0.2–46.3)  
Hypopharynx, other (148–149) 0 nr  
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
All Dow PCP-Exposed Workers (All workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
1940–2005 (n = 2,122) (buccal, pharynx; ICD-9 140–149) 5 0.8 (0.3–1.8)  
PCP and TCP (n = 720) 1 0.5 (0.0–2.7)  
PCP (no TCP) (n = 1,402) 4 0.9 (0.2–2.3)  
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354 (Cohort 3) 7 1.1 (0.4–2.2) Burns CJ et al., 2011
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM (oral cavity, pharynx)     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Never 33 0.9 (0.6–1.3)  
Ever 15 0.5 (0.3–0.9)  
Danish male, female paper workers     Rix et al., 1998
Buccal cavity (ICD-7 140–144)      
Men 24 1.0 (0.7–1.5)  
Women 4 1.5 (0.4–3.8)  
Pharynx (ICD-7 145–149)      
Men 15 2.0 (1.1–3.3)  
Women 2 2.1 (0.2–7.6)  
Tonsil cancers among pharyngeal cancers 11 nr  
Northwestern US paper and pulp workers—5 mills in Washington, Oregon, and California, 3,523 worked ≥ 1 yr 1945–1955, mortality through March 1977     Robinson et al., 1986
  90% CI  
Buccal cavity, pharynx (ICD-7 140–148) 1 0.1 (0.0–0.7)  
Nasal (ICD-7 160) 0 nr  
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
DENMARK      
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Danish self-employed farmers      
Lip 182 1.8 (p < 0.05)  
Tongue 9 0.6 (nr)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Salivary glands 13 0.9 (nr)  
Mouth 14 0.5 (p < 0.05)  
Pharynx 13 0.3 (p < 0.05)  
Nasal cavities, sinuses 11 0.6 (nr)  
Danish farming employees      
Lip 43 2.1 (p < 0.05)  
Tongue 2 0.6 (nr)  
Salivary glands 0 0.0 (nr)  
Mouth 0 0.0 (p < 0.05)  
Pharynx 9 1.1 (nr)  
Nasal cavities, sinuses 5 1.3 (nr)  
Danish gardeners—incidence from 3,156 male and 859 female gardeners (buccal cavity, pharynx, ICD-7 140–148)   Herbicides Hansen et al., 2007
10-yr follow-up (1975–1984) reported in Hansen et al. (1992)      
6 1.1 (0.4–2.5)  
25-yr follow-up (1975–2001)      
Born before 1915 (high exposure) 3 0.7 (0.2–2.3)  
Born 1915–1934 (medium exposure) 6 0.7 (0.3–1.4)  
Born after 1934 (low exposure) 0 0.0 (0.0–1.0)  
FINNISH Phenoxy Herbicide Sprayers (1,909 men working 1955–1971 ≥ 2 wks) not IARC   Phenoxy herbicides Asp et al., 1994
Buccal, pharynx (ICD-8 140–149)      
Incidence 5 1.0 (0.3–2.3)  
Mortality 1972–1989 0 0.0 (0.0–3.0)  
“Other Respiratory” (ICD-8 160, 161, 163)—nose, larynx, pleura      
Incidence 4 1.1 (0.3–2.7)  
Mortality 1972–1989 1 0.5 (0.0–2.9)  
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401) (buccal cavity, pharynx) 18 0.3 (0.2–0.5) Torchio et al., 1994
Italian Farmers—mortality odds ratios from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Self-employed 13 0.9 (nr)  
Employee 4 0.5 (nr)  
NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of 649 incident buccal cavity cancer cases and 49 incident nasopharynx cancer cases vs 19,904 men with any incident cancer     Reif et al., 1989
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Forestry workers (n = 134)   Herbicides  
Buccal cavity 3 0.7 (0.2–2.2)  
Nasopharynx 2 5.6 (1.6–19.5)  
Aged 20–59 1 3.5 (0.6–22.6)  
Aged ≥ 60 1 13.4 (2.7–65.1)  
Sawmill workers (n = 139)   Herbicides, chlorophenols  
Nasopharynx 0  
NORWEGIAN farmers born 1925–1971—incidence, lip cancer   Pesticides Nordby et al., 2004
Reported pesticide use nr 0.7 (0.4–1.0)  
SWEDEN      
Swedish pesticide applicators—incidence     Wiklund et al., 1989a
Lip cancer 14 1.8 (1.0–2.9)
Incident cancer cases 1961–1973 with agriculture as economic activity in 1960 census     Wiklund, 1983
(male, female)   99% CI  
Lip 508 1.8 (1.6–2.2)  
Tongue 32 0.4 (0.2–0.6)  
Salivary gland 68 1.0 (0.7–1.4)  
Mouth 70 0.6 (0.5–0.8)  
Throat 84 0.5 (0.4–0.7)  
Nose, nasal sinuses 64 0.8 (0.6–1.2)  
THE NETHERLANDS      
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 2000     Swaen et al., 2004
Nose 0
Pharynx 0
UNITED STATES      
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Men      
Whites (n = 119,648) 21 2.3 (1.4–3.5)  
Nonwhites (n = 11,446) 0  
Women      
Whites (n = 2,400) 1 12.2 (0.2–68.0)  
Nonwhites (n = 2,066) 0 0.0 (0.0–103.6)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence      
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Private applicators 93 0.6 (0.5–0.7)
Commercial applicators 5 0.5 (0.2–1.3)  
Spouses 22 0.6 (0.4–1.0)  
Enrollment through 2002—buccal cavity     Alavanja et al., 2005
Private applicators (men and women) 66 0.7 (0.5–0.8)
Lip 25 1.4 (0.9–2.1)  
Spouses of private applicators (> 99% women) 14 0.7 (0.4–1.2)  
Lip 2 1.4 (0.2–5.1)  
Commercial applicators 5 0.9 (0.3–2.2)  
Lip 3 2.7 (0.6–8.0)  
Mortality      
Enrollment through 2007, vs state rates (buccal cavity, pharynx) 16 0.3 (0.2–0.6) Waggoner et al., 2011
Enrollment through 2000, vs state rates (buccal cavity, pharynx)     Blair et al., 2005a
Private applicators (men and women) 5 0.3 (0.1–0.7)  
Spouses of private applicators (> 99% women) 0 0.0 (0.0–25.4)  
White Male Residents of Iowa—Lip cancer on death certificate, usual occupation: farmers vs not   Herbicides  
> 20 yrs old when died 1971–1978—PMR 20 2.1 (p < 0.01) Burmeister, 1981
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Incidence      
10-yr follow-up to 1991—men     Bertazzi et al., 1993
Buccal cavity (140–149)    
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Zone B 6 1.7 (0.8–3.9)  
Zone R 28 1.2 (0.8–1.7)  
Nose, nasal cavities (160)      
Zone R 0 nr  
10-yr follow-up to 1991—women     Bertazzi et al., 1993
Buccal cavity (140–149)    
Zone B 0 nr  
Zone R 0 nr  
Nose, nasal cavities (160)      
Zone R 2 2.6 (0.5–13.3)  
CASE-CONTROL STUDIES
US Case-Control Studies      
US males born 1929–1953, all 70 nasal cancers (carcinomas, 11 lymphomas, 5 sarcomas) in   Herbicides, pesticides Caplan et al., 2000
CDC (1990a) study population      
Selected landscaping, forestry occupation 26 1.8 (1.1–3.1)  
Living, working on farm 23 0.5 (0.3–0.8)  
Herbicides, pesticides 19 0.7 (0.4–1.3)  
Phenoxy herbicides 5 1.2 (0.4–3.3)  
International Case-Control Studies      
Residents of northern Sweden (44 nasal, 27 nasopharyngeal cancers)   Phenoxy acids, chlorophenols Hardell et al., 1982
Phenoxy herbicide exposed 8 2.1 (0.9–4.7)  
Chlorophenol exposure 9 6.7 (2.8–16.2)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, 2,4-dichlorophenoxypropanoic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, 2 methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; MOS, military occupational specialty; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); PCP, pentachlorophenol; PCMR, proportionate cancer mortality ratios; PM, proportionate mortality; PMR, proportionate mortality ratio; SEA, Southeast Asia; SIR, standardized incidence ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; VA, US Department of Veteran Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

185,265 male Vietnam veterans who were alive in 1992 and were followed for cancer incidence through 2003 and for mortality through 2005. For the internal comparison analysis of high- versus low-exposure categories derived from the Exposure Opportunity Index (EOI) scores generated by the EOI model, Yi and Ohrr (2014) reported statistically significant increased hazard ratios (HRs) for cancers of the mouth [ICD-10 C03–C06] (HR = 2.54, 95% CI 1.13–5.70) and salivary glands [ICD-10 C07–C08] (relative risk [RR] = 6.98, 95% CI 1.50–32.3), and a non-significant increase in the risk of oropharyngeal cancer [ICD-10 C10] (HR = 1.98, 95% CI 0.48–8.17). Tonsil cancer [ICD-10 C09], which is rarely reported separately, has been the object of some focused attention in VAO updates, but no difference between the high- and low-exposure groups was found (HR = 0.88, 95% CI 0.35–2.20). Differences in incidence also were not observed for the other head and neck cancers analyzed separately: lip [ICD-10 C10], tongue [ICD-10 C01–C02], nasopharynx [ICD-10 C11], hypopharynx [ICD-10 C12–C13], and nose and sinuses [ICD-10 C30–C31]. In contrast to the incidence analyses of separate head and neck cancers, Yi et al. (2014b) reported only on these cancers as a group defined by ICD-10 codes C00–C14 and found no association when comparing the high- versus low-exposure categories (HR = 1.07, 95% CI 0.68–1.68, based on a total of 82 deaths, with 45 of them in high-exposure category) nor in the analysis based on the logarithms of the individual EOI scores (HR = 1.05, 95% CI 0.94–1.17).

Occupational, Environmental, and Case-Control Studies

There have been no occupational, environmental, or case-control studies of exposure to the COIs and oral, nasal, or pharyngeal cancers published since Update 2012.

Biologic Plausibility

As noted above, evidence exists linking HPV to cancers of the head and neck (Marur et al., 2010; Szentirmay et al., 2005), to tonsillar and base-of-tongue cancers (Ramqvist et al., 2015), and to oropharyngeal cancers in particular (Gillison and Shah, 2001; Gillison et al., 2012). There is considerable evidence from laboratory studies that TCDD may increase susceptibility to viral infection, but to date it is unknown whether exposure to the other COIs contributes to susceptibility to viral infection or action, however, this potential link warrants further exploration. Moreover, the sparseness of data on the specific tumor site and a general lack of information on smoking, drinking, and viral exposure status in the few available epidemiologic studies preclude exploration of this hypothesis in the current literature.

Long-term animal studies have examined the effects of exposure to the COIs on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). An NTP study (Yoshizawa et al., 2005a) reported

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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an increase in the incidence of gingival squamous-cell carcinoma in female rats treated orally (by gavage) with TCDD at 100 ng/kg 5 days/week for 104 weeks. The incidence of gingival squamous-cell hyperplasia was significantly increased in all groups treated at 3–46 ng/kg. In addition, squamous-cell carcinoma of the oral mucosa of the palate was increased. This NTP study did not, however, find any pathologic effect of TCDD on nasal tissues (Nyska et al., 2005). Increased neoplasms of the oral mucosa were previously observed and described as carcinomas of the hard palate and nasal turbinates (Kociba et al., 1978). Kociba et al. (1978) also reported a small increase in the incidence of tongue squamous-cell carcinoma.

Recently, DiNatale et al. (2012) utilized head and neck squamous-cell carcinoma cell lines to investigate mechanisms for tumor progression associated with AHR activation. This tumor type typically produces large amounts of cytokines, and its IL6 expression levels correlate with disease aggressiveness. In this model, AHR activation by TCDD enhances IL-6 production induced by another cytokine (IL 1β), so TCDD may promote head and neck squamous-cell carcinoma.

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

Tonsil cancers, or more generally squamous-cell carcinomas, remain of interest to Vietnam veterans and the committee, but very limited new information on them with respect to possible herbicide exposure became available in this update. The Korean Health Study did not find an association between herbicide exposure and the risk of tonsillar cancers. However, the Korean study reported a statistically significant 2.5-fold increased risk for oral cancer and a suggestive increase for oropharyngeal cancers, excluding tonsils, associated with the herbicide exposure group (Yi and Ohrr, 2014). There is some uncertainty about the reliability of exposure estimates derived from EOI scores used in studying the Korean Vietnam veterans. Moreover, a lack of information on potential confounding factors such as smoking, alcohol, and HPV exposure limits the interpretation of the results for the few positive associations. Among New Zealand veterans there was modest increased risk for incident head and neck cancers, but a significant 2.2-fold increased risk of death from head and neck cancers in comparison to general population.

In combination with the previously reviewed literature, the inconsistent results of these two new cohort studies do not support an association between the cancers of oral cavity, nose, or pharynx with the herbicides sprayed in Vietnam.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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determine whether there is an association between exposure to the COIs and oral, nasal, or pharyngeal cancers.

CANCERS OF THE DIGESTIVE ORGANS

Until Update 2006, VAO committees had reviewed “gastrointestinal tract tumors” as a group consisting of stomach, colorectal, and pancreatic cancers; esophageal cancer has been formally included only since Update 2004. With more evidence from occupational studies available, VAO updates now address cancers of the digestive organs individually. The findings on cancers of the digestive organs as a group (ICD-9 150–159) are too broad for useful etiologic analysis and will no longer be considered.

Esophageal cancer (ICD-9 150), stomach cancer (ICD-9 151), colon cancer (ICD-9 153), rectal cancer (ICD-9 154), and pancreatic cancer (ICD-9 157) are among the most common cancers. ACS estimated that about 223,230 people would receive diagnoses of those cancers in the United States in 2015 and that 116,570 people would die from them (Siegel et al., 2015). Other digestive cancers (for example, small intestine, anal, and hepatobiliary cancers) added about 67,920 new diagnoses and 32,730 deaths to the 2015 estimates for the United States (Siegel et al., 2015). Collectively, tumors of the digestive organs were expected to account for 18 percent of new cancer diagnoses and 25 percent of cancer deaths in 2015. The average annual incidences of gastrointestinal cancers are presented in Table 8-3.

The incidences of stomach, colon, rectal, and pancreatic cancers increase with age. In general, the incidences are higher in men than in women and higher in blacks than in whites. Risk factors for the cancers vary but always include family history of the same form of cancer, some diseases of the affected organ, and diet. Tobacco use is a risk factor for pancreatic cancer and possibly stomach cancer (Maisonneuve and Lowenfels, 2015; Stewart et al., 2008). Infection with the bacterium Helicobacter pylori increases the risk of stomach and pancreatic cancers. Type 2 diabetes is associated with an increased risk of colorectal and pancreatic cancers (ACS, 2013a).

It is noteworthy that there has been one report of Vietnam veterans that included all gastrointestinal cancers collectively. Cypel and Kang (2010) published an update on disease-related mortality in ACC veterans who handled or sprayed herbicides in Vietnam in comparison with their non-Vietnam veteran peers or US men in general. The participant’s vital status was determined through December 31, 2005. In the analyses, the site-specific rates of digestive cancers were not examined. No statistically significant excess mortality from all cancers of the digestive tract was found in ACC Vietnam veterans compared with non-Vietnam veterans (adjusted relative risk [RR] = 1.01, 95% CI 0.56–1.83).

Several studies identified for the present update did analyses that combined several digestive cancers, so the results are not particularly informative for any

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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TABLE 8-3 Average Annual Incidence (per 100,000) of Selected Gastrointestinal Cancers in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Stomach:
Men 23.8 22.0 35.3 35.8 32.0 52.8 47.9 42.7 77.7
Women 10.4 8.9 16.8 15.3 12.9 22.0 23.2 19.1 39.5
Esophagus:
Men 24.3 25.4 27.9 32.1 34.1 30.4 36.0 38.5 36.4
Women 4.0 4.0 6.7 6.0 5.8 9.8 8.7 8.4 13.3
Colon (excluding rectum):
Men 75.5 71.3 112.5 113.6 109.3 164.5 158.4 155.4 223.5
Women 54.4 51.0 86.6 82.2 78.5 119.6 120.7 119.1 157.5
Rectum and Rectosigmoid Junction:
Men 41.5 39.4 53.3 53.5 51.9 56.9 62.4 61.3 68.3
Women 23.0 22.1 28.6 30.3 29.0 35.3 35.1 34.7 34.2
Liver and Intrahepatic Bile Duct:
Men 46.5 40.0 87.5 42.8 37.2 62.8 49.8 44.0 51.7
Women 11.3 9.8 17.3 15.0 13.0 16.9 19.8 17.1 17.7
Pancreas:
Men 37.1 36.4 54.4 52.4 52.2 66.8 68.9 70.4 77.7
Women 25.1 24.5 35.0 38.2 37.1 55.3 54.0 53.1 68.3
Small Intestine:
Men 7.0 6.9 10.6 9.4 9.1 16.1 11.7 11.5 20.6
Women 5.5 5.3 9.6 6.5 6.4 10.9 7.9 7.7 13.9
Anus, Anal Canal, and Anorectum:
Men 3.5 3.7 3.9 4.4 4.9 3.7 4.8 5.0 5.1
Women 6.1 6.9 3.1 6.5 7.1 5.0 6.8 7.6 4.9
Other Digestive Organs:
Men 1.6 1.4 3.1 2.0 1.8 2.7 3.1 3.2 4.7
Women 1.2 1.1 1.8 1.6 1.6 1.9 2.3 2.3 2.2
Gallbladder:
Men 1.7 1.5 2.6 2.9 2.6 4.7 4.2 3.9 7.7
Women 3.3 3.0 5.1 5.2 4.9 7.3 6.9 6.9 8.0
Other Biliary:
Men 5.2 5.1 4.0 7.8 7.5 5.9 11.4 10.8 10.9
Women 3.2 2.9 4.3 5.1 4.9 4.5 7.4 7.2 7.7

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

cancers in the group. Boers et al. (2012) reported on stomach and pancreatic cancers, leaving an additional 28 cases of other digestive cancers, which closely matched expectation. CJ Burns et al. (2011) reported on cancers of the stomach, colon, rectum, and pancreas individually, leaving eight deaths from “other GI and digestive cancers” (SIR = 0.73, 95% CI 0.32–1.44). After reporting on cancers of the esophagus, stomach, colon, rectum, and pancreas separately, 5 of 58 digestive

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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cancers remained unidentified in the update on mortality in the Hamburg cohort (Manuwald et al., 2012).

Esophageal Cancer

Epithelial tumors of the esophagus (squamous-cell carcinomas and adenocarcinomas) are responsible for more than 95 percent of all esophageal cancers (ICD-9 150); 16,980 newly diagnosed cases and 15,590 deaths were estimated for 2015 (Siegel et al., 2015). The considerable geographic variation in the incidence of esophageal tumors suggests a multifactorial etiology. The rates of esophageal cancer have been increasing in the past two decades, and nearly 50 percent of all cases occur in northwest Europe and North America. In the United States, adenocarcinoma of the esophagus has slowly replaced squamous-cell carcinoma as the most common type of esophageal malignancy; although squamous-cell carcinoma continues to be the most common form of esophageal cancer worldwide (Rubenstein and Shaheen, 2015). Squamous-cell esophageal carcinoma rates are higher in blacks than in whites and higher in men than in women. Smoking and alcohol ingestion are associated with the development of squamous-cell carcinoma; these risk factors have been less thoroughly studied for esophageal adenocarcinoma, but they appear to be associated. The rapid increase in obesity in the United States has been linked to increasing rates of gastroesophageal reflux disease (GERD), and the resulting rise in chronic inflammation has been hypothesized as explaining the link between GERD and esophageal adenocarcinoma (Rubenstein and Shaheen, 2015). The average annual incidence of esophageal cancers is shown in Table 8-3.

Conclusions from VAO and Previous Updates

The committee responsible for VAO explicitly excluded esophageal cancer from the group of gastrointestinal tract tumors, for which it was concluded that there was limited or suggestive evidence of no association with exposure to the herbicides used by the US military in Vietnam. Esophageal cancer was not separately evaluated and was not categorized with this group until Update 2004, so by default it fell into the category of inadequate or insufficient evidence of an association. The committee responsible for Update 2006 concluded that there was not enough evidence on each of the COIs to sustain that negative conclusion for any of the cancers in the gastrointestinal group and that, because these various types of cancer are generally regarded as separate disease entities, the evidence on each should be evaluated separately. Esophageal cancer was thus formally placed into the inadequate or insufficient category. No additional studies of esophageal cancer were reviewed in Update 2008.

Update 2010 considered a series of papers on mortality in TCP and PCP workers employed by Dow Chemical Company in Midland, Michigan, from

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

1937 to 1980. Collins et al. (2009b) followed 1,615 workers who worked at least 1 day in a department that had potential TCDD exposure, among whom five esophageal-cancer deaths were observed, for an SMR of 1.0 (95% CI = 0.3–2.2); none of the five had concurrent PCP exposure. Collins et al. (2009c) described mortality in 773 PCP workers who were exposed to chlorinated dioxins that did not include TCDD; there were two observed deaths from esophageal cancer (SMR = 0.8, 95% CI 0.1–2.9). McBride et al. (2009a) reported on a mortality follow-up of the workers in the Dow AgroSciences plant in New Plymouth, New Zealand, who were potentially exposed to TCDD. The SMR for esophageal-cancer deaths in exposed workers was 2.5 (95% CI 0.7–6.4) compared with an SMR of 2.1 (95% CI 0.1–12.2) in the never-exposed group. In following up on cancer incidence in the men and women exposed to dioxin in the Seveso accident, Pesatori et al. (2009) observed no esophageal cancers in the high-exposure zone and no exposure-related pattern in the occurrence of esophageal cancer in the medium- and low-exposure areas.

In Update 2012, the strongest evidence came from an occupational cohort of workers at a chemical plant in Hamburg, which reported a significant increased esophageal-cancer mortality relative to men in the general population of Hamburg (SMR = 2.56, 95% CI 1.27–4.57), whereas no deaths from esophageal cancer were observed among female workers, who made up a smaller portion of this cohort (Manuwald et al., 2012). By contrast, in the NIOSH cohort Ruder and Yiin (2011) reported no excess mortality of esophageal cancer in comparison with the US population (SMR = 0.99, 95% CI 0.43–1.96). In the AHS study, Koutros et al. (2010a), found a significant decrease in the incidence of esophageal cancer in the private applicators (52 cases, SIR = 0.64, 95% CI 0.48–0.85) in comparison with the general population, which could indicate a healthy worker effect.

Table 8-4 summarizes the results of the relevant studies concerning esophageal cancer.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies Several recent publications examined esophageal cancer incidence (Yi, 2013; Yi and Ohrr, 2014) and cancer-specific mortality (Yi et al., 2014b) in the Korean Veterans Health Study, a large prospective cohort of 185,265 male Vietnam veterans alive in 1992, who were followed for cancer incidence through 2003 and for mortality through 2005. Comparing the Vietnam veterans to the general Korean population, Yi (2013) reported a statistically significant decrease in the incidence of esophageal cancer (SIR = 0.70, 95% CI 0.64–0.85), which may be due to a “healthy soldier” effect. However, in the internal comparison of those with high versus low EOI scores, Yi and Ohrr (2014) reported a statistically significant 36 percent increased risk for esophageal cancer (HR = 1.36, 95% CI 1.00–1.85). This result was based on a large number of incident esophageal cancers (n = 184) observed during follow-up, of which 113 cases

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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TABLE 8-4 Selected Epidemiologic Studies—Esophageal Cancer (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans      
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Mortality      
1965–2000 6 1.2 (0.4–4.0) Boehmer et al., 2004
State Studies of US Vietnam Veterans      
Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs non-deployed 9 0.9 (0.4–1.6) Vistainer et al., 1995
International Studies of Vietnam Veterans      
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence      
All branches, 1982–2000 70 1.2 (0.9–1.5) ADVA, 2005b
Navy 19 1.6 (0.9–2.4)  
Army 40 1.1 (0.7–1.4)  
Air Force 11 1.5 (0.8–2.8)  
Mortality      
All branches, return–2001 67 1.1 (0.8–1.3) ADVA, 2005a
Navy 13 1.0 (0.5–1.7)  
Army 42 1.0 (0.7–1.3)  
Air Force 12 1.5 (0.8–2.6)  
1980–1994 23 1.2 (0.7–1.7) CDVA, 1997a
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence      
1982–2000 9 1.9 (0.6–6.6) ADVA, 2005c
Mortality      
1966–2001 10 1.3 (0.5–3.6) ADVA, 2005c
1982–1994 1 1.3 (0.0– > 10) CDVA, 1997b
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—esophagus (C15) categorized high (n = 113) vs low (n = 71) 113 1.4 (1.0–1.9) Yi and Ohrr, 2014
Mortality (1992–2005)—esophagus categorized high (n = 98) vs low (n = 64)   1.3 (0.9–1.8) Yi et al., 2014b
HR per unit of log EOI (n = 180,639) 162 1.0 (0.9–1.1)  
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Mortality 1939–1992 28 1.0 (0.7–1.4) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 20 1.3 (0.8–1.9)  
7,553 not exposed to highly chlorinated PCDDs 6 0.5 (0.2–1.1)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort     Saracci et al., 1991
8 0.6 (0.3–1.2)  
British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)   MCPA  
Mortality through 1983 8 0.9 (0.4–1.9) Coggon et al., 1986
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)   Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP  
Mortality 1952–2007 (ICD-9 150)     Manuwald et al., 2012
Men 11 2.6 (1.3–4.6)  
Women 0 nr  
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality 1969–2004     McBride et al., 2009a
Ever-exposed workers 4 2.5 (0.7–6.4)
Never-exposed workers 1 2.1 (0.1–12.2)  
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)      
Mortality 1969–2000 2 2.0 (0.2–7.0) ’t Mannetje et al., 2005
Phenoxy herbicide sprayers (> 99% men) 1 0.7 (0.0–4.0)  
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (in IARC and   2,4,5-T; 2,4,5-TCP  
NIOSH cohorts)      
1942–2003 (n = 1,615)     Collins et al., 2009b
Trichlorophenol workers 5 1.0 (0.3–2.2)
Pentachlorophenol workers 2 0.8 (0.1–2.9)  
All Dow PCP-Exposed Workers—all workers from two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
1940–2005 (n = 2,122) 8 1.0 (0.4–2.0)  
PCP and TCP (n = 720) 2 0.8 (0.1–3.0)  
PCP (no TCP) (n = 1,402) 6 1.1 (0.4–2.3)  
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries,     McLean et al., 2006
TCDD among 27 agents assessed by JEM      
Exposure to nonvolatile organochlorine compounds      
Never 27 0.7 (0.4–1.0)  
Ever 26 0.8 (0.5–1.2)  
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
DENMARK      
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Men      
Self-employed 32 0.4 (p < 0.05)  
Employee 13 0.9 (nr)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Women      
Self-employed 1 1.4 (nr)  
Employee 2 0.4 (nr)  
FINNISH Phenoxy Herbicide Sprayers (1,909 men working 1955–1971 ≥ 2 wks) not IARC   Phenoxy herbicides  
Incidence 3 1.6 (0.3–4.6) Asp et al., 1994
Mortality 1972–1989 2 1.3 (0.2–4.7)  
NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of 385 incident esophageal cancer cases vs remainder of 19,904 men with any incident cancer     Reif et al., 1989
Forestry workers (n = 134)   Herbicides  
  4 1.8 (0.7–4.8)  
Aged 20–59 1 1.6 (0.2–11.3)  
Aged ≥ 60 3 1.9 (0.6–5.8)  
Sawmill workers (n = 139)   Herbicides, Chlorophenols  
  2 0.7 (0.2–2.9)  
SWEDEN      
Incidence cancer cases 1961–1973 with agriculture as economic activity in 1960 census (male, female) 169 99% CI 0.6 (0.5–0.7) Wiklund, 1983
UNITED STATES      
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence      
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Private applicators 52 0.6 (0.5–0.9)  
Commercial applicators 2 nr  
Spouses 2 nr  
Mortality      
Enrollment through 2007, vs state rates     Waggoner et al., 2011
Applicators (n = 1,641) 48 0.5 (0.4–0.7)
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Spouses (n = 676) 3 nr  
Enrollment through 2000, vs state rates     Blair et al., 2005a
Private applicators (men and women) 16 0.5 (0.3–0.9)
Spouses of private applicators (> 99% women) 1 0.3 (0.1–1.9)  
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group)   TCDD  
Incidence      
20-yr follow-up to 1996—men and women      
Zone A 0   Pesatori et al., 2009
Zone B 1 0.3 (0.0–1.9)
Zone R 35 1.3 (0.9–1.9)  
CASE-CONTROL STUDIES
US Case-Control Studies      
Nebraska—agricultural pesticide use and adenocarcinoma of the esophagus   Phenoxy Lee et al., 2004b
137 herbicides, 2.4-D
Insecticides   0.7 (0.4–1.1)  
Herbicides   0.7 (0.4–1.2)  
International Case-Control Studies      
UK men, 18–35 yrs of age from counties with particular chemical manufacturing—mortality   Herbicides, Chlorophenols Magnani et al., 1987
Herbicides nr 1.6 (0.7–3.6)  
Chlorophenols nr 1.2 (0.7–2.2)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DCP, 2,4-dichlorophenol; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, 2 methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PM, proportionate mortality; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCP, pentachlorophenol; SIR, standardized incidence ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

were among veterans in the high-exposure category. Yi et al. (2014b) reported a non-significant increase in mortality from esophageal cancer (HR = 1.26, 95% CI 0.91–1.75) when comparing those in the higher exposure category with those with lower estimated exposure; these results were based on 162 deaths due to esophageal cancer, of which 98 deaths occurred in the higher exposure category, Similarly, mortality from esophageal cancer was not found to be associated with the individual, log-transformed EOI scores (HR = 1.02, 95% CI 0.94–1.17) (Yi et al., 2014b). Information on smoking and alcohol consumption was not available, and thus some of the modest association could be due to confounding. Data from the self-reported questionnaires collected in a sub-cohort of Korean veterans who were alive in 2004 indicated that the prevalence of smoking was relatively high in this cohort (45 percent and 36 percent were former and current smokers, respectively), and 11 percent of veterans reported a high prevalence of drinking (> 5 drinks/week). However, the distributions of smoking and drinking habits were similar for veterans with high and low EOI scores (Yi et al., 2013b).

Occupational and Environmental Studies There have been no occupational or environmental studies of exposure to the COIs and esophageal cancers published since Update 2012.

Case-Control Studies There have been no case-control studies of exposure specifically to the COIs and esophageal cancers published since Update 2012.

However, a recently published hospital-based case-control study examined the risk of Barrett’s esophagus and occupational exposures to asbestos, metal dust, organic solvents, and pesticides (Qureshi et al., 2013). Barrett’s esophagus is a disorder characterized by intestinal metaplasia of the normally stratified squamous epithelium of the esophagus and is associated with an increased risk of adenocarcinoma of the esophagus. This study included 226 cases and 1,424 controls selected from among patients undergoing endoscopy at a VA medical center in Houston, Texas, from 2008 through 2010. They reported no association between self-reported use of pesticides and the risk of Barrett’s esophagus (odds ratio [OR] = 0.97, 95% CI 0.50–1.90). The major limitations include the potential for selection/referral bias as well as recall bias because pesticide exposure information was collected via a self-reported questionnaire. The authors did not address TCDD or the specific herbicides of interest, and thus this study is not regarded as being informative for the committee’s task.

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the COIs on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004), and no increase in the incidence of esophageal cancer has been reported in laboratory animals after exposure to them. A previous biomarker

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

study analyzed esophageal-cell samples from patients who had been exposed to indoor air pollution of different magnitudes and did or did not have high-grade squamous-cell dysplasia or a family history of upper gastrointestinal-tract (UGI) cancer (Roth et al., 2009). AHR expression was higher in patients that had a family history of UGI cancer, but it was not associated with indoor air pollution, esophageal squamous-cell dysplasia category, age, sex, or smoking. These results might be interpreted to suggest that enhanced expression of the AHR in patients who had a family history of UGI cancer may contribute to UGI-cancer risk associated with AHR ligands—such as polycyclic aromatic hydrocarbons, which are found in cigarette smoke—and with TCDD.

In a small series of studies, AHR expression was found to be higher in esophageal tumors than in corresponding normal mucosa and, somewhat surprisingly, played a role in the suppression of metastatic potential, in contrast to many other cancers (Safe et al., 2013). The significance of these observations and the mechanism underlying increased AHR expression was not determined (Zhang et al., 2012).

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

In this update, the only study that provided some evidence for a potential association between esophageal cancer and exposure to herbicides was the Korean Veterans Health Study, which reported a modestly increased risk for both incidence (RR = 1.36, 95% CI 1.00–1.85) and mortality from esophageal cancer (RR = 1.26, 95% CI 0.91–1.75) when comparing high- versus low-exposure categories. Despite several advantages, including the large sample size of this cohort and adequate numbers of cases both for incidence of and mortality from esophageal cancer, the difficulty in determining the validity and reliability of the herbicide exposure opportunity score developed by Stellman et al. (2003b) as well as a lack of information on smoking and alcohol consumption (two main risk factors for esophageal cancer) limit the interpretation of the results.

In combination with the studies reviewed previously, however, this single new finding did not provide adequate evidence to establish an association between exposure to the COIs and esophageal cancer. No toxicologic studies provide evidence of the biologic plausibility of an association between the COIs and tumors of the esophagus.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and esophageal cancer.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Stomach Cancer

The incidence of stomach cancer (ICD-9 151) increases with age. ACS estimated that 15,540 men and 9,050 women would receive diagnoses of stomach cancer in the United States in 2015 and that 6,500 men and 4,220 women would die from it (Siegel et al., 2015). In general, the incidence is higher in men than in women and in blacks than in whites. Other risk factors include a family history of this cancer, some diseases of the stomach, and diet. Infection with Helicobacter pylori increases the risk of stomach cancer. Tobacco or alcohol use and the consumption of nitrite- and salt-preserved food may also increase the risk (Ang and Fock, 2014; Brenner et al., 2009; Key et al., 2004). The average annual incidence of stomach cancer is shown in Table 8-3.

Conclusions from VAO and Previous Updates

Update 2006 considered stomach cancer independently for the first time. Prior updates had developed a table of results for stomach cancer but drew conclusions about the adequacy of the evidence of its association with herbicide exposure in the context of gastrointestinal tract cancers. The committee responsible for VAO concluded that there was limited or suggestive evidence of no association between exposure to the herbicides used by the US military in Vietnam and gastrointestinal tract tumors, including stomach cancer. The committee responsible for Update 2006 concluded that there was not enough evidence on each of the COIs to sustain that negative conclusion for any of the cancers in the gastrointestinal group and that, because these various types of cancer are generally regarded as separate disease entities, the evidence on each should be evaluated separately. Stomach cancer was thus reclassified into the default category of inadequate or insufficient evidence to determine whether there is an association. The conclusion that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and stomach cancer has been maintained by the committees responsible for subsequent updates.

Table 8-5 summarizes the results of the relevant studies concerning stomach cancer. Results new to this update are shaded.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies Since Update 2012, cohort studies of Vietnam veterans from New Zealand and Korea have reported on stomach cancer.

Mortality from (Yi et al., 2014b) and incidence of (Yi and Ohrr, 2014) stomach cancer were assessed among Korean veterans who had served in Vietnam between 1964 and 1973. In analyses of cancer incidence, Yi and Ohrr (2014) reported a modestly increased risk of stomach cancer (HR = 1.14, 95% CI 1.04–1.24) in the internal comparison of the high- and low-exposure groups based on

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-5 Selected Epidemiologic Studies—Stomach Cancer (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans      
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)   All COIs  
Incidence      
1982–2003—White SEA comparison veterans only (n = 1,482). Serum TCDD (pg/g) based on model with exposure variable loge(TCDD)     Pavuk et al., 2005
Per unit increase of –loge(TCDD) (pg/g) 24 1.8 (0.8–3.9)  
Quartiles (pg/g):      
0.4–2.6 4 nr  
2.6–3.8 3 1.0 (0.2–4.8)  
3.8–5.2 7 2.0 (0.5–8.2)  
> 5.2 10 3.3 (0.9–12.5)  
Number of years served in SEA (per year of service)      
Quartiles (years in SEA): 24 1.2 (1.0–1.4)  
0.8–1.3 4 nr  
1.3–2.1 4 1.0 (0.2–3.8)  
2.1–3.7 5 1.1 (0.3–4.2)  
3.7–16.4 11 2.1 (0.6–7.3)  
Through 1999—White subjects vs national rates     Akhtar et al., 2004
Ranch Hand veterans (n = 1,189) 16 0.6 (0.4–1.0)  
With tours from 1966 through 1970 14 0.6 (0.4–1.1)  
SEA comparison veterans (n = 1,776) 31 0.9 (0.6–1.2)  
With tours from 1966 through 1970 24 0.9 (0.6–1.3)  
Mortality      
Through 1999—White subjects vs national rates     Akhtar et al., 2004
Ranch Hand veterans (n = 1,189) 6 0.4 (0.2–0.9)  
SEA comparison veterans (n = 1,776) 14 0.7 (0.4–1.1)  
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Mortality      
1965–2000 5 nr Boehmer et al., 2004
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1982     Breslin et al., 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 88 1.1 (0.9–1.5)  
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 17 0.8 (0.4–1.6)  
State Studies of US Vietnam Veterans      
923 White male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans 1 nr Anderson et al., 1986a,b
International Vietnam-Veteran Studies      
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence      
All branches, 1982–2000 104 0.9 (0.7–1.1) ADVA, 2005b
Navy 28 1.1 (0.7–1.6)  
Army 66 0.9 (0.7–1.1)  
Air Force 10 0.7 (0.3–1.3)  
Mortality      
All branches, return–2001 76 0.9 (0.7–1.2) ADVA, 2005a
Navy 22 1.3 (0.8–1.8)  
Army 50 0.9 (0.7–1.2)  
Air Force 4 0.4 (0.1–1.0)  
1980–1994 32 1.1 (0.7–1.4) CDVA, 1997a
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence      
1982–2000 11 0.6 (0.2–1.2) ADVA, 2005c
Mortality      
1966–2001 7 0.7 (0.2–2.0) ADVA, 2005c
1982–1994 4 1.7 (0.3– > 10) CDVA, 1997b
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008) 9 0.8 (0.4–1.6)  
Mortality (1988–2008) 9 1.3 (0.6–2.4)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—Stomach (C16) categorized high (n = 1,154) vs low (n = 973)   1.1 (1.0–1.2) Yi and Ohrr, 2014
Mortality (1992–2005)—Stomach (C16) categorized high (n = 613) vs low (n = 464)   1.2 (1.0–1.3) Yi et al., 2014b
HR per unit of log EOI (n =180,639) 1,077 1.1 (1.0–1.1)  
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates   Phenoxy herbicides, chlorophenols  
Mortality 1939–1992 72 0.9 (0.7–1.1) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 42 0.9 (0.7–1.2)
7,553 not exposed to highly chlorinated PCDDs 30 0.9 (0.6–1.3)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort     Saracci et al., 1991
Nested case-control study 40 0.9 (0.6–1.2)  
Mortality, incidence of women in production (n = 699) and spraying (n = 2) compared to national death rates and cancer incidence rates 1 TCDD 1.4 (nr) Kogevinas et al., 1993
British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)   MCPA  
Mortality through 1983 26 0.9 (0.6–1.3) Coggon et al., 1986
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)   Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP  
Incidence 1943–1982     Lynge, 1985
Men 12 1.3 (nr)  
Women 1 0.7 (nr)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality 1955–2006 14 1.1 (0.8–1.5) Boers et al., 2012
TCDD plasma level (HRs, by tertile)    
Background (≤ 0.4) 8  
Low (0.4–1.9) 1 0.1 (0.0–1.0)  
Medium (1.9–9.9) 2 0.5 (0.1–2.6)  
High (≥ 9.9) 3 2.5 (0.7–9.2)  
Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)   Dioxins, 2,4,5-T, 2,4,5-TCP  
Mortality 1955–2006 (HRs for lagged TCDD plasma levels) 6 1.5 (1.1–2.2) Boers et al., 2012
Mortality 1955–2006 5 2.2 (0.4–13.2) Boers et al. 2010
Mortality 1955–1991 3 1.0 (0.2–2.9) Hooiveld et al., 1998
Mortality 1955–1985 2 0.9 (0.1–3.4) Bueno de Mesquita et al., 1993
Dutch production workers in Plant B (414 men exposed during production 1965–1986; 723 unexposed) (in IARC cohort)   2,4-D; MCPA; MCPP; highly chlorinated dioxins unlikely  
Mortality 1965–2006 4 1.2 (0.3–4.7) Boers et al., 2010
Mortality 1965–1986 0 0.0 (0.0–6.5) Bueno de Mesquita et al., 1993
German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 mo in 1951–1976) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4,5-TCP  
Mortality 1951–1992 0 nr Becher et al., 1996
German Production Workers at Bayer Plant in Dormagen (520 men working > 1 mo in 1965–1989) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Mortality 1965–1989 0 nr Becher et al., 1996
German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 mo in 1957–1987) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality 1956–1989 2 0.6 (0.1–2.3) Becher et al., 1996
BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)   Focus on TCDD  
Incidence      
1960–1992 3 1.0 (0.2–2.9) Ott and Zober, 1996a
TCDD < 0.1 µg/kg of body weight 0 0.0 (0.0–3.4)
TCDD 0.1–0.99 µg/kg of body weight 1 1.3 (0.0–7.0)  
TCDD > 1.0 µg/kg of body weight 2 1.7 (0.2–6.2)  
Mortality      
Through 1987   90% CI Zober et al., 1990
  3 3.0 (0.8–7.7)
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)   Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP  
Mortality 1952–2007 (ICD-9 140–149) 17 1.0 (0.6–1.6) Manuwald et al., 2012
Men 17 1.3 (0.7–2.0)
Women 0 nr  
Mortalilty 1952–1989 12 1.3 (0.7–2.2) Becher et al., 1996
Mortality 1952–1989—stats on men only, 1,184 (tables all for 1,148 men, not necessarily German nationals) vs national rates (also vs gas workers); same observation period as Becher et al., 1996 12 1.2 (0.6–2.1) Manz et al., 1991
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Ever-exposed workers 4 1.4 (0.4–3.6)
Never-exposed workers 2 2.3 (0.3–8.4)  
Production Workers (713 men and 100      
women worked > 1 mo in 1969–1984)      
Mortality 1969–2000 2 1.1 (0.1–4.0) ’t Mannetje et al., 2005
Phenoxy herbicide sprayers (> 99% men) 3 1.4 (0.3–4.0)
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Through 1993 13 1.0 (0.6–1.8) Steenland et al., 1999
Through 1987 10 1.0 (0.5–1.9) Fingerhut et al., 1991
≥ 1-yr exposure, ≥ 20-yr latency 4 1.4 (0.4–3.5)
Mortality—754 Monsanto workers, among most highly exposed workers from Fingerhut et al. (1991) 0 0.0 (0.0–1.1) Collins et al., 1993
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (in IARC and NIOSH cohorts)   2,4,5-T; 2,4,5-TCP  
1942–2003 (n = 1,615) 8 1.4 (0.6–2.7) Collins et al., 2009b
1940–1994 (n = 2,187 men) nr 1.5 (0.7–2.7) Bodner et al., 2003
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
1940–2005 (n = 2,122) 9 0.9 (0.4–1.7)  
PCP and TCP (n = 720) 3 1.0 (0.2–2.9)  
PCP (no TCP) (n = 1,402) 6 0.8 (0.3–1.8)  
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354 (Cohort 3) 3 0.8 (0.2–2.3) Burns CJ et al., 2011
Through 1994 (n = 1,517) (digestive organs, peritoneum) 16 0.7 (0.4–1.2) Burns et al., 2001
Through 1982 (n = 878) 0 nr (0.0–3.7) Bond et al., 1988
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) 4 1.2 (0.3–3.1) Collins et al., 2009c
Mortality 1940–1989 (n = 770)     Ramlow et al., 1996
0-yr latency 4 1.7 (0.5–4.3)  
15-yr latency 3 1.8 (0.4–5.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Other Studies of Industrial Workers (not related to IARC or NIOSH phenoxy cohorts)   Dioxins, phenoxy herbicides  
1,412 white male US flavor and fragrance chemical plant workers (1945–1965) 6 Dioxin, 2,4,5-T Expected exposed cases Thomas, 1987
    4.2  
Automobile workers from Hubei province in China (worked 1 yr during 1980–1985)   PCDD/F Wang et al., 2013
Mortality (1980–2005) (n = 3,529) 15 1.3 (0.6–2.7)  
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Never 146 0.9 (0.8–1.1)  
Ever 98 0.9 (0.7–1.1)  
14,362 Danish paper workers employed 1943–1990, followed through 1993     Rix et al., 1998
Men 48 1.1 (0.8–1.4)  
Women 7 1.0 (0.4–2.1)  
New Hampshire pulp and paper workers, 883 white men working ≥1 yr, mortality through July 1985 5 1.2 (0.4–2.8) Henneberger et al., 1989
Pulp and paper cohorts independent of IARC cohort      
United Paperworkers International, 201 white men employed ≥ 10 yr and dying 1970–1984 1 0.5 (0.1–3.0) Solet et al., 1989
Northwestern US paper and pulp workers—5 mills in Washington, Oregon, and California, 3,523 worked ≥ 1 yr 1945–1955, mortality through March 1977 17 90% CI 1.2 (0.8–1.9) Robinson et al., 1986
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
CANADA      
Canadian Farm Operator Study—156,242 men farming in Manitoba, Saskatchewan, and Alberta in 1971; mortality from stomach cancer June 1971–Dec 1987      
Linkage of records for ~70,000 male Saskatchewan farmers (1971–1985) 246 0.9 (0.8–1.0) Wigle et al., 1990
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
DENMARK      
Danish farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Men      
Self-employed 286 0.9 (nr)  
Employee 71 1.2 (nr)  
Women      
Self-employed 5 1.0 (nr)  
Employee 5 1.7 (nr)  
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401) 126 0.7 (0.6–0.9) Torchio et al., 1994
Italian rice growers with documented phenoxy use (n = 1,487) 39 Phenoxy herbicides 1.0 (0.7–1.3) Gambini et al., 1997
NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of incident stomach cancer cases vs remainder of 19,904 men with any incident cancer     Reif et al., 1989
Forestry workers (n = 134)   Herbicides  
  13 2.2 (1.3–3.9)  
Aged 20–59 3 0.7 (0.2–2.2)  
Aged ≥ 60 10 2.4 (1.2–4.5)  
Sawmill workers (n = 139)   Herbicides, Chlorophenols  
  7 1.0 (0.4–2.1)  
SWEDEN      
348 Swedish railroad workers (1957–October, 1978)—total exposure to herbicides 3 Phenoxy acids 2.2 (nr) Axelson et al., 1980
Incident stomach cancer cases 1961–1973 with agriculture as economic activity in 1960 census 2,599 99% CI 1.1 (1.0–1.2) Wiklund, 1983
THE NETHERLANDS      
Dutch licensed herbicide sprayers—1,341 certified before 1980      
Through 2000 (stomach, small intestine) 3 0.4 (0.1–1.3) Swaen et al., 2004
Through 1987 (stomach, small intestine) 1 0.5 (0.0–2.7) Swaen et al., 1992
UNITED STATES      
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Men      
Whites (n = 119,648) 657 1.0 (1.0–1.1)  
Nonwhites (n = 11,446) 115 1.1 (0.9–1.3)  
Women      
Whites (n = 2,400) 12 1.2 (0.6–2.0)  
Nonwhites (n = 2,066) 23 1.9 (1.2–2.8)  
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence      
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Private applicators 61 0.9 (0.7–1.1)  
Commercial applicators 2 nr  
Spouses 15 0.9 (0.5–1.5)  
Enrollment through 2002     Alavanja et al., 2005
Private applicators 462 0.8 (0.8–0.9)
Spouses of private applicators (> 99% women) 161 0.9 (0.7–1.0)  
Commercial applicators 24 1.0 (0.6–1.4)  
Mortality      
Enrollment through 2007, vs state rates     Waggoner et al., 2011
Applicators (n = 1,641) 26 0.5 (0.3–0.8)
Spouses (n = 676) 5 0.4 (0.1–1.0)  
Enrollment through 2000, vs state rates     Blair et al., 2005a
Private applicators (men and women) 10 0.5 (0.2–1.0)
Spouses of private applicators (> 99% women) 4 1.1 (0.3–2.8)  
California United Farm Workers of America   2,4-D  
Nested case-control study of agricultural exposure and gastric cancer in UFW cohort     Mills and Yang, 2007
Ever worked in area where 2,4-D used Quartile of lifetime exposure to 2,4-D (lb) 42 1.9 (1.1–3.3)  
0 58 1.0  
1–14 17 2.2 (1.0–4.6)  
15–85 14 1.6 (0.7–3.5)  
85–1,950 11 2.1 (0.9–5.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 of stomach cancer   Herbicides  
Agricultural extension agents 10 0.7 (0.4–1.4) Alavanja et al., 1988
Forest conservationists 9 p-trend < over yrs worked 0.7 (0.3–1.3) Alavanja et al., 1989
Soil conservationists      
Florida pesticide applicators licensed 1965–1966 (n = 3,827)—mortality through 1976   Herbicides Blair et al., 1983
Any pesticide (dose–response by length of licensure)   Expected exposed cases  
  4 3.3  
White Male Residents of Iowa—stomach cancer on death certificate, usual occupation: farmers vs not   Herbicides  
> 30 yrs old when died 1964–1978—case-control 1,812 1.3 (p < 0.05) Burmeister et al., 1983
H0: only for “modern methods” → born after 1900      
Born before 1880 458 1.3 (p < 0.05)  
Born 1980–1900 639 1.3 (p < 0.05)  
Born after 1900 715 1.3 (p < 0.05)  
> 20 yrs old when died 1971–1978—PMR 338 1.1 (p < 0.01) Burmeister, 1981
ENVIRONMENTAL      
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Incidence      
20-yr follow-up to 1996—men and women      
Zone A 3 0.9 (0.3–2.7) Pesatori et al., 2009
Zone B 19 0.9 (0.6–1.4)
Zone R 131 0.8 (0.7–1.0)  
10-yr follow-up to 1991—men     Bertazzi et al., 1993
Zone B 7 1.0 (0.5–2.1)
Zone R 45 0.9 (0.7–1.2)  
10-yr follow-up to 1991—women     Bertazzi et al., 1993
Zone B 2 0.6 (0.2–2.5)
Zone R 25 1.0 (0.6–1.5)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality      
25-yr follow-up to 2001—men and women     Consonni et al., 2008
Zone A 3 0.7 (0.2–2.0)
Zone B 24 0.8 (0.5–1.2)  
Zone R 212 1.0 (0.8–1.1)  
20-yr follow-up to 1996     Bertazzi et al., 2001
Zones A and B—men 16 0.9 (0.5–1.5)
Zones A and B—women 11 1.0 (0.6–1.9)  
15-yr follow-up to 1991—men     Bertazzi et al., 1997, 1998
Zone B 10 0.8 (0.4–1.5)
Zone R 76 0.9 (0.7–1.1)  
15-yr follow-up to 1991—women     Bertazzi et al., 1997, 1998
Zone A 1 0.9 (0.0–5.3)
Zone B 7 1.0 (0.4–2.1)  
Zone R 58 1.0 (0.8–1.3)  
10-yr follow-up to 1986—men     Bertazzi et al., 1989a
Zone A, B, R 40 0.8 (0.6–1.2)
10-yr follow-up to 1986—women     Bertazzi et al., 1989a
Zone A, B, R 22 1.0 (0.6–1.5)
10-yr follow-up to 1986—men     Bertazzi et al., 1989b
Zone B 7 1.2 (0.6–2.6)
Ecological Study of Residents of Chapaevsk, Russia   Dioxin Revich et al., 2001
Incidence—crude incidence rate in 1998 vs      
Men      
Regional (Samara) nr 44.0 (nr)  
National (Russia) nr 48.1 (nr)  
Women      
Regional (Samara) nr 17.6 (nr)  
National (Russia) nr 20.7 (nr)  
Mortality—1995–1998 (SMR vs regional rates)      
Men 59 1.7 (1.3–2.2)  
Women 45 0.7 (0.5–0.9)  
FINLAND      
Finnish fishermen (n = 6,410) and spouses (n = 4,260) registered between 1980 and 2002 compared to national statistics   Serum dioxin Turunen et al., 2008
Fisherman 16 0.8 (0.5–1.3)  
Spouses 2 0.3 (0.0–1.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
JAPAN      
Residents of municipalities with and without waste incineration plants (cross-sectional)   Dioxin emissions age-adjusted mortality (per 100,000) Fukuda et al., 2003
Men      
With   38.2 ± 7.8 vs  
Without   39.0 ± 8.8 (p = 0.29)  
Women      
With   20.7 ± 5.0 vs  
Without   20.7 ± 5.8 (p = 0.92)  
SWEDEN      
Swedish fishermen (high consumption of fish with persistent organochlorines)   Organochlorine compounds Svensson et al., 1995a
Incidence      
East coast 24 1.6 (1.0–2.4)  
West coast 71 0.9 (0.7–1.2)  
Mortality      
East coast 17 1.4 (0.8–2.2)  
West coast 63 0.9 (0.7–1.2)  
CASE-CONTROL STUDIES      
US Case-Control Studies      
Eastern Nebraska—population-based case-control, agricultural pesticide use and adenocarcinoma of stomach 170 Herbicides, pesticides Lee et al., 2004b
Insecticides   0.9 (0.6–1.4)  
Herbicides   0.9 (0.5–1.4)  
International Case-Control Studies      
Swedish—population-based case-control study of residents (40–79 yrs of age) with gastric adenocarcinoma (February 1989–January 1995)   Phenoxy herbicides Ekström et al., 1999
All occupational herbicide exposures 75 1.6 (1.1–2.2)  
Phenoxyacetic acid exposure 62 1.8 (1.3–2.6)  
Hormoslyr (2,4-D, 2,4,5-T) 48 1.7 (1.2–2.6)  
2,4-D only 3 nr (vs 0 controls)  
MCPA 11 1.8 (0.8–4.1)  
Duration of Exposure      
Unexposed to all herbicides 490 1.0  
< 1 mo 11 1.6 (0.7–3.5)  
1–6 mo 30 1.9 (1.1–3.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
7–12 months 7 1.7 (0.6–4.7)  
> 1 yr 13 1.4 (0.6–3.0)  
Other herbicide exposure 13 1.0 (0.5–1.9)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCDF, polychlorinated dibenzofuran; PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; pg/g, picogram per gram; PMR, proportionate mortality ratio; SEA, Southeast Asia; SIR, standardized incidence ratio; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; UFW, United Farm Workers of America; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

the EOI scores. Similarly, for stomach cancer mortality, Yi et al. (2014b) reported a modestly increased risk for the high- versus low-exposure groups (HR = 1.17, 95% CI 1.03–1.33) and a positive association with the individual log-transformed EOI scores (HR = 1.05, 95% CI 1.02–1.08).

In a study of mortality and cancer incidence among 2,783 New Zealand Vietnam veterans who served in Vietnam between 1964 and 1975, McBride et al. (2013) reported that stomach cancer mortality was slightly elevated in the cohort (SMR = 1.27, 95% CI 0.58–2.42, based on nine deaths), while stomach cancer incidence was slightly less than expected (SIR = 0.82, 95% CI 0.38–1.56, based on nine cases).

Occupational Studies Wang et al. (2013) reported on mortality from 1980 to 2005 in a cohort of 3,529 workers, who had worked at least 1 year from 1980 through 1985 in an automobile foundry factory located in Hubei province in China with potential exposure to PCDD/Fs. When compared to the general population, the modest elevation in the risk of gastric cancers was not statistically significant (SMR = 1.28, 95% CI 0.60–2.74).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Environmental and Case-Control Studies No environmental or case-control studies of exposure to the COIs and stomach cancer have been published since Update 2012.

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the COIs (2,4-D and TCDD) on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). No increase in the incidence of gastrointestinal cancers has been reported in laboratory animals. However, studies of laboratory animals have observed dose-dependent increases in the incidence of squamous-cell hyperplasia of the forestomach or fundus of the stomach after administration of TCDD (Hebert et al., 1990; Walker et al., 2006). Similarly, in a long-term TCDD-treatment study in monkeys, hypertrophy, hyperplasia, and metaplasia were observed in the gastric epithelium (Allen et al., 1977). A transgenic mouse bearing a constitutively active form of the AHR has been shown to develop stomach tumors (Andersson et al., 2002); the tumors are neither dysplastic nor metaplastic but are indicative of both squamous-cell and intestinal-cell metaplasia (Andersson et al., 2005). The validity of the transgenic-animal model is indicated by the similarities in the phenotype of the transgenic animal (increased relative weight of the liver and heart, decreased weight of the thymus, and increased expression of AHR target gene CYP1A1) and animals treated with TCDD (Brunnberg et al., 2006). Recent cell culture work consistent with the in vivo studies showed that decreased AHR expression in two human gastric cancer cell lines was associated with decreased cell growth, migration, and invasion, all of which are hallmarks of malignant potential (Yin et al., 2013).

In a biomarker study of cancer patients, AHR expression and nuclear translocation were significantly higher in stomach-cancer tissue than in precancerous tissue (Peng et al., 2009a). The results suggest that the AHR plays an important role in stomach carcinogenesis. AHR activation in a stomach-cancer cell line (AGS) has also been shown to enhance stomach-cancer cell invasiveness potentially through a c-Jun-dependent induction of matrix metalloproteinase-9 (Peng et al., 2009b).

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

Several case-control studies addressing agricultural exposures reported evidence of an association of stomach cancer: Both Ekström et al. (1999) and Mills and Yang (2007) found an association with herbicides and with phenoxy herbicides in particular; Cocco et al. (1999) found a relationship with herbicide exposure, but the results were not specific as to the type of herbicide. In contrast,

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

in occupational cohort studies there was little evidence of an exposure-related increase in stomach cancer. Updated mortality findings from Seveso concerning TCDD exposure (Consonni et al., 2008; Pesatori et al., 2009) found no evidence of an increase in stomach cancer. There was a modestly increased risk of stomach cancer in Korean veterans but inconsistent evidence in New Zealand Vietnam veterans, as has been the case in previously reviewed studies of Vietnam veterans.

There is some evidence of biologic plausibility in animal models, but overall the epidemiologic studies do not support an association between exposure to the COIs and stomach cancer.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and stomach cancer.

Colorectal Cancers

Colorectal cancers include malignancies of the colon (ICD-9 153) and of the rectum and anus (ICD-9 154); less prevalent tumors of the small intestine (ICD-9 152) are often included. Findings on cancers of the retroperitoneum and other unspecified digestive organs (ICD-9 159) are considered in this category. Colorectal cancers account for about 55 percent of digestive tract tumors; ACS estimated that 132,700 people would receive diagnoses of colorectal cancer in the United States in 2015 and that 49,700 would die from it (Siegel et al., 2015). Excluding basal-cell and squamous-cell skin cancers, colorectal cancers are the third-most common form of cancer both in men and in women. The average annual incidence of colorectal cancers is shown in Table 8-3.

The incidence of colorectal cancers increases with age; it is higher in men than in women and in blacks than in whites. (Screening can affect the incidence, and screening is recommended for all persons over 50 years old). Other risk factors include a family history of this form of cancer, body weight, lack of physical exercise, and diet (Kamangar et al., 2006). Type 2 diabetes is associated with an increased risk of colorectal cancers (ACS, 2013a).

Conclusions from VAO and Previous Updates

Update 2006 considered colorectal cancers independently for the first time. Prior updates developed tables of results on colon and rectal cancers, but conclusions about the adequacy of the evidence of their association with herbicide exposure were reached only in the context of gastrointestinal tract cancers. The

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

committee responsible for VAO concluded that there was limited or suggestive evidence of no association between exposure to the herbicides used by the US military in Vietnam and gastrointestinal tract tumors, including colorectal cancers. The committee responsible for Update 2006 concluded that there was not enough evidence on each of the COIs to sustain that negative conclusion for any of the cancers in the gastrointestinal group and that, because these various types of cancer are generally regarded as separate disease entities, the evidence on each should be evaluated separately. Colorectal cancers were thus reclassified into the default category of inadequate or insufficient evidence to determine whether there is an association. The additional information considered in subsequent updates did not provide evidence to suggest that colorectal cancers be moved out of the category of inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and colorectal cancers.

The results of the relevant studies concerning colon and rectal cancers are summarized in Table 8-6, in which results new to this update are shaded.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies McBride et al. (2013) reported on mortality among 2,783 male New Zealand veterans who had served in Vietnam between 1964 and 1975 and were alive in 1988 (when the electronic mortality database started). Follow-up was through 2008, with those who emigrated or were lost to follow-up excluded. Colorectal cancer mortality was slightly elevated in the cohort (SMR = 1.04, 95% CI 0.64–1.61, based on 20 deaths), while all-cause mortality was significantly in deficit in the cohort (all-cause SMR = 0.85, 95% CI 0.77–0.94). Colorectal cancer incidence was slightly lower than expected (SIR = 0.95, 95% CI 0.73–1.21, based on 63 cases).

In the internal comparison of high- versus low-exposure opportunity groups, Yi and Ohrr (2014) found a deficit of colon cancer [ICD-10 C18] among the higher exposed (HR = 0.87, 95% CI 0.72–1.08) and a small excess of rectal cancer [ICD-10 C19–C21] (HR = 1.14, 95% CI 0.95–1.38). With regard to mortality from colorectal cancers [ICD-10 C18–C21], Yi et al. (2014b) reported no evidence of an increase in mortality from these cancers combined for high- versus low-exposure opportunity groups (HR = 0.96, 95% CI 0.78–1.19) or in association with the individual log-transformed EOI scores (HR = 1.02, 95% CI 0.97–1.07). Results were presented separately for 30 incident cases of and 19 deaths from cancer of the small intestine [ICD-10 C17]. Comparing the high- versus low-exposure opportunity groups, Yi and Ohrr (2014) found a significant increase in the incidence of this rather uncommon cancer (HR = 2.30, 95% CI 1.03–5.15). For mortality from cancer of the small intestine, Yi et al. (2014b) found elevated risks for both the internal comparison (HR = 2.88, 95% CI 1.00–8.28) and for the analysis of the individual EOI scores (HR = 1.11, 95% CI 0.87–1.40).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-6 Selected Epidemiologic Studies—Colon and Rectal Cancers (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS      
US Vietnam Veterans      
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Mortality      
1965–2000 9 1.0 (0.4–2.6) Boehmer et al., 2004
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1982 (Colon, other gastrointestinal, ICD-8 152–154, 158, 159)     Breslin et al., 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 209 1.0 (0.7–1.3)  
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 33 1.3 (0.7–2.2)  
US VA Cohort of Female Vietnam Veterans   All COIs  
Mortality      
Through 2004     Cypel and Kang, 2008
US Vietnam veterans 11 0.5 (0.2–1.0)
Vietnam-veteran nurses—colon 9 0.6 (0.2–1.4)  
Through 1991     Dalager et al., 1995a
US Vietnam veterans 4 0.4 (0.1–1.2)
Vietnam-veteran nurses—colon 4 0.5 (0.2–1.7)  
State Studies of US Vietnam Veterans      
923 white male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans     Anderson et al., 1986a,b
Colon 6 1.0 (0.4–2.2)  
Rectum 1 nr  
International Studies of Vietnam-Veterans      
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence      
Colon—All branches, 1982–2000 376 1.1 (1.0–1.2) ADVA, 2005b
Navy 91 1.3 (1.0–1.5)  
Army 239 1.1 (0.9–1.2)  
Air Force 47 1.1 (0.8–1.5)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Rectum—All branches, 1982–2000     ADVA, 2005a
Navy 54 1.1 (0.8–1.4)  
Army 152 1.0 (0.8–1.1)  
Air Force 28 1.0 (0.6–1.4)  
Validation Study   Expected number of exposed cases  
Men—colorectal cancer 188 221 (191–251) AIHW, 1999
Men—self-reported colon cancer 405 117 (96–138) CDVA, 1998a
Women—self-reported colon cancer 1 1 (0–5) CDVA, 1998b
Mortality      
Colon—All branches, return–2001 176 1.0 (0.8–1.1) ADVA, 2005a
Navy 49 1.3 (0.9–1.6)  
Army 107 0.9 (0.7–1.0)  
Air Force 21 0.9 (0.5–1.3)  
Rectum—All branches, return–2001     ADVA, 2005a
Navy 13 0.8 (0.4–1.4)  
Army 44 0.9 (0.6–1.1)  
Air Force 12 1.3 (0.6–2.2)  
1980–1994     CDVA, 1997a
Colon 78 1.2 (0.9–1.5)  
Rectum 16 0.6 (0.4–1.0)  
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence      
1982–2000     ADVA, 2005c
Colon 54 0.9 (0.7–1.4)  
Rectum 46 1.4 (0.9–2.2)  
Mortality      
1966–2001     ADVA, 2005c
Colon 29 0.8 (0.5–1.3)  
Rectum 10 1.8 (0.6–5.6)  
1982–1994     CDVA, 1997b
Colon 6 0.6 (0.2–1.5)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Rectum 3 0.7 (0.2–9.5)  
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008) (colorectal) 63 1.0 (0.7–1.2)  
Mortality (1988–2008) (colorectal) 20 1.0 (0.6–1.6)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)     Yi and Ohrr, 2014
Small intestine (C17) (19 vs 11)   2.3 (1.0–5.2)
Colon cancer (C18) (210 vs 228)   0.9 (0.7–1.1)  
Rectal cancer (C19–C20) 265 vs 231)   1.1 (1.0–1.4)  
Anus (C21) (7 vs 2)   3.3 (0.6–17.1)  
Mortality (1992–2005)     Yi et al., 2014b
HR per unit of log EOI (n = 180,639)      
Small intestine (C17) 19 1.1 (0.9–1.4)  
Colorectal (C18–C21) 366 1.0 (1.0–1.1)  
High exposure vs low exposure      
Small intestine (C17) (14 vs 5)   2.9 (1.0–8.3)  
Colorectal (C18–C21) (187 vs 179)   1.0 (0.8–1.2)  
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Non-cancer mortality     Vena et al., 1998
Mortality 1939–1992     Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs    
Colon 86 1.1 (0.9–1.3)  
Rectum 44 1.1 (0.8–1.4)  
7,553 not exposed to highly chlorinated PCDDs      
Colon 52 1.0 (0.8–1.3)  
Rectum 29 1.3 (0.9–1.9)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort     Saracci et al., 1991
Nested case-control study      
Colon (except rectum) 41 1.1 (0.8–1.5)  
Rectum 24 1.1 (0.7–1.6)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)   MCPA Coggon et al., 1986
Mortality through 1983      
Colon 19 1.0 (0.6–1.6)  
Rectum 8 0.6 (0.3–1.2)  
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)   Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP  
Incidence 1943–1982     Lynge, 1985
Men      
Colon 10 1.0 (nr)  
Rectum 14 1.4 (nr)  
Women      
Colon 1 0.3 (nr)  
Rectum 2 1.0 (nr)  
Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)   Dioxins, 2,4,5-T, 2,4,5-TCP  
Mortality 1955–1991     Hooiveld et al., 1998
Colon 3 1.4 (0.3–4.0)
Rectum 1 1.0 (0.0–5.6)  
Mortality 1955–1985     Bueno de Mesquita et al., 1993
Large intestine, except colon 3 2.4 (0.5–7.0)
Rectum 0 0.0 (0.0–5.6)
Dutch production workers in Plant B (414 men exposed during production 1965–1986; 723 unexposed) (in IARC cohort)   2,4-D; MCPA; MCPP; highly chlorinated dioxins unlikely  
Mortality 1965–1986 3 1.8 (0.4–5.4) Bueno de Mesquita et al., 1993
Large intestine, except rectum 0 0.0 (0.0–9.5)
Rectum 0 0.0 (0.0–19.4)
German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 mo in 1951–1976) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4,5-TCP  
Mortality 1951–1992     Becher et al., 1996
Colon 0 nr
Rectum 0 nr  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
German Production Workers at Bayer Plant in Dormagen (520 men working > 1 mo in 1965–1989) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Mortality 1965–1989     Becher et al., 1996
Colon 1 2.2 (0.1–2.2)
Rectum 0 nr  
German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 mo in 1957–1987) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Mortality 1956–1989     Becher et al., 1996
Colon 0 nr
Rectum 1 0.9 (0.0–4.9)  
BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)   Focus on TCDD  
Incidence     Ott and Zober, 1996a
1960–1992—colorectal 5 1.0 (0.3–2.3)
TCDD < 0.1 µg/kg of body weight 2 1.1 (0.1–3.9)
TCDD 0.1–0.99 µg/kg of body weight 2 1.4 (0.2–5.1)  
TCDD > 1.0 µg/kg of body weight 1 0.5 (0.0–3.0)  
Mortality      
Through 1987—colon, rectum 2 90% CI 2.5 (0.4–7.8) Zober et al., 1990
Through 1970—(n = 74; 70 initially exposed, 4 involved with cleaning and testing procedures) 1 0.4 (nr) Theiss et al., 1982
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997) (ICD-9)   Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP  
Mortality 1952–2007 (140–149)     Manuwald et al., 2012
Colon (153) 12 0.7 (0.4–1.3)
Men 7 0.6 (0.3–1.3)  
Women 5 0.9 (0.3–2.1)  
Rectum, rectosigmoid junction, anus (154) 13 1.7 (0.9–2.9)  
Men 11 2.0 (0.98–3.5)  
Women 2 1.0 (0.1–3.7)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortalilty 1952–1989     Becher et al., 1996
Colon 2 0.4 (0.1–1.4)
Rectum 6 1.9 (0.7–4.0)  
Mortality 1952–1989—stats on men only, 1,184 (tables for 1,148 men, not necessarily German nationals) vs national rates (also vs gas workers); same observation period as Becher et al., 1966)     Manz et al., 1991
Colon 8 0.9 (0.4–1.8)  
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Large intestine    
Ever-exposed workers 3 0.6 (0.1–1.7)  
Never-exposed workers 0 0.0 (0.0–2.0)  
Rectum      
Ever-exposed workers 6 2.0 (0.7–4.4)  
Never-exposed workers 2 2.1 (0.3–7.7)  
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)      
Mortality 1969–2000     ’t Mannetje et al., 2005
Phenoxy herbicide producers (men and women)    
Colon 2 0.6 (0.0–2.3)  
Rectum, rectosigmoid junction, anus 5 2.5 (0.8–5.7)  
Phenoxy herbicide sprayers (> 99% men)      
Colon 8 1.9 (0.8–3.8)  
Rectum, rectosigmoid junction, anus 4 1.5 (0.4–3.8)  
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Through 1993     Steenland et al., 1999
Small intestine, colon 34 1.2 (0.8–1.6)
Rectum 6 0.9 (0.3–1.9)  
Through 1987     Fingerhut et al., 1991
Entire NIOSH cohort    
Small intestine, colon 25 1.2 (0.8–1.8)  
Rectum 5 0.9 (0.3–2.1)  
≥ 1-yr exposure, ≥ 20-yr latency      
Small intestine, colon 13 1.8 (1.0–3.0)  
Rectum 2 1.2 (0.1–4.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality, colon cancer—754 Monsanto workers, among most highly exposed workers from Fingerhut et al. (1991) 3 0.5 (0.1–1.3) Collins et al., 1993
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (in IARC and NIOSH cohorts)   2,4,5-T; 2,4,5-TCP  
1942–2003 (n = 1,615)     Collins et al., 2009b
Large intestine 18 1.2 (0.7–1.8)
Rectum 2 0.6 (0.1–2.1)  
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
Intestine (ICD-9 152–153)      
1940–2005 (n = 2,122) 26 1.1 (0.7–1.6)  
PCP and TCP (n = 720) 11 1.4 (0.7–2.6)  
PCP (no TCP) (n = 1,402) 15 0.9 (0.5–1.5)  
Rectum (ICD-9 154)      
1940–2005 (n = 2,122) 2 0.4 (0.0–1.3)  
PCP and TCP (n = 720) 1 0.5 (0.0–3.0)  
PCP (no TCP) (n = 1,402) 1 0.3 (0.0–1.5)  
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3)     Burns CJ et al., 2011
Colon 16 1.0 (0.6–1.6)  
Rectum 6 0.8 (0.3–1.7)  
Through 1982 (n = 878)     Bond et al., 1988
Colon 4 2.1 (0.6–5.4)
Rectum 1 1.7 (0.0–9.3)  
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP)     Collins et al., 2009c
Large intestine 10 1.2 (0.6–2.3)  
Rectum 1 0.5 (0.0–2.9)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality 1940–1989 (n = 770)     Ramlow et al., 1996
0-yr latency    
Colon 4 0.8 (0.2–2.1)  
Rectum 0 nr  
15-yr latency      
Colon 4 1.0 (0.3–2.6)  
Rectum 0 nr  
Other Studies of Industrial Workers (not related to IARC or NIOSH phenoxy cohorts)      
1,412 white male US flavor and fragrance chemical plant workers (1945–1965)   Dioxin, 2,4,5-T Thomas, 1987
Colon 4 0.6 (nr)  
Rectum 6 2.5 (nr)  
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Colon 62 0.7 (0.6–1.0)  
Rectum 60 0.9 (0.7–1.1)  
Danish paper workers     Rix et al., 1998
Men      
Colon 58 1.0 (0.7–1.2)  
Rectum 43 0.9 (0.6–1.2)  
Women      
Colon 23 1.1 (0.7–1.7)  
Rectum 15 1.5 (0.8–2.4)  
New Hampshire pulp and paper workers, 883 white men working ≥ 1 yr, mortality through July 1985     Henneberger et al., 1989
Colon 9 1.0 (0.5–2.0)  
Rectum 1 0.4 (0.0–2.1)  
Pulp and paper cohorts independent of IARC cohort      
United Paperworkers International, 201 white men employed ≥ 10 yr and dying 1970–1984     Solet et al., 1989
Colon 7 1.5 (0.6–3.0)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Northwestern US paper and pulp workers—5 mills in Washington, Oregon, and California, 3,523 worked ≥ 1 yr 1945–1955, mortality through March 1977     Robinson et al., 1986
Intestines (ICD-7 152, 153) 7 0.4 (0.2–0.7)  
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
DENMARK      
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Men      
Self-employed      
Colon 277 0.7 (p < 0.05)  
Rectum 309 0.8 (p < 0.05)  
Employee      
Colon 45 0.6 (p < 0.05)  
Rectum 55 0.8 (nr)  
Women      
Self-employed      
Colon 14 0.9 (nr)  
Rectum 5 0.6 (nr)  
Employee      
Colon 112 0.9 (nr)  
Rectum 55 0.8 (nr)  
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 2000     Swaen et al., 2004
Colon 7 1.0 (0.4–2.1)
Rectum 5 2.1 (0.7–4.8)  
Through 1987     Swaen et al., 1992
Colon 4 2.6 (0.7–6.5)
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401)     Torchio et al., 1994
Colon 84 0.6 (0.5–0.7)  
Rectum nr nr  
Italian rice growers with documented phenoxy use (n = 1,487   Phenoxy herbicides Gambini et al., 1997
Intestines 27 1.1 (0.7–1.6)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of incident cancer cases (colon, rectum, or small intestine) vs remainder of 19,904 men with any incident cancer     Reif et al., 1989
Forestry workers (n = 134)   Herbicides  
Colon 7 0.5 (0.2–1.1)  
Rectum 10 1.2 (0.6–2.3)  
Small intestine 2 5.2 (1.4–18.9)  
Aged 20–59 2 11.2 (3.4–36.4)  
Aged ≥ 60 0  
Sawmill workers (n = 139)   Herbicides, chlorophenols  
Small intestine 0  
SWEDEN      
Incident cancer cases 1961–1973 with agriculture as economic activity in 1960 census     Wiklund, 1983
Colon 1.332    
Rectum   99% CI  
  1,083 0.8 (0.7–0.8)  
UNITED STATES      
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides
PCMRs
Blair et al., 1993
Colon      
Men      
Whites (n = 119,648) 2,291 1.0 (0.9–1.0)  
Nonwhites (n = 11,446) 148 0.8 (0.7–0.9)  
Women      
Whites (n = 2,400) 59 1.0 (0.8–1.3)  
Nonwhites (n = 2,066) 40 1.0 (0.7–1.3)  
Rectum      
Men      
Whites (n = 119,648) 367 1.0 (0.9–1.1)  
Nonwhites (n = 11,446) 22 0.7 (0.5–1.1)  
Women      
Whites (n = 2,400) 4 0.5 (0.1–1.3)  
Nonwhites (n = 2,066) 5 1.1 (0.3–2.5)  
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Incidence      
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Colon      
Private applicators 339 0.9 (0.8–1.0)  
Commercial applicators 17 1.0 (0.6–1.6)  
Spouses 144 0.8 (0.7–1.0)  
Rectum      
Private applicators 117 0.9 (0.7–1.1)  
Commercial applicators 8 1.2 (0.5–2.3)  
Spouses 30 0.7 (0.5–1.0)  
Enrollment through 2005—Interactions between dicamba and body mass index     Andreotti et al., 2010
Trend (with dicamba use reported) 96 1.1 (1.0–1.1)  
Trend (with no dicamba use reported) 102 1.0 (1.0–1.1)  
Enrollment through 2005—colorectal cancer     Lee WJ et al., 2007
2.4-D 204 0.7 (0.5–0.9)
2,4,5-T 65 0.9 (0.7–1.2)  
2,4,5-TP 24 0.8 (0.5–1.2)  
Dicamba 110 0.9 (0.7–1.2)  
Enrollment through 2002—colon cancer     Samanic et al., 2006
Dicamba—lifetime days exposure    
None 76 1.0  
1– < 20 9 0.4 (0.2–0.9)  
20– < 56 20 0.9 (0.5–1.5)  
56– < 116 13 0.8 (0.4–1.5)  
≥ 116 17 1.4 (0.8–2.9) p-trend = 0.10  
Dicamba—intensity-weighted quartiles      
None 76 1.0  
Lowest 16 0.6 (0.4–1.1)  
Second 17 0.7 (0.4–1.2)  
Third 6 0.5 (0.2–1.2)  
Highest 20 1.8 (1.0–3.1) p-trend = 0.02  
Enrollment through 2002     Alavanja et al., 2005
Colon    
Private applicators (men, women) 208 0.9 (0.8–1.0)  
Spouses of private applicators (> 99% women) 87 0.9 (0.7–1.1)  
Commercial applicators (men, women) 12 0.2 (0.6–2.1)  
Rectum      
Private applicators (men, women) 94 0.8 (0.7–1.0)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Spouses of private applicators (> 99% women) 23 0.6 (0.4–0.9)  
Commercial applicators (men, women) 7 1.3 (0.5–2.6)  
Mortality      
Enrollment through 2007, vs state rates     Waggoner et al., 2011
Intestine    
Applicators (n = 1,641) 158 0.8 (0.6–0.9)  
Spouses (n = 676) 68 0.9 (0.7–1.1)  
Rectum      
Applicators (n = 1,641) 32 0.7 (0.5–1.0)  
Spouses (n = 676) 4 nr  
Enrollment through 2000, vs state rates     Blair et al., 2005a
Colon    
Private applicators (men, women) 56 0.7 (0.6–1.0)  
Spouses of private applicators (> 99% women) 31 1.2 (0.8–1.6)  
Rectum      
Private applicators (men, women) nr nr  
Spouses of private applicators (> 99% women) nr nr  
US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 of cancer   Herbicides  
Agricultural extension agents     Alavanja et al., 1988
Colon 41 1.0 (0.7–1.5)  
Rectum 5 nr  
Forest conservationists   p-trend < over yrs worked Alavanja et al., 1989
Colon 44 1.5 (1.1–2.0)  
Rectum 9 1.0 (0.5–1.9)  
Soil conservationists      
Florida Licensed Pesticide Applicators [common phenoxy use assumed but not documented; had been listed by Blair et al., 1983]   Herbicides  
Pesticide applicators in Florida licensed 1965–1966 (n = 3,827)—mortality through 1976   Herbicides Blair et al., 1983
Any pesticide (dose–response by length of licensure)      
Colon 5 0.8 (nr)  
Rectum 2 nr  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
White Male Residents of Iowa—colon cancer on death certificate, usual occupation: farmers vs not   Herbicides  
> 20 yrs old when died 1971–1978—PMR     Burmeister, 1981
Colon 1,064 0.9 (0.9–1.0)
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Incidence      
20-yr follow-up to 1996—men and women      
Zone A     Pesatori et al., 2009
Colon 2 0.7 (0.2–2.7)
Rectum 0    
Zone B      
Colon 19 1.0 (0.7–1.6)  
Rectum 17 1.8 (1.1–2.9)  
Zone R      
Colon 137 1.0 (0.9–1.3)  
Rectum 71 1.1 (0.8–1.4)  
10-yr follow-up to 1991—men     Bertazzi et al., 1993
Zone B    
Colon 2 0.5 (0.1–2.0)  
Rectum 3 1.4 (0.4–4.4)  
Zone R      
Colon 32 1.1 (0.8–1.6)  
Rectum 17 1.1 (0.7–1.9)  
10-yr follow-up to 1991—women     Bertazzi et al., 1993
Zone B    
Colon 2 0.6 (0.1–2.3)  
Rectum 2 1.3 (0.3–5.4)  
Zone R      
Colon 23 0.8 (0.5–1.3)  
Rectum 7 0.6 (0.3–1.3)  
Mortality      
25-yr follow-up to 2001—men and women     Consonni et al., 2008
Zone A    
Colon 3 1.0 (0.3–3.0)  
Rectum 1 0.9 (0.1–6.4)  
Zone B      
Colon 12 0.6 (0.3–1.1)  
Rectum 11 1.5 (0.8–2.8)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Zone R      
Colon 137 0.9 (0.7–1.3)  
Rectum 50 0.9 (0.7–1.3)  
20-yr follow-up to 1996     Bertazzi et al., 2001
Zones A and B—men    
Colon 10 1.0 (0.5–1.9)  
Rectum 9 2.4 (1.2–4.6)  
Zones A and B—women      
Colon 5 0.6 (0.2–1.4)  
Rectum 3 1.1 (0.4–3.5)  
15-yr follow-up to 1991—men     Bertazzi et al., 1997
Zone B    
Colon 5 0.8 (0.3–2.0)  
Rectum 7 2.9 (1.2–5.9)  
Zone R      
Colon 34 0.8 (0.6–1.1)  
Rectum 19 1.1 (0.7–1.8)  
15-yr follow-up to 1991—women     Bertazzi et al., 1997
Zone A    
Colon 2 2.6 (0.3–9.4)  
Zone B      
Colon 3 0.6 (0.1–1.8)  
Rectum 2 1.3 (0.1–4.5)  
Zone R      
Colon 33 0.8 (0.6–1.1)  
Rectum 12 0.9 (0.5–1.6)  
10-yr follow-up to 1986—men     Bertazzi et al., 1989a,b
Zone A, B, R—colon 20 1.0 (0.6–1.5)
Zone A, B, R—rectum 10 1.0 (0.5–2.7)  
Zone B—rectum 2 1.7 (0.4–7.0)  
10-yr follow-up to 1986—women     Bertazzi et al., 1989a
Zone A, B, R—colon 12 0.7 (0.4–1.2)
Zone A, B, R—rectum 7 1.2 (0.5–2.7)  
Ecological Study of Residents of Chapaevsk, Russia   Dioxin Revich et al., 2001
Incidence— Crude incidence rate in 1998 vs      
Men      
Regional (Samara)      
Colon nr 21.7 (nr)  
Rectum nr 17.1 (nr)  
National (Russia)      
Colon nr 17.9 (nr)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Rectum nr 16.6 (nr)  
Women      
Regional (Samara)      
Colon nr 15.4 (nr)  
Rectum nr 11.2 (nr)  
National (Russia)      
Colon nr 14.1 (nr)  
Rectum nr 10.3 (nr)  
Mortality—1995–1998 (SMR vs regional rates)      
Men      
Colon 17 1.3 (0.8–2.2)  
Rectum 21 1.5 (1.0–2.4)  
Women      
Colon 24 1.0 (0.7–1.5)  
Rectum 24 0.9 (0.6–1.4)  
FINLAND      
Finnish community exposed to chlorophenol contamination (men and women)   Chlorophenol Lampi et al., 1992
Colon—men, women 9 1.1 (0.7–1.8)  
Finnish fishermen (n = 6,410) and spouses (n = 4,260) registered between 1980 and 2002 compared to national statistics   Serum dioxin Turunen et al., 2008
Fisherman   SMRs  
Colon 8 0.5 (0.2–1.0)  
Rectum 8 0.8 (0.4–1.6)  
Spouses      
Colon 10 1.3 (0.6–2.4)  
Rectum 8 2.1 (0.9–4.2)  
SWEDEN      
Swedish fishermen (high consumption of fish with persistent organochlorines)   Organochlorine compounds Svensson et al., 1995a
Incidence      
East coast      
Colon 5 0.4 (0.1–0.9)  
Rectum 9 0.9 (0.4–1.6)  
West coast      
Colon 82 1.0 (0.8–1.2)  
Rectum 59 1.1 (0.8–1.4)  
Mortality      
East coast      
Colon 1 0.1 (0.0–0.7)  
Rectum 4 0.7 (0.2–1.9)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
West coast      
Colon 58 1.0 (0.8–1.3)  
Rectum 31 1.0 (0.7–1.5)  
CASE-CONTROL STUDIES
International Case-Control Studies      
421 Egyptian colorectal cancer cases and 439 hospital controls   Herbicides 5.5 (2.4–12.3) Lo et al., 2010
Swedish patients (1970–1977) nr Phenoxy acids, chlorophenols Hardell, 1981
Colon      
Exposed to phenoxy herbicides 11 1.3 (0.6–2.8)  
Exposed to chlorophenols 6 1.8 (0.6–5.3)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; PMR, proportionate mortality ratio; SIR, standardized incidence ratio; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Environmental, Occupational, and Case-Control Studies No occupational, environmental, or case-control studies of exposure to the COIs and colorectal cancers have been published since Update 2012.

Biologic Plausibility

Long-term animal studies examining the effect of exposure to the COIs on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004) have reported no increase in the incidence of colorectal cancers. Recently, Xie et al. (2012) reported that AHR activation by TCDD induces robust proliferation in two human colon-cancer cell lines through Src-mediated epidermal growth factor receptor activation. That novel finding suggests

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

that TCDD and other AHR ligands may contribute to increased proliferation of colonic cells, but more studies are needed to understand the relation of increased proliferation of these cells to colorectal cancers, if any, and the potential role of AHR activation in colorectal and intestinal carcinogenesis.

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

Epidemiologic findings for colorectal cancers have not been particularly suggestive of an association with exposure to the COIs. The exceptionally large cohort of Korean Vietnam veterans generated results for cancer of the small intestine that presented a pattern of increased risk for both incidence and mortality, but no other epidemiologic findings for cancer of the small intestine have been encountered in these updates that could be used to appraise consistency.

There is no evidence of biologic plausibility of an association between exposure to any of the COIs and tumors of the colon or rectum or the small intestine. Overall, the available evidence does not support an association between the COIs and colorectal cancers.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and colorectal cancers.

Hepatobiliary Cancers

Hepatobiliary cancers include cancers of the liver (ICD-9 155.0, 155.2) and the intrahepatic bile duct (ICD-9 155.1). ACS estimated that 25,510 men and 10,150 women would receive diagnoses of liver cancer or intrahepatic bile duct cancer in the United States in 2015 and that 17,030 men and 7,520 women would die from these cancers (Siegel et al., 2015). Gallbladder cancer and extrahepatic bile duct cancer (ICD-9 156) are fairly uncommon and, when they are addressed, are often grouped with liver cancer.

In the United States, liver cancers account for about 2 percent of new cancer cases and 4 percent of cancer deaths. Misclassification of metastatic cancers as primary liver cancer can lead to an overestimation of the number of deaths attributable to liver cancer (Chuang et al., 2009). In developing countries, especially those in sub-Saharan Africa and Southeast Asia, liver cancers are common and are among the leading causes of death (Kamangar et al., 2006). Known risk factors for liver cancer include chronic infection with hepatitis B or hepatitis C virus

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

and exposure to the carcinogens aflatoxin and vinyl chloride. Alcohol cirrhosis and obesity-associated metabolic syndrome may also contribute to the risk of liver cancer (Chuang et al., 2009; Farazi et al., 2006). In the general population, the incidence of liver and intrahepatic bile duct cancers is higher in men than in women and higher in blacks than in whites (NCI, 2015). The average annual incidence of hepatobiliary cancers is shown in Table 8-3.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and hepatobiliary cancers. Additional information available to the committees responsible for subsequent updates did not change that conclusion.

Table 8-7 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies McBride et al. (2013) did not report results for this outcome.

Recent publications examined incidence of (Yi, 2013; Yi and Ohrr, 2014) and mortality from (Yi et al., 2014b) cancers among 185,265 Korean male Vietnam veterans in the Korean Veterans Health Study. When compared to the general Korean population, there was no evidence of excess liver cancer risk (SIR = 1.00, 95% CI 0.96–1.05) (Yi, 2013). In the internal comparison of the high- versus low-exposure opportunity group, Yi and Ohrr (2014) reported a marginal elevation in liver cancer for the higher group (RR = 1.09, 95% CI 0.99–1.20). Yi et al. (2014b) reported modestly increased risk of liver cancer mortality in the internal comparison (RR = 1.12, 95% CI 1.02–1.23) and from the analysis of the individual EOI scores (RR = 1.03, 95% CI 1.00–1.05).

Occupational Studies Among 3,529 employees of a Chinese automobile foundry, Wang et al. (2013) found a significantly elevated risk of liver cancer mortality (SMR = 1.71, 95% CI 1.21–2.42, based on 32 cancer deaths).

Environmental and Case-Control Studies No environmental or case-control studies of exposure to the COIs and liver cancer have been published since Update 2012.

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the COIs on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). Studies performed in laboratory animals have

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-7 Selected Epidemiologic Studies—Hepatobiliary Cancers (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS      
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Mortality      
1965–2000—liver, intrahepatic bile ducts (ICD-9 155) 5 nr Boehmer et al., 2004
US CDC Selected Cancers Study—case-control study of incidence (Dec 1, 1984–Nov 30, 1989) among US males born 1929–1953 8 All COIs
1.2 (0.5–2.7)
CDC, 1990a
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1982—liver, bile duct     Breslin et al., 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 34 1.0 (0.8–1.4)  
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 6 1.2 (0.5–2.8)  
State Studies of US Vietnam Veterans      
923 white male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans 0 nr Anderson et al., 1986a,b
International Vietnam-Veteran Studies      
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence      
All branches, 1982–2000 27 0.7 (0.4–1.9) ADVA, 2005b
Navy 8 1.0 (0.4–1.9)  
Army 18 0.7 (0.4–1.1)  
Air Force 1 0.2 (0.0–1.2)  
Mortality      
All branches, return–2001 48 0.9 (0.6–1.1) ADVA, 2005a
Navy 11 1.0 (0.5–1.7)  
Army 33 0.9 (0.6–1.2)  
Air Force 4 0.6 (0.2–1.5)  
1980–1994     CDVA, 1997a
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Liver (ICD-9 155) 8 0.6 (0.2–1.1)  
Gallbladder (ICD-9 156) 5 1.3 (0.4–2.8)  
Australian Conscripted Army National Service 18,940 deployed vs 24,642 non-deployed   All COIs  
Incidence      
1982–2000 2 2.5 (0.1–147.2) ADVA, 2005c
Mortality      
1966–2001 (liver, gallbladder) 4 2.5 (0.4–27.1) ADVA, 2005c
1982–1994 1 nr CDVA, 1997b
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual E4 exposure opportunity scores) (HRs)   All COIs  
Incidence (1992–2003)—categorized high (n = 85,809) vs low (n = 94,442)     Yi and Ohrr, 2014
Liver (C22) 1,023 1.1 (1.0–1.2)  
Gall bladder, etc. (C23–C24) 125 1.2 (0.9–1.6)  
Mortality (1992–2005)—categorized high (n = 85,809) vs low (n = 94,442)     Yi et al., 2014b
HR per unit of log EOI (n = 2,053)      
Liver (C22) 2,053 1.0 (1.0–1.1)  
Gallbladder (C23–C24) 215 1.1 (1.0–1.1)  
High exposure vs low exposure      
Liver (C22) (1,107 vs 946)   1.1 (1.0–1.2)  
Gallbladder (C23–C24) (120 vs 95)   1.2 (0.9–1.6)  
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Mortality 1939–1992 15 0.7 (0.4–1.2) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 12 0.9 (0.5–1.5)
7,553 not exposed to highly chlorinated PCDDs 3 0.4 (0.1–1.2)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort     Saracci et al., 1991
Liver, gallbladder, bile duct (ICD-8 155–156) 4 0.4 (0.1–1.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)   Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP  
Incidence 1943–1982     Lynge, 1985
Men 3 1.0 (nr)  
Women 0 nr  
German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 mo in 1951–1976) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4,5-TCP  
Mortality 1951–1992 0 Becher et al., 1996
German Production Workers at Bayer Plant in Dormagen (520 men working > 1 mo in 1965–1989) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Mortality 1965–1989 0 Becher et al., 1996
German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 mo in 1957–1987) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Mortality 1956–1989 1 1.2 (0.0–6.9) Becher et al., 1996
BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)   Focus on TCDD  
Incidence      
1960–1992—liver, gallbladder, bile duct 2 2.1 (0.3–7.5) Ott and Zober, 1996a
TCDD < 0.1 µg/kg of body weight 1 2.8 (0.1–15.5)
TCDD 0.1–0.99 µg/kg of body weight 0 0.0 (0.0–15.4)  
TCDD > 1.0 µg/kg of body weight 1 2.8 (0.1–15.5)  
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)   Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortalilty 1952–1989 0 Becher et al., 1996
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Ever-exposed workers 2 1.4 (0.2–5.1)
Never-exposed workers 0 0.0 (0.0–8.2)  
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)      
Mortality 1969–2000—ICD-9 155     ’t Mannetje et al., 2005
Phenoxy herbicide producers (men and women) 1 1.6 (0.0–8.8)
Phenoxy herbicide sprayers (> 99% men) 0 0.0 (0.0–4.2)  
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Through 1993     Steenland et al., 1999
Liver, biliary tract (ICD-9 155–156) 7 0.9 (0.4–1.6)
Through 1987 (liver, biliary tract) 6 1.2 (0.4–2.5) Fingerhut et al., 1991
≥ 1-yr exposure, ≥ 20-yr latency 1 0.6 (0.0–3.3)
Mortality—754 Monsanto workers, among most highly exposed workers from     Collins et al., 1993
Fingerhut et al. (1991); liver, biliary tract 2 1.4 (0.2–5.2)  
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (in IARC and NIOSH cohorts)   2,4,5-T; 2,4,5-TCP  
1942–2003 (n = 1,615) 2 0.5 (0.1–1.6) Collins et al., 2009b
March 1949–1978 (n = 121); 121 TCP workers with chloracne 0 nr Zack and Suskind, 1980
     
Through 1982 (n = 878); liver, biliary tract (ICDA-8 155–156) 0 1.2 (nr) Bond et al., 1988
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
1940–2005 (n = 2,122) (liver and biliary; ICD–9 155–156) 9 1.2 (0.6–2.3)  
PCP and TCP (n = 720) 0 – (0.0–1.6)  
PCP (no TCP) (n = 1,402) 9 1.8 (0.8–3.4)  
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) 0 0.0 (0.0–1.7) Collins et al., 2009c
Mortality 1940–1989 (n = 770); liver, primary (ICDA-8 155–156)     Ramlow et al., 1996
0-yr latency 0 nr  
15-yr latency 0 nr  
Other Studies of Industrial Workers (not related to IARC or NIOSH phenoxy cohort)      
Automobile workers from Hubei province in China (worked 1 yr during 1980–1985)   PCDD/F Wang et al., 2013
Mortality (1980–2005) (n = 3,529) 32 1.7 (1.2–2.4)  
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Never 27 0.9 (0.6–1.3)  
Ever 16 0.7 (0.4–1.1)  
Danish paper workers     Rix et al., 1998
Men      
Liver 10 1.1 (0.5–2.0)  
Gallbladder 9 1.6 (0.7–3.0)  
Women      
Liver 1 0.6 (0.0–3.2)  
Gallbladder 4 1.4 (0.4–3.7)  
Pulp and paper cohorts independent of IARC cohort      
United Paperworkers International, 201 white men employed ≥ 10 yr and dying 1970–1984 2 2.0 (0.2–7.3) Solet et al., 1989
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
DENMARK      
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Men      
Liver      
Self-employed 23 0.4 (p < 0.05)  
Employee 9 0.8 (nr)  
Gallbladder      
Self-employed 35 0.8 (nr)  
Employee 7 0.8 (nr)  
Women      
Liver      
Family workers 5 0.5 (nr)  
Gallbladder      
Self-employed 7 2.7 (p < 0.05)  
Employee 1 0.7 (nr)  
Family workers 17 1.0 (nr)  
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 2000 0 nr Swaen et al., 2004
FINNISH Phenoxy Herbicide Sprayers (1,909 men working 1955–1971 ≥ 2 wks) not IARC (liver, biliary tract)   Phenoxy herbicides  
Incidence 3 0.9 (0.2–2.6) Asp et al., 1994
Mortality 1972–1989 2 0.6 (0.1–2.2)  
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401) 15 0.6 (0.3–0.9) Torchio et al., 1994
Italian rice growers with documented phenoxy use (n = 1,487)   Phenoxy herbicides Gambini et al., 1997
  7 1.3 (0.5–2.6)  
NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of incident hepatobiliary cancer cases vs remainder of 19,904 men with any incident cancer     Reif et al., 1989
Forestry workers (n = 134)   Herbicides  
Liver 1 0.8 (0.1–5.8)  
Gallbladder 3 4.1 (1.4–12.0)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Aged 20–59 1 6.3 (1.1–36.6)  
Aged ≥ 60 2 3.5 (0.9–13.3)  
Sawmill workers (n = 139)   Herbicides, chlorophenols  
Gallbladder 2 2.3 (0.6–9.1)  
SWEDEN      
Incident stomach cancer cases 1961–1973 with agriculture as economic activity in 1960 census   99% CI Wiklund, 1983
Liver (primary) 103 0.3 (0.3–0.4)  
Biliary tract 169 0.6 (0.5–0.7)  
Liver (unspecified) 67 0.9 (0.7–1.3)  
UNITED STATES      
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Men      
Whites (n = 119,648) 326 1.0 (0.9–1.1)  
Nonwhites (n = 11,446) 24 0.7 (0.5–1.1)  
Women      
Whites (n = 2,400) 6 0.7 (0.3–1.6)  
Nonwhites (n = 2,066) 2 0.4 (0.0–1.3)  
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence      
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Liver    
Private applicators 32 0.7 (0.5–1.0)  
Commercial applicators 1 nr  
Spouses 6 0.8 (0.3–1.7)  
Gallbladder      
Private applicators 8 1.3 (0.6–2.6)  
Commercial applicators 0 nr  
Spouses 7 1.1 (0.4–2.3)  
Enrollment through 2002     Alavanja et al., 2005
Liver    
Private applicators (men, women) 35 1.0 (0.7–1.4)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Spouses of private applicators (> 99% women) 3 0.9 (0.2–2.5)  
Commercial applicators (men, women) nr 0.0 (0.0–4.2)  
Gallbladder      
Private applicators (men, women) 8 2.3 (1.0–4.5)  
Spouses of private applicators (> 99% women) 3 0.9 (0.2–2.5)  
Commercial applicators (men, women) nr 0.0 (0.0–35.8)  
Mortality      
Enrollment through 2007, vs state rates (liver and gallbladder)     Waggoner et al., 2011
Applicators (n = 1,641) 50 0.7 (0.5–0.9)  
Spouses (n = 676) 18 0.8 (0.5–1.3)  
Enrollment through 2000, vs state rates     Blair et al., 2005a
Liver    
Private applicators (men, women) 8 0.6 (0.2–1.1)  
Spouses of private applicators (> 99% women) 4 1.7 (0.4–4.3)  
Rectum      
Private applicators (men, women) 3 2.0 (0.4–5.7)  
Spouses of private applicators (> 99% women) 2 1.3 (0.1–4.6)  
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Incidence      
20-yr follow-up to 1996—men and women     Pesatori et al., 2009
Zone A    
Liver 0    
Biliary 0    
Zone B      
Liver 14 1.3 (0.8–2.2)  
Biliary 6 2.3 (1.0–5.2)  
Zone R      
Liver 56 0.7 (0.6–1.0)  
Biliary 16 0.8 (0.5–1.4)  
10-yr follow-up to 1991—men     Bertazzi et al., 1993
Zone B    
Liver 4 2.1 (0.8–5.8)  
Gallbladder (ICD-9 156) 1 2.3 (0.3–17.6)
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Zone R      
Liver 3 0.2 (0.1–0.7)  
Gallbladder (ICD-9 156) 3 1.0 (0.3–3.4)  
10-yr follow-up to 1991—women     Bertazzi et al., 1993
Zone B    
Gallbladder (ICD-9 156) 4 4.9 (1.8–13.6)  
Zone R      
Liver 2 0.5 (0.1–2.1)  
Gallbladder (ICD-9 156) 7 1.0 (0.5–2.3)  
Mortality      
25-yr follow-up to 2001—men and women     Consonni et al., 2008
Zone A    
Liver 3 1.0 (0.3–3.2)  
Biliary 0 0.0 (nr)  
Zone B      
Liver 16 0.9 (0.5–1.4)  
Biliary 2 0.6 (0.1–2.3)  
Zone R      
Liver 107 0.8 (0.7–1.0)  
Biliary 31 1.2 (0.8–1.7)  
20-yr follow-up to 1996     Bertazzi et al., 2001
Zones A and B—men    
Liver, gallbladder 6 0.5 (0.2–1.0)  
Liver 6 0.5 (0.2–1.1)  
Zones A and B—women      
Liver, gallbladder 7 1.0 (0.5–2.2)  
Liver 6 1.3 (0.6–2.9)  
15-yr follow-up to 1991—men     Bertazzi et al., 1997
Zone B    
Liver, gallbladder 4 0.6 (0.2–1.4)  
Liver 4 0.6 (0.2–1.6)  
Zone R      
Liver, gallbladder 35 0.7 (0.5–1.0)  
Liver 31 0.7 (0.5–1.0)  
15-yr follow-up to 1991—women     Bertazzi et al., 1997
Zone B    
Liver, gallbladder 4 1.1 (0.3–2.9)  
Liver 3 1.3 (0.3–3.8)  
Zone R      
Liver, gallbladder 25 0.8 (0.5–1.3)  
Liver 12 0.6 (0.3–1.1)  
10-yr follow-up to 1986—men     Bertazzi et al., 1989b
Zone B—liver 3 1.2 (0.4–3.8)
Zone R—liver 7 0.4 (0.2–0.8)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
10-yr follow-up to 1986—women     Bertazzi et al., 1989b
Zone A—gallbladder (ICD-9 156) 1 12.1 (1.6–88.7)
Zone B—gallbladder (ICD-9 156) 2 3.9 (0.9–16.2)  
Zone R      
Liver 3 0.4 (0.1–1.4)  
Gallbladder (ICD-9 156) 5 1.2 (0.5–3.1)  
Quail Run Mobile Home Cohort   TCDD Hoffman et al., 1986
154 exposed residents vs 155 unexposed area residents 0 nr
SWEDEN      
Swedish fishermen (high consumption of fish with persistent organochlorines)   Organochlorine compounds Svensson et al., 1995a
Incidence      
East coast 1 0.5 (0.0–2.7)  
West coast 9 0.9 (0.4–1.7)  
Mortality      
East coast 6 1.3 (0.5–2.9)  
West coast 24 1.0 (0.6–1.5)  
VIETNAM      
Risk factor for hepatocellular carcinoma in Hanoi   Herbicides Cordier et al., 1993
Military service in South Vietnam for ≥ 10 yrs after 1960 11 8.8 (1.9–41.0)  
CASE-CONTROL STUDIES      
International Case-Control Studies      
Swedish patients (25–80 yrs of age) diagnosed with liver cancer (ICD-7 155, 156) between 1974–June 1981 vs national rates 102 Phenoxy acids, chlorophenols 1.8 (0.9–4.0) Hardell et al., 1984

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; CATI, computer-assisted telephone interview; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; ICDA, International Classification of Diseases, Adapted for Use in the United States; JEM, job–exposure matrix; MCPA, methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratio; PCP, pentachlorophenol; SIR, standardized incidence ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

consistently demonstrated that long-term exposure to TCDD results in the formation of liver adenomas and carcinomas (Knerr and Schrenk, 2006; Walker et al., 2006). Furthermore, TCDD increases the growth of hepatic tumors that are initiated by treatment with a complete carcinogen. Pathologic liver changes have been observed after exposure to TCDD, including nodular hyperplasia and massive inflammatory cell infiltration (Kociba et al., 1978; NTP, 2006; Walker et al., 2006; Yoshizawa et al., 2007); inflammation can be heavily involved in the development and progression of many cancers, including liver cancers (Mantovani et al., 2008). In monkeys treated with TCDD, hyperplasia and an increase in cells that stain positive for alpha-smooth muscle actin have been observed (Korenaga et al., 2007). Postive staining for alpha-smooth muscle actin is thought to be indicative of a process (the epithelial–mesenchymal transition) that is associated with the progression of malignant tumors (Weinberg, 2008). Zucchini-Pascal et al. (2012) showed that TCDD exposure induced an epithelial-to-mesenchymal transition in primary cultured human hepatocytes.

Bile duct hyperplasia (but not tumors) has been reported in rodents following chronic treatment with TCDD (Knerr and Schrenk, 2006; Walker et al., 2006; Yoshizawa et al., 2007). Similarly, monkeys treated with TCDD developed metaplasia, hyperplasia, and hypertrophy of the bile duct (Allen et al., 1977). Hollingshead et al. (2008) showed that TCDD-activated AHR in human breast and endocervical cell lines induces sustained high concentrations of the IL-6 cytokine, which has tumor-promoting effects in numerous tissues, including cholangiocytes; thus, TCDD might promote carcinogenesis in biliary tissue.

TCDD may contribute to tumor progression by inhibiting p53 regulation (phosphorylation and acetylation) triggered by genotoxicants through the increased expression of the metastasis marker AGR2 (Ambolet-Camoit et al., 2010) and a functional interaction between the AHR and FHL2 (Kollara and Brown, 2009). The AHR was also shown to be a regulator of c-Raf and proposed cross-talk between the AHR and the mitogen-activated protein kinase signaling pathway in chemically induced hepatocarcinogenesis (Borlak and Jenke, 2008). TCDD inhibits ultraviolet-C radiation-induced apoptosis in primary rat hepatocytes and Huh-7 human hepatoma cells, which supports the hypothesis that TCDD acts as a tumor promoter by preventing initiated cells from undergoing apoptosis (Chopra et al., 2009). TCDD inhibited the proliferation of isolated mouse oval cells, which are liver precursor cells, via an AHR-dependent pathway, suggesting that these cells are not the precursor for TCDD-induced tumors in the mouse (Faust et al., 2013a).

Elyakim et al. (2010) found that human microRNA miR-191 was upregulated in hepatocellular carcinoma and that miR-191 was upregulated after TCDD treatment and may contribute to the mechanism of the carcinogenic activity of TCDD. Ovando et al. (2010) used toxicogenomics to identify genomic responses that may contribute to the development of hepatotoxicity in rats treated chronically with the AHR ligands, TCDD, or PCB 126. The researchers identified 24, 17, and 7

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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genes that were differentially expressed in the livers of rats exposed to those AHR ligands and in, respectively, human cholangiocarcinoma, human hepatocellular adenoma, and rat hepatocellular adenoma. These findings may help elucidate the mechanisms by which dioxin-like compounds induce their hepatotoxic and carcinogenic effects.

In rodents, TCDD may promote hepatocarcinogenesis through cytotoxicity, chronic inflammation, and liver regeneration and through hyperplastic and hypertrophic growth due to the sustained activation of the AHR (Köhle and Bock, 2007; Köhle et al., 2008). For example, dioxin (TCDD) exposure was reported to increase liver fibrosis in mice via an AHR-dependent pathway. A recent study by Kennedy et al. (2014) addressed two of these issues by using transgenic mouse strains to measure dioxin-induced liver cancers in a model in which TCDD was used as a tumor promoter. One set of experiments showed that the number of TCDD-induced liver tumors was significantly higher in mice that expressed AHR with high binding affinity to TCDD than in an isogenic strain that expressed a low-binding-affinity AHR. A second set of experiments showed that the genetic ablation of inflammatory cytokines reduced significantly TCDD-induced liver tumors. Likewise, genetic ablation of AHR reduced TCDD-induction of the inflammatory cytokines (Pierre et al., 2014). Species differences associated with AHR activation are demonstrated by the divergence in the transcriptomic responses to TCDD in mouse, rat, and human liver (Boutros et al., 2008, 2009; Carlson et al., 2009; Kim et al., 2009), but it should be noted that the in vitro human hepatocyte studies may not reflect the in vivo response of human liver to TCDD. In vitro studies with transformed cell lines and primary hepatocytes cannot replicate the complexity of a tissue response that is important in eliciting the toxic responses observed in vivo (Dere et al., 2006). Finally, a recent study showed that AHR expression is significantly elevated in human liver cancers, although the absolute level of increase is only about 30 to 40 percent, but the biological significance of this observation is not known (Liu et al., 2013).

In a study of gene-expression changes in adult female primary human and rat hepatocytes exposed to TCDD in vitro, Black et al. (2012) used whole-genome microarrays to show that TCDD produced different gene-expression profiles in rat and human hepatocytes both on an ortholog basis (conserved genes in different species) and on a pathway basis. For commonly affected orthologs or signaling pathways, the human hepatocytes were about one-fifteenth as sensitive as rat hepatocytes. Such findings are consistent with epidemiologic studies that show humans to be less sensitive to TCDD-induced hepatotoxicity. A more recent study of gene-expression changes in cultured rat liver cells (the WB-F344 cell line) showed that the AHR agonist PCB126 identified hundreds of dysregulated genes that increased in number as a function of time after exposure from 6 to 72 hours; these included the Wnt and TGF-b signaling pathways, which are involved in tumorogenesis (Faust et al., 2013b).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Chronic exposure of rats to TCDD was associated with fatty liver degeneration and necrosis (Chen X et al., 2012). Another group reported that the hepatotoxic effects of TCDD were exacerbated in mice that had glutathione deficiency (Chen YJ et al., 2012). The combined exposure to PCBs and TCDD induced significant hepatotoxicity in rats (Lu C et al., 2010). Studying the effects of environmental chemicals on nuclear hormone receptors, Shah et al. (2011) demonstrated that in vitro assays for stratifying environmental contaminants can serve as surrogates in combination with rodent toxicity evaluations.

Cacodylic acid (DMAIII and DMAV) is carcinogenic and has been shown to induce renal cancer. In F344/DuCrj rats treated with a mixture of carcinogens for 4 weeks, subsequent exposure to DMA (not indicated whether this was DMAIII or V) via the drinking water for 24 weeks caused tumor promotion in the liver, kidney, urinary bladder, and thyroid gland but inhibited induction of tumors of the nasal passages (Yamamoto et al., 1995). Recent studies have also found that oral exposure of adult mice to 200 ppm DMAV in addition to fetal arsenic exposure can act as a promoter of renal and hepatocellular carcinoma, markedly increasing tumor incidence beyond that produced by fetal arsenic exposure alone (Tokar et al., 2012).

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

Since the previous report the additional literature provides modest evidence of excess liver cancer among Korean veterans and among Chinese foundry workers, although confounding remains a concern. The lack of evidence of association between exposure and this outcome in most occupational and environmental studies does not support this association. Despite the evidence of TCDD’s activity as a hepatocarcinogen in animals, the evidence from epidemiologic studies remains inadequate to link the COIs with hepatobiliary cancers, which has a relatively low incidence in Western populations.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and hepatobiliary cancers.

Pancreatic Cancer

The incidence of pancreatic cancer (ICD-9 157) increases with age. ACS estimated that 24,840 men and 24,120 women would receive a diagnosis of

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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pancreatic cancer in the United States in 2015 and that 20,710 men and 19,850 women would die from it (Siegel et al., 2015). The incidence is higher in men than in women and in blacks than in whites. Other risk factors include family history, diet, and tobacco use. Chronic pancreatitis, obesity, and type 2 diabetes are also associated with an increased risk of pancreatic cancer (ACS, 2013a). The average annual incidence of pancreatic cancer is shown in Table 8-3.

Conclusions from VAO and Previous Updates

Update 2006 considered pancreatic cancer independently for the first time. Prior updates developed tables of results for pancreatic cancer but reached conclusions about the adequacy of the evidence of its association with herbicide exposure in the context of gastrointestinal tract cancers. The committee responsible for VAO concluded that there was limited or suggestive evidence of no association between exposure to the herbicides used by the US military in Vietnam and gastrointestinal tract tumors, including pancreatic cancer. The committee responsible for Update 2006 concluded that there was not enough evidence on each of the COIs to sustain that negative conclusion for any of the cancers in the gastrointestinal group and that, because these various types of cancer are generally regarded as separate disease entities, the evidence on each should be evaluated separately. Pancreatic cancer was thus reclassified into the default category of inadequate or insufficient evidence of an association.

In reviewing the existing evidence concerning an association between herbicide exposure and pancreatic cancer, the committee for Update 2006 noted a report of increased rates of pancreatic cancer in US female Vietnam nurse veterans (Dalager et al., 1995a) but concluded that it alone did not constitute limited or suggestive evidence of an association. That increase persisted in the follow-up study of the American female veterans (Cypel and Kang, 2008), but committees for subsequent updates have concurred with the decision of the committee for Update 2006. Table 8-8 summarizes the results of the relevant studies concerning pancreatic cancer.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies Among 2,783 New Zealand veterans who served in Vietnam between 1964 and 1975, McBride et al. (2013) reported that pancreatic cancer mortality was in deficit in the cohort in comparison to the general population of New Zealand (SMR = 0.67, 95% CI 0.22–1.56, based on five deaths). Pancreatic cancer incidence was also lower than expected (SIR = 0.72, 95% CI 0.26–1.57, based on six cases). The wide confidence intervals resulting from the small number of observed cases make these results largely uninformative.

Kang et al. (2014) updated the vital status of 4,734 women who served in the US Army, Navy, Air Force, or Marines in Vietnam between July 4, 1965,

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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TABLE 8-8 Selected Epidemiologic Studies—Pancreatic Cancer (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Mortality
1965–2000 5 1.0 (0.3–3.5) Boehmer et al., 2004
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1982     Breslin et al., 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 82 0.9 (0.6–1.2)  
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 18 1.6 (0.5–5.8)  
US VA Cohort of Female Vietnam-era Veterans served in Vietnam (n = 4,586; nurses only = 3,690); non-deployed (n = 5,325; nurses only = 3,282)   All COIs  
Mortality
Through 2010—Vietnam-era veterans 50 1.7 (1.0–3.1) Kang et al., 2014
Vietnam nurses only 35 2.1 (1.0–4.3)
Through 2004—Vietnam-era veterans 17 2.1 (1.0–4.5) Cypel and Kang, 2008
Vietnam-veteran nurses 14 2.5 (1.0–6.0)
Through 1991—Vietnam-era veterans 7 2.8 (0.8–10.2) Dalager et al., 1995a
Vietnam nurses only 7 5.7 (1.2–27.0)
Through 1987—Vietnam-era veterans (Vietnam nurses not reported separately) 5 2.7 (0.9–6.2) Thomas et al., 1991
State Studies of US Vietnam Veterans
Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs non-deployed 14 1.0 (0.6–1.7) Visintainer et al., 1995
Non-black 9 0.7 (0.3–1.3)  
Black 5 9.1 (2.9–21.2)  
923 White male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans 4 nr Anderson et al., 1986a,b
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 86 1.2 (0.9–1.4) ADVA, 2005b
Navy 14 0.9 (0.5–1.5)  
Army 60 1.2 (0.9–1.5)  
Air Force 12 1.3 (0.7–2.3)  
Mortality
All branches, return–2001 101 1.2 (1.0–1.5) ADVA, 2005a
Navy 18 1.0 (0.6–1.6)  
Army 71 1.3 (1.0–1.6)  
Air Force 11 1.1 (0.5–1.8)  
1980–1994 38 1.4 (0.9–1.8) CDVA, 1997a
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence
1982–2000 17 2.5 (1.0–6.3) ADVA, 2005c
Mortality
1966–2001 19 3.1 (1.3–8.3) ADVA, 2005c
1982–1994 6 1.5 (nr) CDVA, 1997b
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008) 6 0.7 (0.3–1.6)  
Mortality (1988–2008) 5 0.7 (0.2–1.6)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—pancreas (C25) categorized high (n = 100) vs low (n = 84) 100 1.1 (0.8–1.5) Yi and Ohrr, 2014
Mortality (1992–2005)—pancreas (C25) categorized high (n = 141) vs low (n = 114)     Yi et al., 2014b
HR per unit of log EOI (n = 180,639) 255 1.0 (1.0–1.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Mortality 1939–1992 47 0.9 (0.7–1.3) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 30 1.0 (0.7–1.4)
7,553 not exposed to highly chlorinated PCDDs 16 0.9 (0.5–1.4)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort 26 1.1 (0.7–1.6) Saracci et al., 1991
British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)   MCPA  
Mortality through 1983 9 0.7 (0.3–1.4) Coggon et al., 1986
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)   Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP  
Incidence
Incidence 1943–1982     Lynge, 1985
Men 3 0.6 (nr)  
Women 0 nr  
Mortality
Mortality 1955–2006 7 1.2 (0.8–1.7) Boers et al., 2012
Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)   Dioxins, 2,4,5-T, 2,4,5-TCP  
Mortality 1955–2006 (HRs for lagged TCDD plasma levels) 6 0.9 (0.5–1.6) Boers et al., 2012
Mortality 1955–2006 4 0.9 (0.2–4.2) Boers et al., 2010
Mortality 1955–1991 4 2.5 (0.7–6.3) Hooiveld et al., 1998
Mortality 1955–1985 3 2.9 (0.6–8.4) Bueno de Mesquita et al., 1993
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Dutch production workers in Plant B (414 men exposed during production 1965–1986; 723 unexposed) (in IARC cohort)   2,4-D; MCPA; MCP; highly chlorinated dioxins unlikely  
Mortality 1965–2006 1 nr Boers et al., 2010
Mortality 1965–1986 0 0.0 (0.0–10.9) Bueno de Mesquita et al., 1993
German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 mo in 1951–1976) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4,5-TCP  
Mortality 1951–1992 0 Becher et al., 1996
German Production Workers at Bayer Plant in Dormagen (520 men working > 1 mo in 1965–1989) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Mortality 1965–1989 0 Becher et al., 1996
German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 mo in 1957–1987) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Mortality 1956–1989 2 1.7 (0.2–6.1) Becher et al., 1996
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)   Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP  
Mortality 1952–2007 (ICD-9 157) 10 0.9 (0.4–1.7) Manuwald et al., 2012
Men 7 0.9 (0.4–1.9)
Women 3 1.0 (0.2–2.9)  
Mortality 1952–1989 2 0.6 (0.1–2.3) Becher et al., 1996
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality 1969–2004     McBride et al., 2009a
Ever-exposed workers 3 1.3 (0.3–3.9)
Never-exposed workers 0 0.0 (0.0–4.9)  
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)      
Mortality 1969–2000     ’t Mannetje et al., 2005
Phenoxy herbicide producers (men, women) 3 2.1 (0.4–6.1)
Phenoxy herbicide sprayers (> 99% men) 0 0.0 (0.0–2.1)  
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Through 1993 16 1.0 (0.6–1.6) Steenland et al., 1999
Through 1987 10 0.8 (0.4–1.6) Fingerhut et al., 1991
≥ 1-yr exposure, ≥ 20-yr latency 4 1.0 (0.3–2.5)
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (in IARC and NIOSH cohorts)   2,4,5-T; 2,4,5-TCP  
1942–2003 (n = 1,615) 6 0.7 (0.2–1.4) Collins et al., 2009b Ruder and Yiin, 2011
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP
1940–2005 (n = 2,122) 18 1.3 (0.8–2.0)  
PCP and TCP (n = 720) 6 1.4 (0.5–3.0)  
PCP (no TCP) (n = 1,402) 12 1.3 (0.7–2.2)  
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3) 2 0.4 (0.1–1.5) Burns CJ et al., 2011
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) 5 1.1 (0.3–2.5) Collins et al., 2009c
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality 1940–1989 (n = 770)     Ramlow et al., 1996
0-yr latency 2 0.7 (0.1–2.7)
15-yr latency 2 0.9 (0.1–3.3)  
Other Studies of Industrial Workers (not related to IARC or NIOSH phenoxy cohorts)      
1,412 white male US flavor and fragrance chemical plant workers (1945–1965) 6 Dioxin, 2,4,5-T
1.4 (nr)
Thomas, 1987
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Never 67 0.8 (0.7–1.1)  
Ever 69 1.1 (0.9–1.4)  
Danish paper workers     Rix et al., 1998
Men 30 1.2 (0.8–1.7)  
Women 2 0.3 (0.0–1.1)  
New Hampshire pulp and paper workers, 883 white men working ≥ 1 yr, mortality through July 1985 9 1.9 (0.9–3.6) Henneberger et al., 1989
United Paperworkers International, 201 white men employed ≥ 10 yr and dying 1970–1984 1 0.4 (0.0–2.1) Solet et al., 1989
Northwestern US paper and pulp workers—5 mills in Washington, Oregon, and California, 3,523 worked ≥ 1 yr 1945–1955, mortality through March 1977 4 90% CI 0.3 (0.1–0.8) Robinson et al., 1986
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
DENMARK
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Men
Self-employed 137 0.6 (p < 0.05)  
Employee 23 0.6 (p < 0.05)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Women      
Self-employed 7 1.2 (nr)  
Employee 4 1.3 (nr)  
Family workers 27 0.7 (p < 0.05)  
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 2000 5 1.2 (0.4–2.7) Swaen et al., 2004
Through 1987 3 2.2 (0.4–6.4) Swaen et al., 1992
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401) 32 0.7 (0.5–1.0) Torchio et al., 1994
Italian rice growers with documented phenoxy use (n = 1,487)   Phenoxy herbicides Gambini et al., 1997
  7 0.9 (0.4–1.9)  
NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of incident pantreatic cancer cases vs remainder of 19,904 men with any incident cancer   Herbicides Reif et al., 1989
Forestry workers (n = 134) 6 1.8 (0.8–4.1)  
Aged 20–59 0  
Aged ≥ 60 6 2.4 (1.1–5.4)  
Sawmill workers (n = 139)   Herbicides, chlorophenols  
  2 0.5 (0.1–1.8)  
SWEDEN
Incident pancreatic cancer cases 1961–1973 with agriculture as economic activity in 1960 census 777 99% CI 0.8 (0.8–0.9) Wiklund, 1983
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides
PCMRs
Blair et al., 1993
Men      
Whites (n = 119,648) 1,133 1.1 (1.1–1.2)  
Nonwhites (n = 11,446) 125 1.2 (1.0–1.4)  
Women      
Whites (n = 2,400) 23 1.0 (0.6–1.5)  
Nonwhites (n = 2,066) 16 0.7 (0.4–1.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence      
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Private applicators 80 0.7 (0.6–0.9)  
Commercial applicators 5 1.0 (0.3–2.3)  
Spouses 32 0.7 (0.5–1.0)  
Nested case-control (applicators, spouses combined)     Andreotti et al., 2009
2,4-D 48 0.9 (0.5–1.5)  
Dicamba 23 0.9 (0.6–1.6)  
Enrollment through 2002     Alavanja et al., 2005
Private applicators 46 0.7 (0.5–1.0)
Spouses of private applicators (> 99% women) 20 0.9 (0.6–1.4)  
Commercial applicators 3 1.1 (0.2–3.2)  
Mortality      
Enrollment through 2007, vs state rates     Waggoner et al., 2011
Applicators (n = 1,641) 171 0.8 (0.7–1.0)
Spouses (n = 676) 1 nr  
Enrollment through 2000, vs state rates     Blair et al., 2005a
Private applicators (men and women) 29 0.6 (0.4–0.9)
Spouses of private applicators (> 99% women) 10 0.7 (0.3–1.2)  
US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 of pancreatic cancer   Herbicides  
Agricultural extension agents 21 1.3 (0.8–1.9) Alavanja et al., 1988
Forest conservationists 22 1.5 (0.9–2.3) Alavanja et al., 1989
Florida Licensed Pesticide Applicators (common phenoxy use assumed but not documented; had been listed by Blair et al., 1983)   Herbicides  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Pesticide applicators in Florida licensed 1965–1966 (n = 3,827)—mortality through 1976   Herbicides Blair et al., 1983
Any pesticide (dose–response by length of licensure)   Expected exposed cases  
  4 4.0  
White Male Residents of Iowa—pancreatic cancer on death certificate, usual occupation: farmers vs not   Herbicides  
> 20 yrs old when died 1971–1978—PMR 416 1.1 (nr) Burmeister, 1981
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group)   TCDD  
Incidence
20-yr follow-up to 1996—men and women      
Zone A 1 1.2 (0.2–8.2) Pesatori et al., 2009
Zone B 3 0.6 (0.2–1.7)
Zone R 38 1.0 (0.7–1.4)  
10-yr follow-up to 1991—men     Pesatori et al., 1992
Zone A, B 2 1.0 (0.3–4.2)
10-yr follow-up to 1991—women     Pesatori et al., 1992
Zone A, B 1 1.6 (0.2–12.0)
Mortality      
25-yr follow-up to 2001—men and women     Consonni et al., 2008
Zone A 2 1.2 (0.3–4.7)
Zone B 5 0.5 (0.2–1.1)  
Zone R 76 1.0 (0.7–1.7)  
20-yr follow-up to 1996     Bertazzi et al., 2001
Zones A and B—men 4 0.7 (0.3–1.9)
Zones A and B—women 1 0.3 (0.0–2.0)  
15-yr follow-up to 1991—men     Bertazzi et al., 1997
Zone A 1 1.9 (0.0–10.5)
Zone B 2 0.6 (0.1–2.0)  
Zone R 20 0.8 (0.5–1.2)  
15-yr follow-up to 1991—women     Bertazzi et al., 1997
Zone B 1 0.5 (0.0–3.1)
Zone R 11 0.7 (0.4–1.3)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
10-yr follow-up to 1986—men     Bertazzi et al., 1989a,b
Zone A, B, R 9 0.6 (0.3–1.2)
Zone B 2 1.1 (0.3–2.7)  
10-yr follow-up to 1986—women     Bertazzi et al., 1989a
Zone A, B, R 4 1.0 (0.3–2.7)
SWEDEN
Swedish fishermen (high consumption of fish with persistent organochlorines)   Organochlorine compounds Svensson et al., 1995a,b
Incidence
East coast 4 0.6 (0.2–1.6)  
West coast 37 1.0 (0.7–1.4)  
Mortality
East coast 5 0.7 (0.2–1.6)  
West coast 33 0.8 (0.6–1.2)  
CASE-CONTROL STUDIES
International Case-Control Studies      
UK men, 18–35 yrs of age from counties with particular chemical manufacturing—mortality   Herbicides, Chlorophenols Magnani et al., 1987
Herbicides nr 0.7 (0.3–1.5)  
Chlorophenols nr 0.8 (0.5–1.4)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; PM, proportionate mortality; PMR, proportionate mortality ratio; SIR, standardized incidence ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; UK, United Kingdom; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

and March 28, 1973. Using the cohort of Vietnam-era veterans who remained in the United States as the referent yielded an increased risk of pancreatic cancer mortality (RR = 1.74, 95% CI 0.97–3.14) for those deployed to Vietnam. Further analyses restricted to female nurses, again using the non-deployed cohort as the referent, yielded a slightly higher risk of mortality from pancreatic cancer (RR = 2.07, 95% CI 1.00–4.25) for those nurses deployed to Vietnam.

Among 185,265 Korean male Vietnam veterans, Yi (2013) found no evidence of excess pancreatic cancer [ICD-10 C25] risk in comparison to the general population (SIR = 0.92, 95% CI 0.80–1.06). In the internal comparison analysis of high- versus low-exposure opportunity groups, Yi and Ohrr (2014) reported a small excess of pancreatic cancer incidence (RR = 1.12, 95% CI 0.83–1.51). Yi et al. (2014b) reported little indication of increased risk of mortality from pancreatic cancers in association with herbicide exposure from either the internal comparison of the high- and low-exposure opportunity groups (RR = 1.15, 95% CI 0.89–1.48) or the analysis of the individual EOI scores (RR = 1.03, 95% CI 0.97–1.09).

Occupational, Environmental, and Case-Control Studies No occupational, environmental, or case-control studies of exposure to the COIs and pancreatic cancer have been published since Update 2012.

Biologic Plausibility

Long-term animal studies have examined the effect on tumor incidence of exposure to each of the COIs: 2,4-D and 2,4,5-T (Charles et al., 1996), TCDD (Walker et al., 2006), picloram (Stott et al., 1990), and DMA (Wanibuchi et al., 1996, 2004). No increase in the incidence of pancreatic cancer in laboratory animals after the administration of cacodylic acid, 2,4-D, or picloram has been reported. A 2-year study of female rats reported increased incidences of pancreatic adenomas and carcinomas after treatment at the highest dose of TCDD (100 ng/kg per day) (Nyska et al., 2004). Other studies have observed chronic active inflammation, acinar-cell vacuolation, and an increase in the proliferation of the acinar cells surrounding the vacuolated cells (Yoshizawa et al., 2005b). As previously discussed, chronic inflammation and hyperproliferation are closely linked to the formation and progression of cancers, including cancers of the pancreas (Hahn and Weinberg, 2002; Mantovani et al., 2008). Metaplastic changes in the pancreatic ducts were also observed in female monkeys treated with TCDD (Allen et al., 1977).

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

The large excess of pancreatic cancers in female Vietnam veterans versus their non-deployed counterparts that was observed by Thomas et al. (1991) and

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Dalager et al. (1995a) was replicated in a study by Cypel and Kang (2008), who found a significant increase in all female Vietnam veterans and in the nurse subset. The recent report by Kang et al. (2014) was also consistent with these findings. The committee responsible for Update 2006 reported a higher incidence of and mortality from pancreatic cancer in deployed Australian National Service veterans than in non-deployed veterans (ADVA, 2005c). The current update notes no excess among New Zealand veterans (McBride et al., 2013). The Korean study of Vietnam veterans suggests a small and insignificant association between estimated herbicide exposure and pancreatic cancer (Yi et al., 2014b). A limitation of all the veteran studies considered has been the lack of control for the effect of smoking. In the 31 female and 62 male cases in the AHS case-control study considered in Update 2010 (Andreotti et al., 2009), the risk of pancreatic cancer was not associated with 2,4-D exposure, so the relative increase in the AHS cohort overall (Waggoner et al., 2011) would most certainly not be attributable to 2,4-D exposure. No increase in risk has been reported in US male Vietnam veterans. The studies of production cohorts provide limited support for an association. Overall, however, the existing evidence does not support a conclusion that exposures to the COIs are associated with the occurrence of pancreatic cancer.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and pancreatic cancer.

LARYNGEAL CANCER

ACS estimated that 10,720 men and 2,840 women would receive diagnoses of cancer of the larynx (ICD-9 161) in the United States in 2015 and that 2,890 men and 750 women would die from it (Siegel et al., 2015). Those numbers constitute a little more than 0.8 percent of new cancer diagnoses and 0.6 percent of cancer deaths. The incidence of cancer of the larynx increases with age, and it is more common in men than in women, with a sex ratio in the United States of about 4:1 in people 50 to 64 years old. The average annual incidence of laryngeal cancer is shown in Table 8-9.

Exposure to tobacco smoke, paint fumes, metalworking fluids, and asbestos have been associated with laryngeal cancer, as has alcohol and occupational exposures to wood dust and employment in the petroleum, plastics, and textile industries (ACS, 2012a; IOM, 2006a).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-9 Average Annual Cancer Incidence (per 100,000) of Laryngeal Cancer in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Men 19.9 19.3 36.5 24.7 24.5 41.1 29.9 30.1 45.1
Women 3.7 3.7 5.5 4.7 4.8 7.6 5.2 5.5 7.4

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to at least one of the COIs and laryngeal cancer on the basis of the evidence discussed below in the section “Synthesis.” Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, Update 2010, and Update 2012 did not change that conclusion.

Table 8-10 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

There have been no studies of US Vietnam veterans that have evaluated exposure to the COIs and laryngeal cancer since Update 2012. However, two cohort studies of Vietnam War veterans (a majority of them male) from New Zealand and Korea have recently reported on cancer incidence and mortality for larynx cancer.

Among 2,783 New Zealand veterans who served in Vietnam between 1964 and 1975, McBride et al. (2013) reported a total of five incident cases and two deaths from larynx cancers, which were ascertained during the follow-up of this cohort from 1988 through 2008. The risk of mortality from cancer of the larynx (SMR = 2.00, 95% CI 0.23–7.39, based on two deaths) was increased compared to expectations based on national rates. Laryngeal cancer incidence was slightly greater than expected (SIR = 1.18, 95% CI 0.38–2.77, based on five cases). The CIs for both point estimates were wide and imprecise due to the few cases observed. The study lacked information on potential confounding factors, including smoking and alcohol. However, both the incidence of and mortality from lung cancer were not elevated in this cohort, and thus potential confounding by smoking is unlikely.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-10 Selected Epidemiologic Studies—Laryngeal Cancer (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Mortality
1965–2000 0 0.0 (nr) Boehmer et al., 2004
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1988 50 1.3 (nr) Watanabe and Kang, 1996
Army, deployed (n = 27,596) vs non-deployed (n = 31,757) 50 1.4 (p < 0.05)
Marine Corps, deployed (n = 6,237) vs non-deployed (n = 5,040) 4 0.7 (nr)  
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 97 1.5 (1.2–1.8) ADVA, 2005b
Navy 21 1.5 (0.9–2.1)
Army 69 1.6 (1.2–1.9)  
Air Force 7 0.8 0.3–1.7)  
Mortality
All branches, return–2001 28 1.1 (0.7–1.5) ADVA, 2005a
Navy 6 1.1 (0.4–2.4)
Army 19 1.1 (0.7–1.7)  
Air Force 3 0.9 (0.2–2.5)  
1980–1994 12 1.3 (0.7–2.2) CDVA, 1997a
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence
1982–2000 8 0.7 (0.2–1.6) ADVA, 2005c
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality
1966–2001 2 0.4 (0.0–2.4) ADVA, 2005c
1982–1994 0 0 (0– > 10) CDVA, 1997b
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008) 5 1.2 (0.4–2.8)  
Mortality (1988–2008) 2 2.0 (0.2–7.4)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—larynx (C32) categorized high (n = 87) vs low (n = 67) 87 1.2 (0.9–1.7) Yi and Ohrr, 2014
Mortality (1992–2005)—larynx (C32) categorized high (n = 50) vs low (n = 32)   1.3 (0.8–2.0) Yi et al., 2014b
HR per unit of log EOI (n = 180,639) 82 1.1 (1.0–1.3)  
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Mortality 1939–1992 21 1.6 (1.0–2.5) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 15 1.7 (1.0–2.8)  
7,553 not exposed to highly chlorinated PCDDs 5 1.2 (0.4–2.9)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort 8 1.5 (0.6–2.9) Saracci et al., 1991
British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)   MCPA  
Mortality through 1983 4 1.7 (0.5–4.5) Coggon et al., 1986
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)   Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP  
Mortality 1952–2007 7 3.5 (1.4–7.2) Manuwald et al., 2012
Men 6 3.8 (1.4–8.2)
Women 1 2.5 (0.0–13.9)  
Mortality 1952–1989—stats on men only, 1,184 (tables all for 1,148 men, not necessarily German nationals)
vs national rates (also vs gas workers); same observation period as Becher et al., 1966
2 2.0 (0.2–7.1) Manz et al., 1991
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Ever-exposed workers 1 2.5 (0.1–14.0)
Never-exposed workers 1 9.7 (0.2–54.3)  
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)      
Mortality 1969–2000 0 nr ’t Mannetje et al., 2005
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Through 1987 7 2.1 (0.8–4.3) Fingerhut et al., 1991
≥ 1-yr exposure, ≥ 20-yr latency 3 2.7 (0.6–7.8)
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (in IARC and NIOSH cohorts)   2,4,5-T; 2,4,5-TCP  
1942–2003 (n = 1,615) 3 1.3 (0.3–3.9) Collins et al., 2009b
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
1940–2005 (n = 2,122) 5 1.5 (0.5–3.4)  
PCP and TCP (n = 720) 1 0.9 (0.0–5.1)  
PCP (no TCP) (n = 1,402) 4 1.7 (0.5–4.3)  
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3) 4 1.1 (0.3–2.9) Burns CJ et al., 2011
Through 1982 (n = 878) 1 3.0 (0.0–16.8) Bond et al., 1988
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) 2 1.7 (0.2–6.2) Collins et al., 2009c
Mortality 1940–1989 (n = 770) 2 2.9 (0.3–10.3) Ramlow et al., 1996
0-yr latency 2 2.9 (0.4–10.3)
15-yr latency 1 nr  
OCCUPATIONAL—PAPER AND PULP TCDD WORKERS      
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Never 18 0.9 (0.5–1.5)  
Ever 20 1.2 (0.8–1.9)  
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
DENMARK
Danish gardeners (n = 3,124) exposed to pesticides 9 0.7 (0.3–1.4) Kenborg et al., 2012
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality 1970–1986 (n = 23,401) 25 0.5 (0.3–0.7) Torchio et al., 1994
Italian rice growers with documented phenoxy use (n = 1,487)   Phenoxy herbicides Gambini et al., 1997
  7 0.9 (0.4–1.9)  
NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of 303 incident laryngeal cancer cases vs remainder of 19,904 men with any incident cancer   Herbicides Reif et al., 1989
Forestry workers (n = 134) 2 1.1 (0.3–4.7)  
SWEDEN
Swedish lumberjacks—Used phenoxys 1954–1967, Incidence 1958–1992     Thörn et al., 2000
Exposed (n = 154)      
Foremen (n = 15) 0 nr  
THE NETHERLANDS
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 2000 1 1.0 (0.0–5.1) Swaen et al., 2004
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Men
Whites (n = 119,648) 162 0.7 (0.6–0.8)  
Nonwhites (n = 11,446) 32 1.1 (0.8–1.5)  
Women
Whites (n = 2,400) 0 nr (0.0–3.3)  
Nonwhites (n = 2,066) 0 nr (0.0–4.8)  
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group)   TCDD  
Mortality
25-yr follow-up to 2001—men and women, all respiratory cancers (ICD-9 160–165) excluding lung cancers (ICD-9 162)     Consonni et al., 2008
Zone A 0 nr  
Zone B ≤ 8 nr  
Zone R ≤ 49 nr  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
20-yr follow-up to 1996—men and women, all respiratory cancers (ICD-9 160–165) excluding lung cancers (ICD-9 162)     Bertazzi et al., 2001
Zone A 0 nr  
Zone B 8 nr  
15-yr follow-up to 1991—men     Bertazzi et al., 1997, 1998
Zone B 6 nr
Zone R 32 nr  
15-yr follow-up to 1991—women     Bertazzi et al., 1997, 1998
Zone B 0 nr
Zone R 6 nr  
Ecological Study of Residents of Chapaevsk, Russia   Dioxin Revich et al., 2001
Incidence— Crude incidence rate in 1998 vs
Men
Regional (Samara)   0  
National (Russia)   11.3  
Women      
Regional (Samara)   0  
National (Russia)   0.4  
Mortality—1995–1998 (SMR vs regional rates)
Men 13 2.3 (1.2–3.8)  
Women 1 0.1 (0.0–0.6)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Several recent publications examined larynx cancer incidence (Yi, 2013; Yi and Ohrr, 2014) and cancer mortality (Yi et al., 2014b) in the Korean Veterans Health Study. A total of 157 incident cases of larynx cancer [ICD-10 C32] were identified in this cohort during follow-up. When compared to the general Korean population, the cohort showed no excess larynx cancer risk (SIR = 0.90, 95% CI 0.77–1.06) (Yi, 2013). Yi and Ohrr (2014) reported a modest increased risk of larynx cancer (RR = 1.21, 95% CI 0.87–1.69), albeit not statistically significant, despite the large number of cases (n = 87) in the high exposure category. The mortality experience of this cohort of Korean veterans of the Vietnam War was also studied. Deaths due to cancer of the larynx were positively associated with the log of EOI scores (HR = 1.13, 95% CI 1.0–1.28, based on 82 deaths), and a comparison of the high- to low-exposure groups yielded a modestly elevated risk (HR = 1.28, 95% CI 0.80–2.03, based on 50 deaths from larynx cancer in the high-exposure category). Adjustments were not made for smoking or drinking habits, but an analysis of the survey data from much of the cohort established that these behaviors did not differ systematically with opportunity for herbicide exposure (Yi et al., 2013b).

Occupational, Environmental, and Case-Control Studies

No occupational and environmental cohort studies, or case-control studies of exposure to the COIs and laryngeal cancer have been published since Update 2012.

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the COIs on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). No increase in the incidence of laryngeal cancer in laboratory animals after the administration of any of the COIs has been reported.

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

The original VAO committee reviewed five studies that presented data on laryngeal cancers separately (Bond et al., 1988; Coggon et al., 1986; Fingerhut et al., 1991; Manz et al., 1991; Saracci et al., 1991). It concluded that “although the numbers are too small to draw strong conclusions, the consistency of a mild increase in relative risk is suggestive of an association for laryngeal cancer.” The weight of evidence with regard to laryngeal cancer has increased since the original VAO committee review. Notable among epidemiological studies

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

contributing to the evidence are studies of workers employed in manufacturing herbicides potentially contaminated with TCDD. An IARC study (Kogevinas et al., 1997) that included essentially all of the phenoxy herbicide production workers who previously had been studied found an elevated rate of laryngeal cancers in workers who were exposed to any phenoxyacetic acid herbicide or chlorophenol (SMR = 1.6, 95% CI 1.0–2.5, based on 21 deaths), especially workers who were exposed to TCDD or higher-chlorinated dioxins (SMR = 1.7, 95% CI 1.0–2.8, based on 15 deaths). Ongoing updates have continued to indicate an increase in larynx cancer in the occupational cohorts making up this IARC cohort.

An environmental study (Revich et al., 2001) of residents of Chapaevsk, Russia, which was heavily contaminated by many industrial pollutants, including dioxin, showed an association with laryngeal cancer in men (RR = 2.3, 95% CI 1.2–3.8). Analyses of Seveso have not reported findings for laryngeal cancer.

With regard to veteran studies, a positive association was found in the study of veterans in Australia that compared mortality from laryngeal cancer with that in the general population (ADVA, 2005a) but not in the study that compared Australian veterans of the Vietnam conflict with non-deployed soldiers (ADVA, 2005c). In contrast, Watanabe and Kang (1996) found a significant 40 percent excess of mortality from laryngeal cancer in Army personnel deployed to the Vietnam theater. The Ranch Hand study was not large enough to have sufficient power to detect an association if one existed. The Korean Vietnam Veterans Health Study reviewed in this update identified a large number of incident cases (n = 157) and deaths (n = 82) from larynx cancer during a 20-year follow-up (Yi, 2013; Yi and Ohrr, 2014b; Yi et al., 2014a,b). Despite the large sample size, the modestly increased risks of both incidence and mortality from larynx cancer were not statistically significant.

Overall, the majority of reports suggest an increased risk of laryngeal cancer although individual studies often are based on small numbers of cases and are not controlled for smoking. In addition, there is evidence of an excess risk of laryngeal cancer among those who experienced chloracne—a marker of high exposure. The literature provides a reasonable level of consistency with regard to evidence of a moderate increase in relative risk of laryngeal cancer. In larger occupational studies with good exposure characterizations that focus on the COIs, the associations are generally strong for laryngeal cancer, while studies of Vietnam veterans provide modest associations.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to at least one COI and laryngeal cancer.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

LUNG CANCER

Lung cancer (carcinoma of the lung or bronchus, ICD-9 162.2–162.9) is the second most common diagnosed non-skin cancer and the leading cause of cancer deaths in the United States. ACS estimated that 115,610 men and 105,590 women would receive diagnoses of lung cancer in the United States in 2015 and that about 86,380 men and 71,660 women would die from it (Siegel et al., 2015). Those numbers represent roughly 13 percent of new cancer diagnoses and 27 percent of cancer deaths in 2015. The principal types of lung neoplasms are identified collectively as bronchogenic carcinoma and carcinoma of the lung. Cancer of the trachea (ICD-9 162.0) is often grouped with cancers of the lung and bronchus under ICD-9 16.2, but it is a rare cancer. The lung is also a common site of metastatic tumors from other organ sites; in this chapter, however, we are only addressing primary lung cancer. The incidence of lung cancer increases with age and there is a racial/ethnic disparity of lung cancer risk; the incidence is consistently higher in black men than in white men or in women (either black or white) (NCI, 2015). The average annual incidence of lung cancer in the United States is shown in Table 8-11.

The Centers for Disease Control and Prevention’s (CDC’s) 2014 Surgeon General report estimates that 82 percent of lung cancer deaths are attributable to cigarette smoking (CDC, 2014). Smoking is a major risk factor for lung cancer and increases the risk of all histologic types of this disease, but the associations with squamous-cell and small-cell carcinomas are the strongest. Other risk factors include exposure to asbestos, uranium, vinyl chloride, nickel chromates, coal products, mustard gas, chloromethyl ethers, gasoline, diesel exhaust, and inorganic arsenic. The latter statement does not imply that cacodylic acid, which is a metabolite of inorganic arsenic, can be assumed to be a risk factor for lung cancer. Important environmental risk factors include exposure to secondary tobacco smoke and radon (ACS, 2013a).

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to at least one COI and lung

TABLE 8-11 Average Annual Incidence (per 100,000) of Lung and Bronchial Cancers in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Men 167.6 163.7 261.6 288.0 289.7 390.4 401.4 409.7 494.9
Women 123.9 129.8 138.9 216.8 230.3 222.2 290.8 311.2 269.5

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, Update 2010, and Update 2012 did not change that conclusion.

Table 8-12 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

Kang et al. (2014) reported on lung cancer mortality in an update of vital status through 2010 of female Vietnam-era veterans who served in Vietnam (n = 4,734) or who remained in the United States (n = 5,313). A total of 95 and 100 deaths from respiratory cancers were ascertained in these two groups of female veterans, respectively, during follow-up. In comparison to the non-deployed women (internal comparison analysis), respiratory cancer mortality was not associated with service in Vietnam for all the women (RR = 1.12, 95% CI 0.84–1.50) or for just the nurses (RR = 0.94, 95% CI 0.66–1.32).

McBride et al. (2013) reported on 2,783 male veterans from New Zealand, who served in Vietnam between 1964 and 1972 and were followed for lung cancer incidence and mortality through 2008. A total of 58 incident cases and 50 deaths from lung cancers were identified in this cohort. When compared to the general male population of New Zealand, there were no excess risks for lung cancer incidence (SIR = 1.13, 95% CI 0.86–1.47) or lung cancer mortality (SMR = 1.15, 95% CI 0.85–1.51).

In the Korean Veterans Health Study, a total of 1,223 incident cases and 1,170 deaths from cancers of the lung and bronchus were identified during follow-up. Compared to the general Korean population, there was no excess lung cancer risk (SIR = 0.99, 95% CI 0.93–1.05) in the entire cohort (Yi, 2013). Comparing veterans with higher opportunity scores to those in the group with lower scores, Yi and Ohrr (2014) reported a modest elevation in lung cancer incidence (HR = 1.12, 95% CI 1.00–1.27, based on 649 incident cases in the higher exposure category). With regard to cancer mortality for lung and bronchus, Yi et al. (2014b) also reported modestly increased lung cancer mortality for the high- versus low-exposure opportunity groups (HR = 1.15, 95% CI 1.02–1.30, based on 673 lung cancer deaths in the higher herbicide exposure category). Information on smoking habits was not available for this cohort during follow-up through 2003, and thus the modest associations could be due to confounding by smoking. Yi et al. (2013b) collected information on cigarette smoking via self-reported questionnaires from 114,562 Korean Vietnam veterans who were alive in July 2004 and found that the prevalence of smoking was relatively high in this cohort (45 percent and 36 percent were former or current smokers, respectively). The distribution of smoking, however, was similar between veterans in the high- and low-exposure groups (Yi et al., 2013b).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-12 Selected Epidemiologic Studies—Lung, Bronchus, or Trachea Cancer (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam-Veterans
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)   All COIs  
Incidence
1982–2003—White SEA comparison veterans only (n = 1,482). Serum TCDD (pg/g) based on model with exposure variable loge(TCDD)     Pavuk et al., 2005
Per unit increase of –loge(TCDD) (pg/g) Quartiles (pg/g): 36 1.7 (0.9–3.2)  
0.4–2.6 6 1.0 (nr)  
2.6–3.8 8 1.1 (0.3–3.4)  
3.8–5.2 9 1.2 (0.4–3.5)  
> 5.2 13 1.9 (0.7–5.5)  
Number of years served in SEA (per year of service)      
Quartiles (years in SEA): 36 1.1 (0.9–1.2)  
0.8–1.3 8 1.0 (nr)  
1.3–2.1 4 0.5 (0.2–1.8)  
2.1–3.7 11 0.7 (0.3–2.0)  
3.7–16.4 13 0.7 (0.3–2.0)  
Through 1999—White subjects vs national rates     Akhtar et al., 2004
Ranch Hand veterans (n = 1,189) 33 1.1 (0.8–1.6)
With tours between 1966–1970 26 1.1 (0.7–1.6)  
SEA comparison veterans (n = 1,776) 48 1.2 (0.9–1.6)  
With tours between 1966–1970 37 1.2 (0.9–1.6)  
Mortality
Through 1999—White subjects vs national rates     Akhtar et al., 2004
Ranch Hand veterans (n = 1,189) 21 0.9 (0.6–1.3)
SEA comparison veterans (n = 1,776) 38 1.1 (0.8–1.5)  
US VA Cohort of Army Chemical Corps—Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 non-deployed) serving during Vietnam era (July 1, 1965–March 28, 1973)   All COIs  
Mortality—Respiratory system cancers      
Through 2005     Cypel and Kang, 2010
Deployed veterans (2,872) vs non-deployed (2,737) 60 vs 26 1.3 (0.8–2.1)
ACC deployed men in Kang et al. (2006) reported sprayed herbicide vs did not spray 19 1.4 (0.5–3.4)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Through 1991 11 1.4 (0.4–5.4) Dalager and Kang, 1997
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Mortality—trachea, bronchus, lung
1965–2000 41 1.0 (0.6–1.5) Boehmer et al., 2004
Low grade pay at time of discharge nr 1.6 (0.9–3.0)  
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1988 (lung)     Watanabe and Kang, 1996
Army, deployed (n = 27,596) vs non-deployed (n = 31,757 ) 1,139 1.1 (nr) (p < 0.05)
Marine Corps, deployed (n = 6,237) vs non-deployed (n = 5,040) 215 1.2 (1.0–1.3)  
US VA Study of Marine Post-service Mortality—sample of Marines serving 1967–1969, deployed (n = 10,716) vs non-deployed (n = 9,346)   All COIs  
Mortality (lung), earlier of discharge or April 1973 through 1991 42 1.3 (0.8–2.1) Watanabe and Kang, 1995
US VA Cohort of Female Vietnam-era Veterans served in Vietnam (n = 4,586; nurses only = 3,690); non-deployed (n = 5,325; nurses only = 3,282)   All COIs  
Mortality
Through 2004—lung 195 1.1 (0.8–1.5) Kang et al., 2014
Vietnam nurses only 137 0.9 (0.7–1.3)
Through 2004—lung 50 1.0 (0.7–1.4) Cypel and Kang, 2008
Vietnam veteran nurses 35 0.8 (0.5–1.2)
Through 1991—lung 15 0.9 (0.4–1.7) Dalager et al., 1995a
Vietnam veteran nurses 9 0.5 (0.2–1.2)
Through 1987—lung (Vietnam veteran nurses not reported separately) 8 0.6 (0.3–1.5) Thomas et al., 1991
US VA using the Patient Treatment Files—329 Vietnam-era veterans and 269 non-cancer controls and 111 colon cancer controls (1983–1990) 134 All COIs
1.4 (1.0–1.9)
Mahan et al., 1997
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
State Studies of US Vietnam Veterans
Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs non-deployed 80 0.9 (0.7–1.1) Vistainer et al., 1995
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 576 1.2 (1.1–1.3) ADVA, 2005b
Navy 141 1.4 (1.2–1.7)
Army 372 1.2 (1.1–1.3)  
Air Force 63 1.0 (0.7–1.2)  
Histologic type—all service branches combined
Adenocarcinoma 188 1.5 (1.2–1.7)  
Squamous 152 1.2 (1.0–1.4)  
Small-cell 87 1.2 (0.97–1.5)  
Large-cell 79 1.1 (0.8–1.3)  
Other 70 1.1 (0.8–1.3)  
Validation Study   Expected number of exposed cases AIHW, 1999
  46 65 (49–81)  
Men–self report 120 65 (49–89) CDVA, 1998a
Mortality      
All branches, return–2001 544 1.2 (1.1–1.3) ADVA, 2005a
Navy 135 1.4 (1.2–1.6)  
Army 339 1.1 (1.0–1.3)  
Air Force 71 1.1 (0.9–1.4)  
1980–1994     CDVA, 1997a
Lung (ICD-9 162) 212 1.3 (1.1–1.4)  
Respiratory systems (ICD-9 163–165) 13 1.8 (1.0–3.0)  
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence
1982–2000 78 1.2 (1.0–1.5) ADVA, 2005c
Histologic type
Adenocarcinoma 27 1.4 (0.8–1.9)  
Squamous 19 1.5 (0.9–2.3)  
Small-cell 14 1.4 (0.8–2.4)  
Large-cell 8 0.7 (0.3–1.3)  
Other 10 1.2 (0.6–2.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality      
1966–2001 67 1.8 (1.2–2.7) ADVA, 2005c
1982–1994 27 2.2 (1.1–4.3) CDVA, 1997b
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008) 58 1.1 (0.9–1.5)  
Mortality (1988–2008) 50 1.2 (0.9–1.5)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—Lung cancer (C33–C34) categorized high (n = 649) vs low (n = 505)   1.1 (1.0–1.3) Yi and Ohrr, 2014
Mortality (1992–2005)—Lung cancer (C33–C34) categorized high (n = 673) vs low (n = 497)   1.2 (1.0–1.3) Yi et al., 2014b
HR per unit of log EOI (n = 180,639) 1,170 1.0 (1.0–1.1)  
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates (ICD-9)      
Mortality 1939–1992     Kogevinas et al., 1997
Lung (162) 380 1.1 (1.0–1.2)
Other respiratory organs (163–165) 12 2.3 (1.2–3.9)  
13,831 exposed to highly chlorinated PCDDs      
Lung (162) 225 1.1 (1.0–1.3)  
Other respiratory organs (163–165) 9 3.2 (1.5–6.1)  
7,553 not exposed to highly chlorinated PCDDs      
Lung (162) 148 1.0 (0.9–1.2)  
Other respiratory organs (163–165) 3 1.2 (0.3–3.6)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort (ICD-9)     Saracci et al., 1991
Trachea, bronchus, lung (162) 173 1.0 (0.9–1.2)  
Mortality, incidence of women in production (n = 699) and spraying (n = 2) compared to national death rates and cancer incidence rates (lung) 2 TCDD
1.4 (0.2–4.9)
Kogevinas et al, 1993
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort) (ICD-8)   MCPA  
Mortality through 1983 (lung, pleura, mediastinum) (162–164) 117 1.2 (1.0–1.4) Coggon et al., 1986
Background exposure 39 1.0 (0.7–1.4)  
Low-grade exposure 35 1.1 (0.8–1.6)  
High-grade exposure 43 1.3 (1.0–1.8)  
British Production Workers at 4 plants (included in IARC cohort) (lung)   Dioxins, but TCDD unlikely; MCPA Coggon et al., 1991
  19 1.3 (0.8–2.1)  
Workers with exposure above background 14 1.2 (0.7–2.1)  
Chinese Automobile Foundry Factory Workers (n = 3,529)   PCDD/F Wang et al., 2013
Lung cancer mortality (1980–2005); comparison with Chinese general population 43 2.1 (1.6–2.9)  
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)   Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP  
Incidence
Incidence 1943–1987 (lung, men only) 13 1.6 (0.9–2.8) Lynge, 1993
Incidence 1943–1982     Lynge, 1985
Men 38 1.2 (nr)  
Women 6 2.2 (nr)  
Dutch production workers in Plant A and Plant B, combined (in IARC cohort)   Dioxins, 2,4,5-T, 2,4,5-TCP  
Mortality 1955–2006 (Plant A, 1,020 workers; Plant B, 1,036 workers) (respiratory cancers) 54 1.0 (0.9–1.2) Boers et al., 2012
TCDD plasma level (HRs, by tertile) (trachea, bronchus, lung) 52 1.0 (0.8–1.2)  
Background (≤ 0.4) 24 Referent  
Low (0.4–4.1) 11 0.5 (0.3–1.1)  
Medium (4.1–20.1) 12 1.2 (0.6–2.3)  
High (≥ 20.1) 5 1.2 (0.5–3.1)  
963 men exposed during production 1955–1985 vs 1,317 unexposed; mortality in 1986 (respiratory system cancers, ICD-8 160–163) 9 vs 3 1.7 (0.5–6.3) Bueno de Mesquita et al., 1993
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)   Dioxins, 2,4,5-T, 2,4,5-TCP  
Mortality 1955–2006 (hazard ratios for lagged TCDD plasma levels)     Boers et al., 2012
Respiratory cancer 30 1.1 (0.9–1.3)  
Trachea, bronchus, lung cancers 28 1.1 (0.9–1.3)  
Mortality 1955–2006     Boers et al., 2010
Respiratory cancer 21 1.1 (0.5–2.5)
Trachea, bronchus, lung cancers 20 1.2 (0.5–2.8)  
Mortality 1955–1985     Bueno de Mesquita et al., 1993
Trachea, bronchus, lung cancers 9 1.0 (0.5–1.9)
Dutch production workers in Plant B (414 men exposed during production 1965–1986; 723 unexposed) (in IARC cohort)   2,4-D; MCPA; MCPP; highly chlorinated dioxins unlikely  
Mortality 1965–2006     Boers et al., 2010
Respiratory cancer 12 1.2 (0.6–2.7)
Trachea, bronchus, lung cancers 12 1.2 (0.6–2.7)  
Mortality 1965–1986     Bueno de Mesquita et al., 1993
Trachea, bronchus, lung cancers 0 0.0 (0.0–1.3)
German Production Workers—2,479 workers at 4 plants (in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
All for plants 47 1.4 (1.1–1.9) Becher et al., 1996
German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 mo in 1951–1976) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4,5-TCP  
Mortality 1951–1992 2 0.7 (0.0–2.5) Becher et al., 1996
German Production Workers at Bayer Plant in Dormagen (520 men working > 1 mo in 1965–1989) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Mortality 1965–1989 3 1.6 (0.3–4.6) Becher et al., 1996
German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 mo in 1957–1987) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Mortality 1956–1989 11 1.5 (0.7–2.6) Becher et al., 1996
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)   Focus on TCDD  
Mortality      
1953–1992     Ott and Zober, 1996a
Respiratory system 13 1.2 (0.6–2.0)
TCDD 0.1–0.99 µg/kg of body weight 2 0.7 (0.1–2.5)  
TCDD ≥ 1 µg/kg of body weight 8 2.0 (0.9–3.9)  
Lung, bronchus 11 1.1 (0.6–2.0)  
TCDD 0.1–0.99 µg/kg of body weight 2 0.8 (0.1–2.8)  
TCDD ≥ 1.0 µg/kg of body weight 8 2.2 (1.0–4.3)  
Through 1987 4 90% CI 2.0 (0.7–4.6) Zober et al., 1990
German Production Workers at Boehringer–Ingelheim Plant in Hamburg—1,144 men working > 1 mo in 1952–1984 (generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)   Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP  
Mortality 1952–2007 73 1.4 (1.1–1.8) Manuwald et al., 2012
Men 68 1.5 (1.2–1.9)
Women 5 0.8 (0.3–1.9)  
Mortalilty 1952–1989 31 1.5 (1.0–2.1) Becher et al., 1996
Mortality (lung) 1952–1989—stats on men only, 1,184 (tables all for 1,148 men, not necessarily German nationals) vs national rates (also vs gas workers); same observation period as Becher et al., 1966 26 1.7 (1.1–2.4) Manz et al., 1991
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Ever-exposed workers    
Respiratory cancer 13 0.9 (0.5–1.6)  
Trachea, bronchus, lung 11 0.8 (0.4–1.5)  
Never-exposed workers      
Respiratory cancer 5 1.2 (0.4–2.7)  
Trachea, bronchus, lung 4 1.0 (0.3–2.5)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984); mortality (1969–2000) (ICD-9)      
Trachea, bronchus, lung (162)
Other respiratory system sites (163–165)
12
1
1.4 (0.7–2.4)
3.9 (0.1–21.5)
’t Mannetje et al., 2005
Sprayers (697 men and 2 women on register of New Zealand applicators, 1973–1984); mortality 1973–2000 (ICD-9)      
Trachea, bronchus, lung (162) Other respiratory system sites (163–165) 5
1
0.5 (0.2–1.1)
2.5 (0.1–13.7)
’t Mannetje et al., 2005
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Through 1993 125 1.1 (0.9–1.3) Steenland et al., 1999
Chloracne subcohort (n = 608) 30 1.5 (0.98–2.1)
Through 1987 (Entire cohort) (ICD-9)     Fingerhut et al., 1991
Trachea, bronchus, lung (162) 89 1.1 (0.9–1.4)
Respiratory system (160–165) 96 1.1 (0.9–1.4)  
≥ 1-yr exposure, ≥ 20-yr latency      
Trachea, bronchus, lung (162) 40 1.4 (1.0–1.9)  
Respiratory system (160–165) 43 1.4 (1.0–1.9)  
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production   2,4,5-T;
2,4,5-TCP
 
1948–1982 in Midland, MI) (in IARC and NIOSH cohorts)      
1942–2003 (n = 1,615) (bronchus, trachea, lung) 46 0.7 (0.5–0.9) Collins et al., 2009b
1940–1994 (n = 2,187 men) (lung) 54 0.8 (0.6–1.1) Bodner et al., 2003
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T;
2,4,5-TCP
Ruder and Yiin, 2011
Respiratory cancer (ICD-9 160–165)      
1940–2005 (n = 2,122) 133 1.4 (1.2–1.6)c  
PCP and TCP (n = 720) 28 0.9 (0.6–1.3)  
PCP (no TCP) (n = 1,402) 105 1.6 (1.3–1.9)c  
Trachea, bronchus, lung (ICD-9 162)      
1940–2005 (n = 2,122) 126 1.4 (1.1–1.6)c  
PCP and TCP (n = 720) 27 0.9 (0.6–1.3)  
PCP (no TCP) (n = 1,402) 99 1.6 (1.3–1.9)c  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354 (Cohort 3) (lung, bronchus) 36 0.9 (0.6–1.3) Burns CJ et al., 2011
Through 1994 (n = 1,517) (respiratory system, ICD-8 160–163) 31 0.9 (0.6–1.3) Burns et al., 2001
Through 1986 (n = 878) vs national vs 36,804 “unexposed” workers at same location     Bloemen et al., 1993
Respiratory system (ICD-8 162–163) 9 0.8 (0.4–1.5)  
Through 1982 (n = 878)     Bond et al., 1988
Lung (ICD-8 162–163) 8 1.0 (0.5–2.0)
Respiratory (ICD-8 160–163) (exposure lagged 15 yrs)      
Low cumulative exposure 1 0.7 (nr)  
Medium cumulative exposure 2 1.0 (nr)  
High cumulative exposure 5 1.7 (nr)  
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 30 1.0 (0.6–1.4) Collins et al., 2009c
196 also having exposure to TCP) (bronchus, trachea, lung)      
Mortality 1940–1989 (n = 770) (ICD-8)     Ramlow et al., 1996
0-yr latency    
Respiratory system (160–163) 18 1.0 (0.6–1.5)  
Lung (162) 16 0.9 (0.5–1.5)  
15-yr latency      
Respiratory system (160–163) 17 1.1 (0.6–1.8)  
Lung (162) 16 1.1 (0.6–1.8)  
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM (ICD-9)     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Lung (162)      
Never 356 1.0 (0.9–1.1)  
Ever 314 1.0 (0.9–1.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Pleura (163)      
Never 17 2.8 (1.6–4.5)  
Ever 4 0.8 (0.2–2.0)  
Other respiratory (164–165)      
Never 8 2.1 (0.9–4.2)  
Ever 2 0.7 (0.1–2.4)  
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
CANADA
Ontario Forestry Workers—1,222 men working ≥ 6 mo 1950–1982   Herbicides  
80 deaths through 1982; 18 cancers (lung greatest with 5) 5 nr Green, 1991
DENMARK
Danish gardeners (n = 3,124) exposed to pesticides 139 1.0 (0.9–1.2) Kenborg et al., 2012
Danish gardeners—incidence from 3,156 male and 859 female gardeners     Hansen et al., 2007
25-yr follow-up (1975–2001)   Herbicides  
Born before 1915 (high exposure) 34 0.9 (0.6–1.3)  
Born 1915–1934 (medium exposure) 72 1.0 (0.8–1.2)  
Born after 1934 (low exposure) 8 0.8 (0.4–1.7)  
10-yr follow-up (1975–1984) of male gardeners 41 1.0 (0.7–1.3) Hansen et al., 1992
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 2000 (trachea, lung) 27 0.7 (0.5–1.0) Swaen et al., 2004
Through 1987 (trachea, lung) 12 1.1 (0.6–1.9) Swaen et al., 1992
FINNISH Phenoxy Herbicide Sprayers (1,909 men working 1955–1971 ≥ 2 wks) not IARC (ICD-8)   Phenoxy herbicides  
Incidence     Asp et al., 1994
Trachea, bronchus, lung (162) 39 0.9 (0.7–1.3)
Other respiratory (160, 161, 163) 4 1.1 (0.7–1.3)  
Mortality 1972–1989      
Trachea, bronchus, lung (162) 37 1.0 (0.7–1.4)  
Other respiratory (160, 161, 163) 1 0.5 (0.0–2.9)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401) (lung) 155 0.5 (0.4–0.5) Torchio et al., 1994
Italian rice growers with documented phenoxy use (n = 1,487)   Phenoxy herbicides Gambini et al., 1997
Lung 45 0.8 (0.6–1.1)  
Pleura 2 2.2 (0.2–7.9)  
NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of 4,224 incident lung cancer cases vs remainder of 19,904 men with any incident cancer   Herbicides Reif et al., 1989
Forestry workers (n = 134) 30 1.3 (0.8–1.9)  
SWEDEN      
Swedish pesticide applicators—incidence     Wiklund et al., 1989a
Trachea, bronchus, lung 38 0.5 (0.4–0.7)
348 Swedish railroad workers (1957–October, 1978)—total exposure to herbicides (lung) 3 Phenoxy acids
1.4 (nr)
Axelson et al., 1980
Swedish lumberjacks—Used phenoxys 1954–1967, Incidence 1958–1992     Thörn et al., 2000
Exposed (n = 154)      
Foremen (n = 15) 1 4.2 (0.0–23.2)  
Lumberjacks (n = 139) 0  
Unexposed lumberjacks (n = 241) 5 1.2 (0.4–2.7)  
UNITED STATES      
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides
PCMRs
Blair et al., 1993
Men      
Whites (n = 119,648) 6,473 0.9 (0.9–0.9)  
Nonwhites (n = 11,446) 664 1.0 (0.9–1.1)  
Women      
Whites (n = 2,400) 57 0.8 (0.6–1.1)  
Nonwhites (n = 2,066) 24 0.6 (0.4–0.9)  
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Incidence
Enrollment through 2006—SIRs for participants (lung, bronchus)     Koutros et al., 2010a
Private applicators 436 0.5 (0.4–0.5)
Commercial applicators 26 0.8 (0.5–1.1)  
Spouses 133 0.4 (0.4–0.5)  
Enrollment through 2002     Samanic et al., 2006
Dicamba—lifetime days exposure    
None 95 1.0  
1– < 20 14 0.8 (0.5–1.5)  
20– < 56 11 0.6 (0.3–1.3)  
56– < 116 12 1.0 (0.5–1.9)  
≥ 116 15 1.5 (0.8–2.7  
    p-trend = 0.13  
Enrollment through 2002     Alavanja et al., 2005
Private applicators    
Lung 266 0.5 (0.4–0.5)  
Respiratory system 294 0.5 (0.4–0.5)  
Spouses of private applicators (> 99% women)      
Lung 68 0.4 (0.3–0.5)  
Respiratory system 71 0.4 (0.3–0.5)  
Commercial applicators      
Lung 12 0.6 (0.3–1.0)  
Respiratory system 14 0.6 (0.3–1.0)  
Mortality      
Enrollment through 2007, vs state rates     Waggoner et al., 2011
Respiratory    
Applicators (n = 1,641) 422 0.4 (0.4–0.5)  
Spouses (n = 676) 110 0.4 (0.3–0.5)  
Trachea, bronchus, lung      
Applicators (n = 1,641) 417 0.4 (0.4–0.5)  
Spouses (n = 676) 108 0.4 (0.3–0.5)  
Other respiratory system      
Applicators (n = 1,641) 5 0.2 (0.1–0.3)  
Spouses (n = 676) 2 nr  
Enrollment through 2000, vs state rates     Blair et al., 2005a
Private applicators (men and women) 129 0.4 (0.3–0.4)
Years handled pesticides      
≤ 10 yrs 25 0.4 (nr) (p < 0.05)  
≥ 10 yrs 80 0.3 (nr) (p < 0.05)  
Spouses of private applicators (> 99% women) 29 0.3 (0.2–0.5)  
Florida Licensed Pesticide Applicators (common phenoxy use assumed but not documented)   Herbicides  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Pesticide applicators in Florida licensed 1965–1966 (n = 3,827)—mortality through 1976   Herbicides Blair et al., 1983
Any pesticide (dose–response by length of licensure)      
Only for lawn and ornamentals (lung, ICD-8 162–163) 7 0.9 (nr)  
Minnesota Highway Maintenance Workers (n = 4,849) who worked ≥ l day for the Department of Transportation and ≥ 1 day after January 1, 1945 (1984–1986) (ICD-9)   Herbicides Bender et al., 1989
Trachea, bronchus, lung (162.0–162.8) 54 0.7 (0.5–0.9)  
All respiratory (160.0–165.9) 57 0.7 (0.5–0.9)  
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Incidence
20-yr follow-up to 1996—men and women (lung ICD-9 162)     Pesatori et al., 2009
Zone A 7 1.1 (0.5–2.4)  
Zone B 37 1.0 (0.7–1.3)  
Zone R 280 1.0 (0.9–1.2)  
10-yr follow-up to 1991—men     Bertazzi et al., 1993
Zone A 2 0.8 (0.2–3.4)
Zone B 18 1.1 (0.7–1.8)  
Zone R 96 0.8 (0.7–1.0)  
10-yr follow-up to 1991—women     Bertazzi et al., 1993
Zone R 16 1.5 (0.8–2.5)  
Mortality      
25-yr follow-up to 2001—men and women (lung ICD-9 162)     Consonni et al., 2008
Zone A 11 1.1 (0.6–2.0)  
Zone B 62 1.1 (0.9–1.4)  
Zone R 383 1.0 (0.8–1.1)  
20-yr follow-up to 1996 (lung)     Bertazzi et al., 2001
Zones A, B—men 57 1.3 (1.0–1.7)
Zones A, B—women 4 0.6 (0.2–1.7)  
15-yr follow-up to 1991—men (lung)     Bertazzi et al., 1998
Zone A 4 1.0 (0.4–2.6)
Zone B 34 1.2 (0.9–1.7)  
Zone R 176 0.9 (0.8–1.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
15-yr follow-up to 1991—women (lung)     Bertazzi et al., 1998
Zone A 0 nr
Zone B 2 0.6 (0.1–2.3)  
Zone R 29 1.0 (0.7–1.6)  
Ecological Study of Residents of Chapaevsk, Russia   Dioxin Revich et al., 2001
Incidence—Crude incidence rate in 1998 vs    
Men      
Regional (Samara) nr 102.4 (nr)  
National (Russia) nr 89.4 (nr)  
Women      
Regional (Samara) nr 11.1 (nr)  
National (Russia) nr 9.8 (nr)  
Mortality—1995–1998 (SMR vs regional rates)      
Men 168 3.1 (2.6–3.5)  
Women 40 0.4 (0.3–0.6)  
Other International Environmental Studies      
FINLAND      
Finnish fishermen (n = 6,410) and spouses (n = 4,260) registered between 1980 and 2002 compared to national statistics (larynx, trachea, lung, combined)   Serum dioxin Turunen et al., 2008
Fisherman 72 0.8 (0.6–1.0)  
Spouses 8 0.7 (0.3–1.4)  
JAPAN      
Residents of municipalities with and without waste incineration plants (cross-sectional)   Dioxin emissions age-adjusted mortality (per 100,000) Fukuda et al., 2003
Men      
With   39.0 ± 6.7 vs  
Without   41.6 ± 9.1 (p = 0.0001)  
Women      
With   13.7 ± 3.8 vs  
Without   14.3 ± 4.6 (p = 0.11)  
SWEDEN
Swedish fishermen (high consumption of fish with persistent organochlorines)   Organochlorine compounds Svensson et al., 1995a
Incidence
East coast (lung) 24 1.2 (0.8–1.8)  
West coast (lung) 73 0.9 (0.7–1.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality
East coast 16 0.8 (0.5–1.3)  
West coast 77 0.9 (0.7–1.1)  
CASE-CONTROL STUDIES
International Case-Control Studies
Saskatchewan, Canada farmers (604 men, 223 women) diagnosed with lung cancer between November 1983 and July 1986   Herbicides McDuffie et al., 1990
Interviews with lung cancer patients (273 men and 103 women) who sprayed herbicides 103 0.6 (nr)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; ACC, Army Chemical Corps; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; MOS, military occupational specialty; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCDF, polychlorinated dibenzofuran; PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; pg/g, picogram per gram; PM, proportionate mortality; SEA, Southeast Asia; SIR, standardized incidence ratio; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

c99% CI.

Occupational Studies

Wang et al. (2013) followed a cohort of 3,529 workers who had worked at least 1 year in 1980–1985 at an automobile foundry located in Hubei province in China. When compared to the general population, there was a 2.1-fold increased risk of lung cancer mortality in this cohort (SMR = 2.13, 95% CI 1.58–2.88; based on 43 deaths). Although there were several measurements of PCDD/Fs in samples collected from six sites of this factory, the authors did not link these exposure estimates with lung cancer mortality in order to do an exposure–response analysis.

Environmental and Case-Control Studies

No environmental studies or case-control studies of exposure to the COIs and cancers of the lung, bronchus, or trachea have been published since Update 2012.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Biologic Plausibility

Long-term animal studies have examined the effect on tumor incidence of exposure to each of the COIs: 2,4-D and 2,4,5-T (Charles et al., 1996), TCDD (Walker et al., 2006), picloram (Stott et al., 1990), and DMA (Wanibuchi et al., 1996, 2004). As noted in previous VAO reports, there is evidence of an increased incidence of squamous-cell carcinoma of the lung in male and female rats exposed to TCDD at high concentrations (Kociba et al., 1978; Van Miller et al., 1977). A significant increase in neoplastic and non-neoplastic lung lesions was found in female rats exposed to TCDD for 2 years (Kociba et al., 1978; NTP, 1982a,b, 2006; Walker et al., 2006, 2007). The most common non-neoplastic lesions were bronchiolar metaplasia and squamous metaplasia of the alveolar epithelium. Cystic keratinizing epithelioma was the most commonly observed neoplasm. The lung was also identified as a target organ in an NTP tumor-promotion study after 60 weeks of exposure to TCDD in ovariectomized female Sprague Dawley rats initiated with a single dose of diethyl-N-nitrosamine (Beebe et al., 1995; Tritscher et al., 2000). Those studies ended with increased incidences of alveolar epithelial hyperplasia and alveolar–bronchiolar metaplasia—results that were similar to what was observed in the earlier NTP studies (Tritscher et al., 2000). A recent study with female mice in the lung cancer sensitive A/J strain background showed that estrogen exposure increased lung tumor incidence significantly in ovariectomized mice treated with a chemical carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), known to induce these tumors. However, TCDD exposure did not increase lung tumor formation further in these ovariectomized and estrogen-treated mice (Chen et al., 2014a). TCDD by itself had little lung tumor–promoting activity in intact female A/J mice, but it exhibited a significant synergistic effect when combined with a low dose of NNK. Cell culture experiments suggested that the TCDD effect was via inhibition of apoptosis (Chen et al., 2014b). The AHR has been implicated in the chemical induction of lung tumors but not linked specifically at this time to TCDD or the other COIs (Tsay et al., 2013).

Cacodylic acid (DMAIII and DMAV) is carcinogenic, but results from studies of DMA exposure and lung cancer in laboratory animals have not been consistent. In the mouse lung, cacodylic acid (DMAV) was been shown to act as a tumor initiator (Yamanaka et al., 1996, 2009) and as a tumor promoter (Mizoi et al., 2005). DMAV can also act as a complete carcinogen, inducing lung tumors in susceptible strains of mice, including those with deficient DNA-repair activity (Hayashi et al., 1998; Kinoshita et al., 2007). However, a 2-year study of F344 rats exposed to cacodylic acid at 0–100 ppm and B6C3F1 mice exposed at 0–500 ppm failed to detect lung neoplasms at any dose (Arnold et al., 2006). 2,4-D causes lung damage, and a recent report provided evidence that this effect occurs via disruption of the microtubule network (Ganguli et al., 2014).

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Synthesis

The recent evidence is consistent with and further strengthens the conclusion that there is limited but suggestive evidence of an association between exposure to at least one COI and the risk of developing or dying from lung cancer. In the past, the most compelling evidence has come from studies of heavily exposed occupational cohorts, including British 2-methyl-4-chlorophenoxyacetic acid (MCPA) production workers (Coggon et al., 1986), German production workers (Becher et al., 1996), a BASF cohort (Ott and Zober, 1996a), a NIOSH cohort (Fingerhut et al., 1991; Steenland et al., 1999), and Danish production workers (Lynge, 1993). The occupational study of Wang and colleagues reviewed in this update also reported a statistically significant two-fold increased risk of lung cancer mortality in this cohort in comparison to the general population (Wang et al., 2013). However, there was no exposure–response analysis conducted despite the fact that concentrations of PCDD/Fs were collected from six sites in the foundry factory. The methodologically sound AHS did not show any increased risk of lung cancer, but, although there was substantial 2,4-D exposure in this cohort (Blair et al., 2005b), dioxin exposure of the contemporary farmers was probably negligible.

In large part, the environmental studies have not been supportive of an association, although in the cancer-incidence update from Seveso (Pesatori et al., 2009), the highest risks of lung cancer occurred in the most exposed.

In veterans’ studies, Cypel and Kang (2010) found a significantly increased lung-cancer risk in ACC veterans who used herbicides in Vietnam. The findings from the Ranch Hand study (Pavuk et al., 2005) suggested an increase in risk with serum TCDD concentration even in subjects who made up the comparison group, whose TCDD exposure was considerably lower than that of the Ranch Hand cohort (but not zero). The American and Australian cohort studies of Vietnam veterans (ADVA, 2005a,b,c; Dalager and Kang, 1997), which presumably cover a large proportion of exposed soldiers, showed higher than expected incidence of and mortality from lung cancer. The main limitations of those studies are that there was no assessment of exposure—as there was in, for example, the Ranch Hand study—and that some potential confounding variables, notably smoking, could not be accounted for. The committee believes that it is unlikely that the distribution of smoking differed greatly between the two cohorts of veterans, so confounding by smoking is probably minimal. The studies therefore lend support to the findings of the Ranch Hand study.

In this update, however, data from the US veteran women showed no excess lung cancer mortality in comparison to the US cohort of non-deployed women or those from the US general population. Similar results were observed also among male Vietnam veterans in New Zealand, although that cohort study was rather small and also lacked information on smoking. In contrast, the Korean Vietnam Veterans Health Study (Yi, 2013; Yi and Ohrr, 2014; Yi et al., 2014b) found

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

modestly elevated relative risks of both lung cancer incidence and mortality. The results were not adjusted for smoking, but earlier self-reported information from a large portion of the cohort indicated that smoking behavior did not appear related to the extent of a veteran’s exposure to herbicides. Despite their limitations, these new studies of Vietnam veterans are largely suggestive of modest associations between herbicide exposure and lung cancer incidence and mortality.

Finally, the several lines of mechanistic activity discussed in the section on biologic plausibility provide further support for the conclusion that the evidence of an association is limited or suggestive.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between the exposure to at least one COI and carcinomas of the lung, bronchus, and trachea.

BONE AND JOINT CANCERS

ACS estimated that about 1,640 men and 1,330 women would receive diagnoses of bone or joint cancer (ICD-9 170) in the United States in 2015 and that 850 men and 640 women would die from these cancers (Siegel et al., 2015). Primary bone cancers are among the least common malignancies, but the bones are frequent sites of tumors secondary to cancers that have metastasized. Only primary bone cancer is considered here. The average annual incidence of bone and joint cancer is shown in Table 8-13.

Bone cancer is more common in teenagers than in adults. It is rare among people in the age groups of most Vietnam veterans (55–69 years). Among the risk factors for bone and joint cancer in adults are gender, ethnicity, genetic and familial factors, exposure to ionizing radiation in treatment for other cancers and a history of some non-cancer bone diseases, including Paget disease (Chung and Van Hul, 2012; Ottaviani and Jaffe, 2009).

TABLE 8-13 Average Annual Incidence (per 100,000) of Bone and Joint Cancers in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Men 1.3 1.4 0.9 1.6 1.7 0.9 2.2 2.3 1.5
Women 1.0 1.1 0.5 1.1 1.2 1.1 1.4 1.3 1.9

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and bone and joint cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, Update 2010, and Update 2012 did not change that conclusion.

Table 8-14 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

Since the Update 2012, two studies of Vietnam veterans from countries other than the United States have generated publications addressing exposure to the COIs and bone cancer (McBride et al., 2013; Yi and Ohrr, 2014; Yi et al., 2014b).

Mortality from (Yi et al., 2014b) and incidence of (Yi and Ohrr, 2014) bone cancer were assessed among Korean Veterans who had served in Vietnam between 1964 and 1973. In analyses of cancer incidence, Yi and Ohrr (2014) reported a decreased risk of bone cancer (HR = 0.70, 95% CI 0.27–1.82) in the internal comparison of the high- and low-exposure groups based on the EOI scores. Similarly for bone cancer mortality, Yi et al. (2014b) reported a decreased risk for the high- versus low-exposure groups (HR = 0.48, 95% CI 0.16–1.49) and a negative association with the individual log-transformed EOI scores (HR = 0.81, 95% CI 0.64–1.04).

Cancer incidence and mortality from 1998 to 2008 were determined for 2,783 male veterans from New Zealand who had survived service in Vietnam between 1964 and 1972 (McBride et al., 2013). Based upon only two deaths, a comparison with the general male population of New Zealand was largely uninformative for an association with bone and cartilage cancers (SIR = 2.78, 95% CI 0.31–10.0).

Occupational, Environmental, and Case-Control Studies

No occupational, environmental, or case-control studies with sufficiently specific characterization of exposure to the COIs and bone or joint cancers have been published since Update 2012.

Biologic Plausibility

No animal studies have reported an increased incidence of bone and joint cancer after exposure to the COIs. The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-14 Selected Epidemiologic Studies—Bone and Joint Cancers (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1982     Breslin et al., 1986, 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 27 0.8 (0.4–1.7)
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 11 1.4 (0.1–21.5)  
State Studies of US Vietnam Veterans
Massachusetts Vietnam-era veterans
Veterans aged 35–64 years in 1993—cases diagnosed 1988–1993 vs unexposed veterans with gastrointestinal cancers 4 0.9 (0.1–11.3) Clapp, 1997
New York
Deployed vs non-deployed veterans 8 1.0 (0.3–3.0) Lawrence et al., 1985
923 White male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans 1 nr Anderson et al., 1986a,b
International Vietnam-Veteran Studies
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence–bone and cartilage (1988–2008) 2 2.8 (0.3–10.0)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—bone cancer (C40–C41) categorized high (n = 8) vs low (n = 11) 8 0.7 (0.3–1.8) Yi and Ohrr, 2014
Mortality (1992–2005)—bone cancer (C40–C41) categorized high (n = 5) vs low (n = 11)   0.5 (0.2–1.5) Yi et al., 2014b
HR per unit of log EOI (n = 180,639) 16 0.8 (0.6–1.0)  
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality 1939–1992 5 1.2 (0.4–2.8) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 3 1.1 (0.2–3.1)
7,553 not exposed to highly chlorinated PCDDs 2 1.4 (0.2–5.2)  
British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)   MCPA  
Mortality through 1983 1 0.9 (0.0–5.0) Coggon et al., 1986
BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)   Focus on TCDD  
Mortality
Through 1987 0 90% CI 0.0 (0.0–65.5) Zober et al., 1990
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004 0 0.0 (0.0–21.8) McBride et al., 2009a
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)      
Mortality 1969–2000 0 nr ’t Mannetje et al., 2005
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Through 1987 2 2.3 (0.3–8.2) Fingerhut et al., 1991
≥ 1-yr exposure, ≥ 20-yr latency 1 5.5 (0.1–29.0)
Mortality—754 Monsanto workers, among most highly exposed workers from Fingerhut et al. (1991) 2 5.0 (0.6–18.1) Collins et al., 1993
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354 (Cohort 3) (bone, soft tissue) 1 0.8 (0.0–4.5) Burns et al., 2011
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Through 1982 (n = 878) 0 nr (0.0–31.1) Bond et al., 1988
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–1989 (n = 770) 0 nr Ramlow et al., 1996
0-yr latency 0 nr  
15-yr latency 0 nr  
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM      
Danish paper workers     Rix et al., 1998
Men 1 0.5 (0.0–2.7)  
Women 0 nr  
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
CANADA
Sawmill Workers in British
Columbia
—23,829 workers for ≥ 1 yr at 11 mills using chlorophenates 1940–1985
  Chlorophenates, not TCDD  
Incidence 1969–1989 4 1.1 (0.4–2.4) Hertzman et al., 1997
Mortality 1950–1989 5 1.3 (0.5–2.7)  
No exposed to highly chlorinated PCDDs 2 1.4 (0.2–5.2)  
DENMARK
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Men
Self-employed 9 0.9 (nr)  
Employee 0 nr  
Women
Self-employed 0 0.0  
Employee 1 6.3 (p < 0.05)  
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 2000 0 nr Swaen et al., 2004
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401) 10 0.8 (0.4–1.4) Torchio et al., 1994
Italian rice growers with documented phenoxy use (n = 1,487)   Phenoxy herbicides Gambini et al., 1997
  1 0.5 (0.0–2.6)  
NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of incident bone cancer cases vs remainder of 19,904 men with any incident cancer   Herbicides Reif et al., 1989
Forestry workers (n = 134) 1 1.7 (0.2–13.3)  
SWEDEN
Incident bone cancer cases 1961–1973 with agriculture as economic activity in 1960 census 44 99% CI 1.0 (0.6–1.4) Wiklund, 1983
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides
PCMRs
Blair et al., 1993
Men
Whites (n = 119,648) 49 1.3 (1.0–1.8)  
Nonwhites (n = 11,446) 4 1.0 (0.3–2.5)  
Women
Whites (n = 2,400) 1 1.2 (0.0–6.6)  
Nonwhites (n = 2,066) 0 0.0 (0.0–6.3)  
White Male Residents of Iowa—bone cancer on death certificate, usual occupation: farmers vs not   Herbicides  
> 20 yrs old when died 1971–1978—PMR 56 1.1 (nr) Burmeister, 1981
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Mortality
15-yr follow-up to 1991—men     Bertazzi et al., 1998
Zone R 2 0.5 (0.1–2.0)
15-yr follow-up to 1991—women     Bertazzi et al., 1998
Zone B 1 2.6 (0.3–19.4)
Zone R 7 2.4 (1.0–5.7)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Ecological Study of Residents of Chapaevsk, Russia   Dioxin Revich et al., 2001
Mortality—1995–1998 (SMR vs regional rates)
Men 7 2.1 (0.9–4.4)  
Women 7 1.4 (0.6–3.0)  
CASE-CONTROL STUDIES
International Case-Control Studies      
European Multicentric study of association between occupational exposure and risk of bone sarcoma (96 cases, 35–69 yrs of age vs 2,632 hospital- and population-based controls 18 Herbicides, pesticides 2.6 (1.5–4.6) Merletti et al., 2005

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; PMR, proportionate mortality ratio; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Synthesis

The small amount of new data, in concert with the previous literature, summarized in Table 8-14 does not indicate an association between exposure to the COIs and bone cancer.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and bone and joint cancer.

SOFT-TISSUE SARCOMAS

Soft-tissue sarcomas (STSs) (ICD-9 164.1, 171) arise in soft somatic tissues in and between organs. Three of the most common types of STS—liposarcomas,

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

fibrosarcomas, and rhabdomyosarcomas—occur in similar numbers in men and women. Because of the diverse characteristics of STS, accurate diagnosis and classification can be difficult. ACS estimated that about 6,110 men and 5,320 women would receive diagnoses of STS in the United States in 2015 and that about 4,870 men and 2,600 women would die from it (Siegel et al., 2015). The average annual incidence of STS is shown in Table 8-15.

Among the risk factors for STS are exposure to ionizing radiation during treatment for other cancers, some inherited genetic conditions (including Ewing’s sarcoma and Li-Fraumeni syndrome), and several chemical exposures (Cormier and Pollock, 2004).

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was sufficient epidemiologic data to support an association between exposure to the COIs and STS. Additional information available to the committees responsible for subsequent updates has not changed that finding.

As seen with Hodgkin lymphoma and non-Hodgkin lymphoma, the available epidemiologic evidence suggests that phenoxy herbicides rather than TCDD may be associated with developing STS. Some of the strongest evidence of an association between STS and exposure to phenoxy herbicides comes from a series of case-control studies conducted in Sweden (Eriksson et al., 1981, 1990; Hardell and Eriksson, 1988; Hardell and Sandstrom, 1979). The studies, involving a total of 506 cases, show an association between STS and exposure to phenoxy herbicides, chlorophenols, or both. The VAO committee concluded that although those studies have been criticized, there is insufficient justification to discount the consistent pattern of increased risks and the clearly described and sound methods used. In addition, a reanalysis of the data by Hardell (1981) to evaluate the potential influence of potential recall bias and interviewer bias confirmed the original results. Hansen et al. (2007) conducted a historical-cohort study of male gardeners who were members of the Danish Union; the cancer incidence was ascertained from 1975 to 2001. Birth date served as a surrogate for potential exposure to pesticides and herbicides, with older cohorts representing higher exposure potential. Men born before 1915 were

TABLE 8-15 Average Annual Incidence (per 100,000) of Soft-Tissue Sarcomas (Including Malignant Neoplasms of the Heart) in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Men 7.2 7.3 7.4 9.8 10.4 6.9 12.3 12.9 8.3
Women 5.2 4.9 7.1 6.3 6.4 6.3 7.8 8.0 7.2

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

much more likely to die from STS, although this finding was based on only three cases. Reif et al. (1989) performed a series of case-control analyses in a sample of specified occupations and found a significant association between STS and having recently been employed as a forestry worker.

Those findings are supported by a significantly increased risk in a NIOSH study of production workers most highly exposed to TCDD (Fingerhut et al., 1991); Steenland et al. (1999) published an update of the NIOSH cohort, but STS was not among the outcomes evaluated. A similar increased risk was seen in the IARC cohort in deaths that occurred 10 to 19 years after first exposure (Kogevinas et al., 1992; Saracci et al., 1991) according to a fairly crude exposure classification. An updated and expanded study of the IARC cohort by Kogevinas et al. (1997) found a non-significantly increased risk of STS when follow-up was extended to 1992. The NIOSH and IARC cohorts are among the largest and the most highly exposed occupational cohorts. Smaller studies of workers that are included in the multinational IARC cohort—Danish herbicide manufacturers (Lynge et al., 1985, 1993) and Dow production workers in Midland, Michigan, and New Zealand (Collins et al., 2009b; ’t Mannetje et al., 2005)—showed an increased risk of STS, but the results were commonly non-significant, possibly because of the small samples (related to the relative rarity of STS in the population).

Several studies have reported on STS in relation to living near waste incinerators that release dioxin as a contaminant. Viel et al. (2000) reported on an investigation of apparent clusters of STS and non-Hodgkin lymphoma cases in the vicinity of a municipal solid waste incinerator in Doubs, France; Comba et al. (2003) and Costani et al. (2000) examined STS in the general population living near a chemical plant in the northern Italian city of Mantua; and Zambon et al. (2007) conducted a population-based case-control study in Venice, Italy, in an area that included 26 waste incinerators and other industrial plants. Each of those studies found a statistically significant excess of STS, but none showed any direct evidence of human exposure.

No cases of STS have been reported in Zones A and B in the Seveso cohort (Consonni et al., 2008); the incidence of STS was slightly increased in Zone R but not significantly (Pesatori et al., 2009). Veteran studies have not found a significant increase in STS. No increase was seen in Ranch Hand veterans (AFHS, 1996, 2000; Michalek et al., 1990) or in VA studies of US Vietnam veterans (Breslin et al., 1986, 1988; Bullman et al., 1990; Watanabe and Kang, 1995; Watanabe et al., 1991). A slight increase in the incidence of STS was seen in Australian Air Force veterans compared with the Australian population but not in Army or Navy personnel (ADVA, 2005a), and no increase in mortality was seen in Australian veterans who served in any of the military branches (ADVA, 2005b). A non-significant increase in mortality from STS was also seen in state studies of veterans in Massachusetts, Michigan, and New York.

Table 8-16 summarizes the relevant studies.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-16 Selected Epidemiologic Studies—Soft-Tissue Sarcomas (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)   All COIs  
Mortality      
Through 1987—Ranch Hand personnel (n = 1,261) vs SEA veterans (19,102) 1 nr Michalek et al., 1990
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1984      
Army, deployed (n = 24,145) vs non-deployed (n = 27,917) 43 1.1 Watanabe et al., 1991
Served in I Corps (n = 6,668) 10 0.9 (0.4–1.6) Bullman et al., 1990
Marine Corps, deployed (n = 5,501) vs non-deployed (n = 4,505) 11 0.7 Watanabe et al., 1991
1965–1982     Breslin et al., 1986, 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 30 1.0 (0.8–1.2)
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 8 0.7 (0.4–1.3)  
US VA Study of Marine Post-service Mortality—sample of Marines serving 1967–1969, deployed (n = 10,716) vs non-deployed (n = 9,346)   All COIs  
Mortality, earlier of discharge or April 1973 through 1991 0 nr Watanabe and Kang, 1995
US VA Case-Control Study
234 Vietnam veterans vs 13,496 Vietnam-era veterans 86 0.8 (0.6–1.1) Kang et al., 1986
State Studies of US Vietnam Veterans
Massachusetts Vietnam-era Veterans
Veterans aged 35–65 years in 1993—cases diagnosed 1988–1993 vs gastrointestinal cancers 18 1.6 (0.5–5.4) Clapp, 1997
Diagnosed 1972–1983 9 5.2 (2.4–11.1) Kogan and Clapp, 1988
Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs non-deployed 8 1.1 (0.5–2.2) Vistainer et al., 1995
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
New York—deployed vs non-deployed 2 1.1 (0.2–6.7) Lawrence et al., 1985
281 STS cases with service in Vietnam vs live matched controls     Greenwald et al., 1984
10 0.5 (0.2–1.3)
923 White male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans 4 nr Anderson et al., 1986a,b
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 35 1.0 (0.7–1.3) ADVA, 2005b
Navy 6 0.8 (0.3–1.7)  
Army 29 1.2 (0.8–1.6)  
Air Force 0 0.0 (0.0–1.1)  
Validation Study 14 Expected number of exposed cases AIHW, 1999
    27 (17–37)  
Men 398 27 (17–37) CDVA, 1998a
Women 2 0 (0–4) CDVA, 1998b
Mortality
All branches, return–2001 12 0.8 (0.4–1.3) ADVA, 2005a,
Navy 3 0.9 (0.2–2.4)  
Army 9 0.8 (0.4–1.5)  
Air Force 0 0.0 (0.0–2.3)  
1980–1994 9 1.0 (0.4–1.8) CDVA, 1997a
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence
1982–2000 10 1.0 (0.4–2.4) ADVA, 2005c
Mortality
1966–2001 3 0.5 (0.1–2.0) ADVA, 2005c
1982–1994 2 0.7 (0.6–4.5) CDVA, 1997b
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
1983–1985 1 1.3 (0.1–20.0) Fett et al., 1987b
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence–connective and soft-tissue (1988–2008) 3 1.0 (0.2–3.0)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—connective and soft tissue (C47, C49) categorized high (n = 13) vs 13 0.6 (0.3–1.3) Yi and Ohrr, 2014
low (n = 20)      
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Mortality 1939–1992     Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 6 2.0 (0.8–4.4)
7,553 not exposed to highly chlorinated PCDDs 2 1.4 (0.2–4.9)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort 4 2.0 (0.6–5.2) Saracci et al., 1991
Nested case-control study      
IARC cohort (men and women)—incidence     Kogevinas et al., 1995
Exposed to 2,4,5-T 5 4.3 (0.7–26.3)  
Exposed to TCDD 5 5.2 (0.9–31.9)  
Mortality—IARC cohort (16,863 men and 1,527 women) 10–19 years since first exposure 4 6.1 (1.7–15.5) Kogevinas et al., 1992
British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)   MCPA  
Mortality through 1983 1 1.1 (0.0–5.9) Coggon et al., 1986
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)   Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP  
Incidence 1943–1987 (men only)
Incidence 1943–1982
5 2.0 (0.7–4.8) Lynge, 1993
Lynge, 1985
Men 5 2.7 (0.9–6.3)  
Women 0 nr  
Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)   Dioxins, 2,4,5-T, 2,4,5-TCP  
Mortality 1955–1991 0 nr Hooiveld et al., 1998
Mortality 1955–1985 0 0.0 (0.0–18.4) Bueno de Mesquita et al., 1993
Dutch production workers in Plant B (414 men exposed during production 1965–1986; 723 unexposed) (in IARC cohort)   2,4-D; MCPA; MCPP; highly chlorinated dioxins unlikely  
Mortality 1965–1986 0 0.0 (0.0–73.8) Bueno de Mesquita et al., 1993
German Production Workers—2,479 workers at 4 plants (in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)   Focus on TCDD  
Incidence
1960–1992     Ott and Zober, 1996a,b
TCDD < 0.1 µg/kg of body weight 0 nr
TCDD 0.1–0.99 µg/kg of body weight 0 nr  
TCDD > 1.0 µg/kg of body weight 0 nr  
Mortality
Through 1987   90% CI Zober et al., 1990
  0 nr  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)   Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP  
Mortality 1952–1989—stats on men only, 1,184 (tables all for 1,148 men, not necessarily German nationals) vs national rates (also vs gas workers); same observation period as Becher et al., 1966 0 nr Manz et al., 1991
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Ever-exposed workers 1 3.4 (0.1–19.5)
Never-exposed workers 0 0.0 (0.0–34.9)  
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)      
Mortality 1969–2000 0 0.0 (0.0–19.3) ’t Mannetje et al., 2005
Sprayers (697 men and 2 women registered any time 1973–1984)      
Mortality 1973–2000 1 4.3 (0.1–23.8) ’t Mannetje et al., 2005
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Through 1993 4 2.3 (0.6–5.9) Steenland et al., 1999
Chloracne subcohort (n = 608) 3 11.3 (2.3–33.1)
Through 1987 4 3.4 (0.9–8.7) Fingerhut et al., 1991
≥ 1-yr exposure, ≥ 20-yr latency 3 9.2 (1.9–27.0)
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (in IARC and NIOSH cohorts)   2,4,5-T; 2,4,5-TCP  
1942–2003 (n = 1,615) 4 4.1 (1.1–10.5) Collins et al., 2009b
1940–1994 (n = 2,187 men) 2 2.4 (0.3–8.6) Bodner et al., 2003
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL) (connective tissue and soft tissue)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
1940–2005 (n = 2,122) (connective tissue and soft tissue) 2 1.5 (0.2–5.5)  
PCP and TCP (n = 720) 1 2.3 (0.1–12.6)  
PCP (no TCP) (n = 1,402) 1 1.1 (0.0–6.4)  
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3) (bone, soft tissue) 1 0.8 (0.0–4.5) Burns CJ et al., 2011
Through 1982 (n = 878) 0 nr Bond et al., 1988
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding     Collins et al., 2009c
196 also having exposure to TCP) 1 2.2 (0.0–12.1)
Mortality 1940–1989 (n = 770) 0 Expected number of exposed cases Ramlow et al., 1996
    0.2  
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Never 8 1.2 (0.5–2.4)  
Ever 4 0.8 (0.2–2.0)  
Danish paper-mill workers     Rix et al., 1998
Men employed in sorting and packing 12 1.2 (0.6–2.0)  
Women employed in sorting and packing 8 4.0 (1.7–7.8)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
CANADA
Sawmill Workers in British Columbia—23,829 workers for ≥ 1 yr at 11 mills using chlorophenates 1940–1985   Chlorophenates, not TCDD  
Incidence 1969–1989 11 1.0 (0.6–1.7) Hertzman et al., 1997
Mortality 1950–1989 6 1.2 (0.5–2.3)
DENMARK
Danish gardeners—incidence from 3,156 male and 859 female gardeners     Hansen et al., 2007
25-yr follow-up (1975–2001)   Herbicides  
Born before 1915 (high exposure) 3 5.9 (1.9–18.2)  
Born 1915–1934 (medium exposure) 0 0.0 (0.0–3.8)  
Born after 1934 (low exposure) 1 1.8 (0.3–12.9)  
10-yr follow-up (1975–1984) of male gardeners 3 5.3 (1.1–15.4) Hansen et al., 1992
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401) 2 1.0 (0.1–3.5) Torchio et al., 1994
NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of 142 incident STS cases vs remainder of 19,904 men with any incident cancer      
Forestry workers (n = 134)   Herbicides Reif et al., 1989
Aged 20–59 4 3.2 (1.2–9.0)  
Aged ≥ 60 0  
SWEDEN
Swedish pesticide applicators—incidence (n = 20,245) 7 99% CI 0.9 (0.8–1.1) Wiklund et al., 1988b, 1989a
354,620 Swedish agricultural and forestry workers identified from 1960 census, followed 1961–1979; compared to reference population 331 0.9 (0.8–1.0) Wiklund and Holmes, 1986
Incident STS cases 1961–1973 with agriculture as economic activity in 1960 census (connective tissue and muscle) 162 1.1 (0.9–1.3) Wiklund, 1983
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Men
Whites (n = 119,648) 98 0.9 (0.8–1.1)  
Nonwhites (n = 11,446) 10 1.5 (0.7–2.8)  
Women
Whites (n = 2,400) 3 1.2 (0.2–3.5)  
Nonwhites (n = 2,066) 0 0.0 (0.0–1.9)  
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence
Enrollment through 2002     Alavanja et al., 2005
Private applicators 10 0.7 (0.3–1.2)
Spouses of private applicators (> 99% women) 3 0.5 (0.1–1.4)  
Commercial applicators nr 0.0 (0.0–3.8)  
Mortality
Enrollment through 2007, vs state rates (connective tissue)     Waggoner et al., 2011
Applicators (n = 1,641) 9 0.7 (0.3–1.5)  
Spouses (n = 676) 6 1.0 (0.4–2.2)  
Enrollment through 2000, vs state rates     Blair et al., 2005a
Private applicators (men and women) 4 0.7 (0.2–1.8)
Spouses of private applicators (> 99% women) 3 1.4 (0.3–4.1)  
US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 of STS   Herbicides  
USDA forest and soil 2 1.0 (0.1–3.6) Alavanja et al., 1989
Florida Pesticide Applicators licensed 1965–1966 (n = 3,827)—mortality through 1976   Herbicides Blair et al., 1983
Any pesticide (dose–response by length of licensure) 0 nr  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Incidence
20-yr follow-up to 1996—men and women
Zone A 0 nr Pesatori et al., 2009
Zone B 0 nr
Zone R 9 1.3 (0.6–2.7)  
10-yr follow-up to 1991—men     Bertazzi et al., 1993;
Zone A 0 nr
Zone B 0 nr Pesatori et al., 1992
Zone R 6 2.8 (1.0–7.3)  
10-yr follow-up to 1991—women     Bertazzi et al., 1993;
Zone A 0 nr
Zone B 0 nr Pesatori et al., 1992
Zone R 2 1.6 (0.3–7.4)  
Mortality
25-yr follow-up to 2001—men and women     Consonni et al., 2008
Zone A 0 nr
Zone B 0 nr  
Zone R 4 0.8 (0.3–2.1)  
20-yr follow-up to 1996     Bertazzi et al., 2001
Zone A—men and women 0 nr
Zone B—men and women 0 nr  
Zones A and B—men 0 nr  
Zones A and B—women 0 nr  
15-yr follow-up to 1991—men     Bertazzi et al., 1997, 1998
Zone A nr
Zone B 0 nr  
Zone R 4 2.1 (0.7–6.5)  
15-yr follow-up to 1991—women     Bertazzi et al., 1997, 1998
Zone A nr
Zone B 0 nr  
Zone R 0 nr  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
10-yr follow-up to 1986—men     Bertazzi et al., 1989a
Zone A, B, R 2 5.4 (0.8–38.6)
Zone R 2 6.3 (0.9–45.0) Bertazzi et al., 1989b
10-yr follow-up to 1986—women     Bertazzi et al., 1989a
Zone A, B, R 1 2.0 (0.2–1.9)
Zone B 1 17.0 (1.8–163.6) Bertazzi et al., 1989b
FINLAND
Finnish community exposed to chlorophenol contamination (men and women)   Chlorophenol Lampi et al., 1992
6 1.6 (0.7–3.5)
FRANCE
Residents near French solid-waste incinerator—incidence   Dioxin Viel et al., 2000
Spatial cluster 45 1.4 (p = 0.004)  
1994–1995 12 3.4 (p = 0.008)  
ITALY
Italian rice growers   Chlorophenoxy acids, chlorophenols Gambini et al., 1997
  1 4.0 (0.1–22.3)  
NEW ZEALAND
Residents of New Plymouth Territorial Authority, New Zealand, near plant manufacturing 2,4,5-T in 1962–1987   2,4,5-T Read et al., 2007
Incidence 56 1.0 (0.8–1.4)c  
1970–1974 7 1.0 (0.4–2.1)  
1975–1979 3 0.4 (0.1–2.1)  
1980–1984 10 1.3 (0.6–2.4)  
1985–1989 11 1.2 (0.6–2.2)  
1990–1994 9 0.9 (0.4–1.7)  
1995–1999 14 1.3 (0.7–2.2)  
2000–2001 2 0.8 (0.1–3.0)  
Mortality 27 1.2 (0.8–1.8)c  
1970–1974 5 1.8 (0.6–4.3)  
1975–1979 1 0.4 (0.0–2.0)  
1980–1984 4 1.1 (0.3–2.9)  
1985–1989 5 1.5 (0.5–3.6)  
1990–1994 5 1.3 (0.4–3.0)  
1995–1999 5 1.3 (0.4–3.0)  
2000–2001 2 0.9 (0.1–3.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
SWEDEN
Swedish fishermen (high consumption of fish with persistent organochlorines)   Organochlorine compounds Svensson et al., 1995a
Incidence
East coast 0 0.0 (0.0–2.6)  
West coast 3 0.5 (0.1–1.4)  
Mortality
East coast 0 nr  
West coast 0 nr  
CASE-CONTROL STUDIES
US Case-Control Studies
Kansas residents–duration and frequency of herbicide use—incidence   Phenoxy herbicides, 2.4-D Hoar et al., 1986
All farmers 95 1.0 (0.7–1.6)  
Farm-use of herbicides 22 0.9 (0.5–1.6)  
Washington state residents—incidence (1983–1985)   Phenoxy herbicides, chlorinated phenols Woods et al., 1987
High phenoxy exposure nr 0.9 (0.4–1.9)  
Self-reported chloracne nr 3.3 (0.8–14.0)  
International Case-Control Studies      
Australian residents in Victorian Cancer Registry (1982–1987)   Phenoxy compounds Smith and Christophers, 1992
  30 1.0 (0.3–3.1)
British agricultural workers   Herbicides Balarajan and Acheson, 1984
Overall 42 1.7 (1.0–2.9)
Under 75 yrs old 33 1.4 (0.8–2.6)  
Cross Canada Study of Pesticides and Health—Men (≥ 19 yrs of age) diagnosed Sept 1991–Dec 1994 (n = 357) vs matched population-based controls (n = 1,506); exposure to:     Pahwa et al., 2011
Phenoxy herbicides 80 vs 1.1 (0.8–1.5)  
  321    
2,4-D 69 vs 1.0 (0.7–1.4)  
  293    
Mecoprop 26 vs 81 1.3 (0.8–2.2)  
MCPA 13 vs 46 1.1 (0.6–2.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Diclofop-methyl 8 vs 25 1.2 (0.4–2.9)  
Cross Canada Study of Pesticides and Health—Men (≥ 19 yrs of age) diagnosed Sept 1991–Dec 1994 (n = 357) vs matched population-based controls (n = 1,506); exposure to:   Phenoxy herbicides Pahwa et al., 2006
Any phenoxyherbicide 80 vs 1.1 (0.7–1.5)  
  321    
2,4-D 69 vs 1.0 (0.6–1.5)  
  293    
Mecoprop 26 vs 81 1.0 (0.5–1.9)  
MCPA 13 vs 46 1.1 (0.5–2.2)  
Finnish STS patients vs controls within quintiles based on TEQ in subcutaneous fat—incidence 110 Dioxin Tuomisto et al., 2004
Quintile 1 (median, ~12 ng/kg TEQ) nr 1.0  
Quintile 2 (median, ~20 ng/kg TEQ) nr 0.4 (0.2–1.1)  
Quintile 3 (median, ~28 ng/kg TEQ) nr 0.6 (0.2–1.7)  
Quintile 4 (median, ~40 ng/kg TEQ) nr 0.5 (0.2–1.3)  
Quintile 5 (median, ~62 ng/kg TEQ) nr 0.7 (0.2–2.0)  
Italy
Population-based Veneto Tumour Registry, Italy, average exposure based on duration and distance of residence from 33 industrial sources—incidence   Dioxin Zambon et al., 2007
Sarcoma (ICD-9 158, 171, 173, visceral sites)      
Men
< 4 TCDD (fg/m3) 31 1.0  
4–6 39 1.1 (0.6–2.0)  
> 6 17 1.9 (0.9–4.0) p-trend = 0.15  
Women
< 4 TCDD (fg/m3) 24 1.0  
4–6 44 1.5 (0.8–2.7)  
> 6 17 2.4 (1.0–5.6) p-trend = 0.04  
Men, women combined
Connective, other soft tissue (ICD-9 171)      
< 4 TCDD (fg/m3) 25 1.0  
4–6 39 1.4 (0.7–2.5)  
> 6 17 3.3 (1.4–7.9)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
    p-trend = 0.01  
Skin (ICD-9 173)
< 4 TCDD (fg/m3) 5 1.0  
4–6 10 0.0 (0.3–4.7)d  
≥ 6 2 0.3 (0.0–3.4) p-trend = 0.48  
Retroperitoneum, peritoneum (ICD-9 158)      
< 4 TCDD (fg/m3) 6 1.0  
4–6 12 1.1 (0.3–3.4)  
≥ 6 3 0.8 (0.1–4.5) p-trend = 0.86  
Visceral sites
< 4 TCDD (fg/m3) 19 1.0  
4–6 22 1.2 (0.6–2.6)  
≥ 6 12 2.5 (1.0–6.3) p-trend = 0.08  
Residents near industrial-waste incinerator in Mantua, Italy—incidence   Dioxin  
Residence within 2 km of incinerator 5 31.4 (5.6–176.1) Comba et al., 2003
Residents near chemical plant in Mantua, Italy—incidence 20 TCDD emissions 2.3 (1.3–3.5) Costani et al., 2000
Italian rice weeders (1981–1983)   Phenoxy herbicides Vineis et al., 1986
Among all living females (n = 31) 5 2.4 (0.4–16.1)  
New Zealand Pesticide Workers   Phenoxy herbicides 90% CI  
Update of New Zealand workers (1976–1982) 133 1.1 (0.7–1.8) Smith and Pearce, 1986
Reanalysis of New Zealand workers (1976–1980) 17 1.6 (0.7–3.8) Smith et al., 1984
New Zealand workers exposed to herbicides (1976–1980) 17 1.6 (0.8–3.2) Smith et al., 1983
Swedish agricultural and forestry workers (1974–1979)   Phenoxy acids, chlorophenols Eriksson et al., 1979,
  25 (2.5–10.4) 5:1 matched 1981
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Swedish patients (1970–1977)   Phenoxy acids, chlorophenols Hardell, 1981;
      Hardell and Sandström, 1979
Exposed to phenoxy herbicides 13 5.5 (2.2–13.8)  
Exposed to chlorophenols 6 5.4 (1.3–22.5)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; CATI, computer-assisted telephone interviewing; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; PM, proportionate mortality; SEA, Southeast Asia; STS, soft-tissue sarcoma; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; TEQ, toxicity equivalent; USDA, US Department of Agriculture; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

cCommittee computed total SMR and SIR by dividing sum of observed values by sum of expected values over all years; 95% CIs on these total ratios were computed with exact methods.

dThere appears to be an error in this entry because lower 95% CI (0.3) is not smaller than odds ratio (0.0)

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

In a study of mortality and cancer incidence among 2,783 New Zealand veterans who served in Vietnam between 1964 and 1975, McBride et al. (2013) reported that connective and soft tissue cancer incidence was slightly elevated in the cohort (SIR = 1.04, 95% CI 0.21–3.04, based on three cases).

Cancer incidence was also assessed among Korean veterans who had served in Vietnam between 1964 and 1973. Yi and Ohrr (2014) reported a decreased risk of connective and soft tissue cancers (ICD-10 C47 and C49) in the internal comparison of the high- (n = 13) and low-exposure (n = 20) groups based on the EOI scores (HR = 0.62, 95% CI 0.30–1.27).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Occupational, Environmental, and Case-Control Studies

No occupational, environmental, or case-control studies of exposure to the COIs and STS have been published since Update 2012.

Biologic Plausibility

In a 2-year study, dermal application of TCDD to Swiss-Webster mice led to an increase in fibrosarcomas in females but not in males (NTP, 1982b). There is some concern that the increase in fibrosarcomas may be associated with the treatment protocol rather than with TCDD. The NTP gavage study (NTP, 1982a) also found an increased incidence of fibrosarcomas in male and female rats and in female mice.

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

Previous committees have concluded that the occupational, environmental, and Vietnam-veteran studies showed sufficient evidence to link herbicide exposure to STS. Although the confidence intervals in the new cohort studies were broad because of the rarity of observed cases in small samples, that conclusion is consistent with the findings of Ruder and Yiin (2011). The rather extensive Canadian case-control study of pesticide exposure and STS (Pahwa et al., 2011), however, did not provide additional supportive evidence.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is sufficient evidence of an association between exposure to at least one of the COIs and STS.

SKIN CANCERS

Skin cancers are generally divided into two broad categories: neoplasms that develop from melanocytes (malignant melanoma, or simply melanoma) and neoplasms that do not. Non-melanoma skin cancers (primarily basal-cell and squamous-cell carcinomas) have a far higher incidence than melanoma but are considerably less aggressive and therefore more treatable. The average annual incidence of melanoma is shown in Table 8-17.

The committee responsible for Update 1998 first chose to address melanoma studies separately from those of non-melanoma skin cancers. Some researchers report results by combining all types of skin cancers without specifying type.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-17 Average Annual Cancer Incidence (per 100,000) of Skin Cancers (Excluding Basal-Cell and Squamous-Cell Cancers) in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Melanomas of the Skin:
Men 66.0 77.3 2.9 93.7 109.1 3.8 116.5 137.1 4.0
Women 35.0 41.4 2.4 42.1 49.8 2.6 45.1 53.0 4.2

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012. SEER incidence data not available for nonmelanocytic skin cancer (NCI, 2015).

The present committee believes that combined information is not interpretable (although there is a supposition that the mortality figures refer predominantly to melanoma and that the high-incidence figures refer to non-melanoma skin cancers); therefore, it is interpreting data only when the results specify melanoma or non-melanoma skin cancers.

ACS estimated that about 46,610 men and 33,490 women would receive diagnoses of cutaneous melanoma (ICD-9 172) in the United States in 2015 and that about 9,120 men and 4,220 women would die from it (Siegel et al., 2015). According to one report, more than 3 million cases of non-melanoma skin cancers (ICD-9 173), primarily basal-cell and squamous-cell carcinomas, are diagnosed in the United States each year (ACS, 2013b); it is not required to report them to registries, so the numbers of cases are not as precise as those of other cancers. ACS reports that although melanoma accounts for less than 5 percent of skin-cancer cases, it is responsible for about 75 percent of skin-cancer deaths (Siegel et al., 2015). It estimates that 3,400 people die each year from non-melanoma skin cancers (Siegel et al., 2015).

Melanoma occurs more frequently in fair-skinned people than in dark-skinned people; the risk in whites is roughly 20 times that in dark-skinned blacks. The incidence increases with age, more strikingly in males than in females. Other risk factors include the presence of particular kinds of moles on the skin, the suppression of the immune system, and excessive exposure to ultraviolet (UV) radiation, typically from the sun. A family history of the disease has been identified as a risk factor, but it is unclear whether that is attributable to genetic factors or to similarities in skin type and sun-exposure patterns (Rastrelli et al., 2014). In addition to the dermal forms of melanoma, these tumors occur much more infrequently in various tissues of the eye.

Excessive exposure to UV radiation is the most important risk factor for nonmelanoma skin cancers; radiation exposure, human papillomavirus, immune system problems, and family history of non-melanoma skin cancers have also been identified as potential risk factors (Bailey et al., 2010). Although exposure to inorganic arsenic is recognized as a risk factor for non-melanoma skin cancers

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

(Dubas and Ingraffea, 2013); this does not imply that exposure to cacodylic acid, which is a metabolite of inorganic arsenic, can be assumed to be a risk factor.

Melanoma

Conclusions from VAO and Previous Update

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and skin cancers. Additional information available to the committee responsible for Update 1996 did not change that conclusion. The committee responsible for Update 1998 considered the literature on melanoma separately from that of non-melanoma skin cancers and found that there was inadequate or insufficient information to determine whether there is an association between the COIs and melanoma. The committees responsible for Update 2000, Update 2002, and Update 2004 concurred with the findings of Update 1998. The committee responsible for Update 2006 was unable to reach a consensus as to whether there was limited or suggestive evidence of an association between exposure to the COIs and melanoma or inadequate or insufficient evidence to determine whether there is an association, so melanoma was left in the latter category. The committee for Update 2008 determined that evidence of an association between exposure to the COIs and melanoma remained inadequate or insufficient to determine whether an association exists.

Cypel and Kang (2010) compared cause-specific mortality between deployed and non-deployed veterans in the Vietnam-era ACC cohort. In the comparison between the deployed and the non-deployed veterans, a moderate but not statistically significant increase in the risk of malignant skin cancer was observed in the deployed cohort. The updates of mortality in TCP workers in New Zealand (McBride et al., 2009a) and in the Dow cohort in Midland, Michigan (Collins et al., 2009b), did not find evidence of an association between the COIs and melanoma. In evaluating the use of specific pesticides and melanoma in the AHS, Dennis et al. (2010) found that only exposure to arsenic-based pesticides, among the COIs, showed any increase in risk, which was weak and far from statistically significant. Updates of cancer incidence in the Seveso cohort for the period 1977–1996 (Pesatori et al., 2009) continued to provide evidence that melanoma is associated with exposure to TCDD.

Table 8-18 summarizes the relevant melanoma studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies In a study of mortality and cancer incidence among 2,783 New Zealand veterans who served in Vietnam between 1964 and 1975, McBride et al. (2013) reported that melanoma mortality (SMR = 0.56, 95% CI

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-18 Selected Epidemiologic Studies—Melanoma (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)   All COIs  
Incidence
1982–2003—White SEA comparison veterans only (n = 1,482). Serum TCDD (pg/g) based on model with exposure variable loge(TCDD)     Pavuk et al., 2005
Per unit increase of –loge(TCDD) (pg/g) Quartiles (pg/g): 25 2.7 (1.1–6.3)  
0.4–2.6 3 1.0  
2.6–3.8 5 2.1 (0.4–11.0)  
3.8–5.2 8 3.2 (0.7–15.5)  
> 5.2 9 3.6 (0.7–17.2)  
Number of years served in SEA (per year of service)      
Quartiles (years in SEA): 25 1.1 (0.9–1.3)  
0.8–1.3 3 1.0  
1.3–2.1 4 1.9 (0.3–10.3)  
2.1–3.7 8 3.2 (0.7–15.3)  
3.7–16.4 10 4.1 (0.9–19.7)  
Through 1999—White subjects vs national rates     Akhtar et al., 2004
Ranch Hand veterans (n = 1,189) 17 2.3 (1.4–3.7)
With tours between 1966–1970 16 2.6 (1.5–4.1)  
SEA comparison veterans (n = 1,776) 15 1.5 (0.9–2.4)  
With tours between 1966–1970 12 1.5 (0.8–2.6)  
White AFHS subjects      
Veterans who spent at most 2 yrs in SEA      
Per unit increase of –loge(TCDD) (pg/g) 14 2.2 (1.3–3.9)  
Comparison group 3 1.0  
Ranch Hand— < 10 TCDD pg/g in 1987 4 3.0 (0.5–16.8)  
Ranch Hand < 118.5 TCDD pg/g at end of service 4 7.4 (1.3–41.0)  
Ranch Hand > 118.5 TCDD pg/g at end of service 3 7.5 (1.1–50.2)  
Only Ranch Hands with 100% service in Vietnam, comparisons with no Vietnam service      
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Per unit increase of –loge(TCDD) (pg/g) 14 1.7 (1.0–2.8)  
Comparison group 2 1.0  
Ranch Hand— < 10 TCDD pg/g in 1987 5 3.9 (0.4–35.3)  
Ranch Hand < 118.5 TCDD pg/g at end of service 4 7.2 (0.9–58.8)  
Ranch Hand > 118.5 TCDD pg/g at end of service 3 5.5 (0.6–46.1)  
Ranch Hand veterans, comparisons through June 1997     Ketchum et al., 1999
Ranch Hand background exposure 4 1.1 (0.3–4.5)  
Ranch Hand low exposure 6 2.6 (0.7–9.1)  
Ranch Hand high exposure 2 0.9 (0.2–5.6)  
Comparisons 9 1.0  
Attended 1987 exam—Ranch Hand personnel (n = 995) vs SEA veterans (n = 1,299) 4 1.3 (0.3–5.2) Wolfe et al., 1990
US VA Cohort of Army Chemical Corps—Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 non-deployed) serving during Vietnam era (July 1, 1965–March 28, 1973)   All COIs  
Through 2005 (mortality)     Cypel and Kang, 2010
Deployed veterans (2,872) vs non-deployed (2,737) 5 vs 4 1.5 (0.4–6.2)
ACC deployed men in Kang et al. (2006) reported sprayed herbicide vs did not spray      
Vietnam cohort 5 1.3 (0.4–3.1)  
Non-Vietnam cohort 4 1.3 (0.4–3.4)  
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
1965–2000 (mortality) 6 1.4 (0.4–4.9) Boehmer et al., 2004
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1982     Breslin et al., 1986, 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 145 1.0 (0.9–1.1)
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 36 0.9 (0.6–1.5)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
State Studies of US Vietnam Veterans
Massachusetts Vietnam-era veterans
Veterans aged 35–65 years in 1993—melanoma cases diagnosed 1988–1993 vs gastrointestinal cancers 21 1.4 (0.7–2.9) Clapp, 1997
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 756 1.3 (1.2–1.4) ADVA, 2005b
Navy 173 1.4 (1.2–1.6)  
Army 510 1.2 (1.2–1.4)  
Air Force 73 1.4 (1.1–1.7)  
Validation Study   Expected number of exposed cases  
  483 380 (342–418)  
Men 2,689 380 (342–418) CDVA, 1998a
Women 7 3 (1–8) CDVA, 1998b
Mortality
All branches, return–2001 111 1.1 (0.9–1.3) ADVA, 2005a
Navy 35 1.6 (1.0–2.1)  
Army 66 1.0 (0.7–1.2)  
Air Force 10 1.0 (0.5–1.8)  
1980–1994 51 1.3 (0.9–1.7) CDVA, 1997a
Sample of 1,000 Male Australian Vietnam Veterans—prevalence   All COIs  
450 interviewed 2005–2006 vs respondents to 2004–2005 national survey nr 4.7 (1.3–8.2) O’Toole et al., 2009
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence
1982–2000 204 1.1 (0.9–1.4) ADVA, 2005c
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality
1966–2001 14 0.6 (0.3–1.1) ADVA, 2005c
1982–1994 16 0.5 (0.2–1.3) CDVA, 1997b
International Vietnam-Veteran Studies
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008) 33 0.7 (0.5–1.0)  
Mortality (1988–2008) 4 0.6 (0.2–1.4)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—categorized high (n = 9) vs low (n = 10) 9 0.9 (0.4–2.3) Yi and Ohrr, 2014
Mortality (1992–2005)—categorized high (n = 6) vs low (n = 5)   1.5 (0.4–5.4) Yi et al., 2014b
HR per unit of log10 EOI (n = 180,639) 11 1.3 (0.9–1.8)  
OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Mortality 1939–1992 9 0.6 (0.3–1.2) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 5 0.5 (0.2–3.2)
7,553 not exposed to highly chlorinated PCDDs 4 0.0 (0.3–2.4)  
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)   Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP  
Incidence
Incidence 1943–1987 (men only) 4 4.3 (1.2–10.9) Lynge, 1993
Mortality
Mortality 1955–2006 7 1.3 (0.9–1.8) Boers et al., 2012
Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)   Dioxins, 2,4,5-T, 2,4,5-TCP  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality 1955–2006 (HRs for lagged TCDD plasma levels) 5 1.3 (0.8–2.2) Boers et al., 2012
Mortality 1955–1991 1 2.9 (0.1–15.9) Hooiveld et al., 1998
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Ever-exposed workers 2 1.0 (0.1–3.7)
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)      
Mortality 1969–2000 0 0.0 (0.0–3.0) ’t Mannetje et al., 2005
Sprayers (697 men and 2 women registered any time 1973–1984)      
Mortality 1973–2000 1 0.6 (0.0–3.4) ’t Mannetje et al., 2005
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (in IARC and NIOSH cohorts)   2,4,5-T; 2,4,5-TCP  
1942–2003 (n = 1,615) 2 0.6 (0.1–2.3) Collins et al., 2009b
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3) 8 1.2 (0.5–2.3) Burns CJ et al., 2011
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) 1 0.7 (0.0–4.0) Collins et al., 2009c
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Never 20 0.8 (0.5–1.3)  
Ever 21 1.2 (0.7–1.8)  
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
CANADA
Canadian Farm Operator Study—156,242 men farming in Manitoba, Saskatchewan, and Alberta in 1971; mortality from melanoma June 1971–Dec 1987      
Deaths among Saskatchewan farmers ≥ 35 yrs of age, 1971–1985 24 1.1 (0.7–1.6) Wigle et al., 1990
Sawmill Workers in British Columbia—23,829 workers for ≥ 1 yr at 11 mills using chlorophenates 1940–1985   Chlorophenates, not TCDD  
Incidence 1969–1989 38 1.0 (0.7–1.3) Hertzman et al., 1997
Mortality 1950–1989 17 1.4 (0.9–2.0)  
DENMARK
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Self-employed 72 0.7 (p < 0.05)  
Employee 17 0.6 (nr)  
Danish gardeners—incidence from 3,156 male and 859 female gardeners   Herbicides Hansen et al., 2007
25-yr follow-up (1975–2001) 31 1.3 (0.9–1.8)  
Born before 1915 (high exposure) 28 0.9 (0.6–1.4)  
Born 1915–1934 (medium exposure) 36 0.6 (0.4–0.9)  
Born after 1934 (low exposure) 5 0.3 (0.1–0.7)  
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 2000 5 3.6 (1.2–8.3) Swaen et al., 2004
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401) 9 1.2 (0.6–2.3) Torchio et al., 1994
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
SWEDEN
Incident melanoma cases 1961–1973 with agriculture as economic activity in 1960 census Swedish lumberjacks—Used phenoxys 1954–1967, Incidence 1958–1992 268 0.8 (0.7–1.0) Wiklund, 1983 Thörn et al., 2000
Exposed (n = 154) 0 nr  
Foremen (n = 15) 0 nr  
Lumberjacks (n = 139) 0 nr  
Unexposed lumberjacks (n = 241) 0 nr  
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Men
Whites (n = 119,648) 244 1.0 (0.8–1.1)  
Nonwhites (n = 11,446) 5 1.2 (0.4–2.9)  
Women
Whites (n = 2,400) 5 1.1 (0.4–2.7)  
Nonwhites (n = 2,066) 1 1.2 (0.0–6.6)  
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Private applicators 173 0.9 (0.8–1.0)
Commercial applicators 13 1.1 (0.6–1.9)  
Spouses 92 1.2 (0.9–1.4)  
Licensed, male pesticide applicators—150 cutaneous melanomas among 24,704 pesticide applicators     Dennis et al., 2010
Ever-exposed to arsenic-based pesticides vs never exposed 11 1.3 (0.7–2.4)  
Ever used lead arsenate insecticide 10 1.2 (0.6–2.3)  
Enrollment through 2002     Samanic et al., 2006
Dicamba—lifetime days exposure    
None 32 1.0  
1– < 20 10 1.0 (0.5–2.1)  
20– < 56 18 1.6 (0.8–3.0)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
56– < 116 6 0.7 (0.3–1.8)  
≥ 116 6 0.8 (0.3–2.1)  
    p-trend = 0.51  
Enrollment through 2002     Alavanja et al., 2005
Private applicators 100 1.0 (0.8–1.2)
Spouses of private applicators (> 99% women) 67 1.6 (1.3–2.1)  
Commercial applicators 7 1.1 (0.4–2.2)  
Mortality
Enrollment through 2007, vs state rates     Waggoner et al., 2011
Applicators (n = 1,641) 38 0.8 (0.5–1.1)
Spouses (n = 676) 10 0.8 (0.4–1.4)  
Enrollment through 2000, vs state rates     Blair et al., 2005a
Private applicators (men and women) 13 0.7 (0.4–1.3)
Spouses of private applicators (> 99% women) 2 0.4 (0.1–1.6)  
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Incidence
20-yr follow-up to 1996—men and women     Pesatori et al., 2009
Zone A 1 1.6 (0.2–11.6)
Zone B 2 0.5 (0.1–2.0)  
Zone R 19 0.7 (0.4–1.1)  
Mortality
25-yr follow-up to 2001—men and women     Consonni et al., 2008
Zone A 1 3.1 (0.4–22.0)
Zone B 2 1.0 (0.2–3.9)  
Zone R 12 0.8 (0.4–1.5)  
20-yr follow-up to 1996     Bertazzi et al., 2001
Zones A and B—men 1 1.5 (0.2–12.5)
Zones A and B—women 2 1.8 (0.4–7.3)  
15-yr follow-up to 1991—men     Bertazzi et al., 1997
Zone A 0 0.0 (0.0–60.2)
Zone B 0 0.0 (0.0–9.1)  
Zone R 3 1.1 (0.2–3.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
15-yr follow-up to 1991—women     Bertazzi et al., 1997
Zone A 1 9.4 (0.1–52.3)
Zone B 0 0.0 (0.0–5.4)  
Zone R 3 0.6 (0.1–1.8)  
10-yr follow-up to 1986—men     Bertazzi et al., 1989a
Zone A, B, R 3 3.3 (0.8–13.9)
10-yr follow-up to 1986—women     Bertazzi et al., 1989a,b
Zone A, B, R 1 0.3 (0.1–2.5)
SWEDEN
Swedish fishermen (high consumption of fish with persistent organochlorines)   Organochlorine compounds Svensson et al., 1995a
Incidence
East coast 0 0.0 (0.0–0.7)  
West coast 20 0.8 (0.5–1.2)  
Mortality
East coast 0 0.0 (0.0–1.7)  
West coast 6 0.7 (0.3–1.5)  
CASE-CONTROL STUDIES
International Case-Control Studies
British Columbia—melanoma cases recruited for a study evaluating effects of ultraviolet exposure and gene variants using plasma specimens and sun-exposure data (80 cases vs 310 controls)   PCBs Gallagher et al., 2011
Highest PCB-exposure quintile 29 6.0 (2.0–18.2)  
dl PCBs 25 2.8 (1.0–8.0)  
Non–dl PCBs 30 7.0 (2.3–21.4)  
European—uveal melanoma patients (n = 323), diagnosed 1994–1997, identified from hospital records (diagnosed 1994–1995) in nine countries and matched controls (n = 3,198)   Herbicides Behrens et al., 2012
Personal application of herbicides 8 0.5 (0.2–1.3)  
Personal mixing of herbicides 6 0.5 (0.2–1.5)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
UK men, 18–35 yrs of age from counties with particular chemical manufacturing—mortality   Herbicides, Chlorophenols Magnani et al., 1987
Herbicides nr 1.2 (0.4–4.0)  
Chlorophenols nr 0.9 (0.4–2.3)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; ACC, Army Chemical Corps; AFHS, Air Force Health Study; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; dl, dioxin-like; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; MOS, military occupational specialty; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; pg/g, picogram per gram; SEA, Southeast Asia; SIR, standardized incidence ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; VA, US Department of Veterans Affairs.

aCohorts are male and outcome mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

0.15–1.42, based on four deaths) and incidence (SIR = 0.74, 95% CI 0.51–1.04, based on 33 cases) were less than expected.

Mortality (Yi et al., 2014b) and cancer incidence of (Yi and Ohrr, 2014) were assessed among Korean Veterans who had served in Vietnam between 1964 and 1973. In analyses of cancer incidence, Yi and Ohrr (2014) reported a decreased risk of melanoma (HR = 0.90, 95% CI 0.36–2.30) in the internal comparison of the high- and low-exposure groups based on the EOI scores. Similarly for melanoma mortality, Yi et al. (2014b) reported a modestly increased risk for the high-versus low-exposure groups (HR = 1.49, 95% CI 0.41–5.40) and the individual log-transformed EOI scores (HR = 1.26, 95% CI 0.89–1.77).

Occupational, Environmental, and Case-Control Studies Since Update 2012, no additional occupational, environmental, or case-control studies have been published on melanoma concerning relevant exposures to the COIs.

Other Studies Considered A recent study of cancer outcomes found an association with malignant melanoma and the total area of greenhouse agricultural fields in the Anatalya region of Turkey (Uysal et al., 2013). These results have limited bearing on the issue of herbicide exposure and melanoma because of the

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

absence of a precise measure of exposure (total area of greenhouse agricultural fields as a proxy for exposure) and the exposure of interest was pesticide usage rather than herbicide, which are not typically used in greenhouse operations.

Biologic Plausibility

TCDD and related herbicides have not been found to cause melanoma in animal models. In general, rodents, which are used in most toxicology studies, are not a good model for studying melanoma. TCDD does produce non-melanoma skin cancers in animal models (Wyde et al., 2004). As discussed elsewhere in this chapter, TCDD is a known tumor-promoter and could act as a promoter for skin cancer initiators, such as UV radiation. Ikuta et al. (2009) examined the physiologic role of the AHR in human skin and theorized that overactivation can lead to skin cancers, but they provided no evidence that melanoma incidence is increased after TCDD exposure. Recent work in this field has shown that the AHR mediates UVB-induced skin tanning in a murine model through an action on melanocytes; this is evidence that skin pigmentation and potentially the regulatory action of the target cell for melanoma may be affected by TCDD. Studies of human cells have also confirmed a role of the AHR in regulation of keratinocytes and melanocytes. Kalmes et al. (2011) showed that AHR signaling in immortalized HaCaT cells is associated with cell-cycle progression. In human melanocytes, Luecke et al. (2010) demonstrated that TCDD exposure induced tyrosinase and tyrosinase-related protein 2 gene expression—an indicatation that AHR signaling after TCDD exposure modulates melanogenesis. O’Donnell et al. (2012) further showed that the activity of the AHR was associated with the proliferation of melanoma cells. Finally, a study of a Han Chinese population (Wang XW et al., 2012) has shown that normal genetic variants of the AHR are associated with the occurrence of vitiligo; this strongly suggests that the AHR is associated with melanocyte distribution in humans.

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

No compelling association between the COIs and melanoma was observed in any of the three new occupational studies.

The committee responsible for Update 2006 was unable to reach a consensus as to whether there was limited or suggestive evidence of an association between exposure to the COIs and melanoma or inadequate or insufficient evidence to determine whether there is an association. That committee considered the findings from the Air Force Health Study (AFHS) on melanoma evaluated in terms of TCDD measurements (Akhtar et al., 2004; Pavuk et al., 2005) to be of prime interest. However, the data from the final AFHS examination cycle indicate that

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

many more melanoma cases were diagnosed in the comparison veterans than in the Ranch Hand subjects. Consequently, the committee responsible for Update 2006 requested that a TCDD-based analysis be performed in a uniform manner on the most recent melanoma counts for all subjects in the AFHS in order to clarify whether the TCDD-based conclusions on updated information for only the comparison subjects (Pavuk et al., 2005) would strengthen or contradict the rather suggestive findings for the Operation Ranch Hand subjects using melanoma information current for an earlier examination cycle (Akhtar et al., 2004) and to permit definitive evaluation of the possible association between the COIs and melanoma. Such a comprehensive analysis of the most current melanoma data from the AFHS has not as yet been published.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and melanoma (dermal or ocular).

Basal-Cell and Squamous-Cell Cancers
(Non-Melanoma Skin Cancers)

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and skin cancers, and additional information available to the committee responsible for Update 1996 did not change that conclusion. The committee responsible for Update 1998 considered the literature on non-melanoma skin cancers separately from that on melanoma and concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and basal-cell or squamous-cell cancers. The committees responsible for Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, Update 2010, and Update 2012 did not change that conclusion.

Table 8-19 summarizes the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies The incidence of non-melanoma skin cancer was assessed among Korean veterans who had served in Vietnam between 1964 and 1973 (Yi and Ohrr, 2014). The researchers reported no increase in “other skin” cancers (HR = 0.99, 95% CI 0.63–1.57) in the internal comparison of the high- and low-exposure groups based on the EOI scores.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-19 Selected Epidemiologic Studies—Other Non-Melanoma (Basal-Cell and Squamous-Cell) Skin Cancers (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)   All COIs  
Incidence—basal cell, squamous cell
1982–2003—White SEA comparison veterans only (n = 1,482). Serum TCDD (pg/g) based on model with exposure variable loge(TCDD) 253 1.2 (0.9–1.4) Pavuk et al., 2005
Per unit increase of –loge(TCDD) (pg/g) Quartiles (pg/g):      
0.4–2.6 50 nr  
2.6–3.8 59 1.2 (0.8–1.8)  
3.8–5.2 71 1.5 (1.1–2.3)  
> 5.2 73 1.4 (0.9–2.0)  
Number of years served in SEA (per year of service) 253 1.0 (0.9–1.1)  
Quartiles (years in SEA):      
0.8–1.3 55 nr  
1.3–2.1 50 0.9 (0.6–1.4)  
2.1–3.7 73 1.1 (0.8–1.6)  
3.7–16.4 75 1.2 (0.8–1.7)  
Attended 1987 exam—Ranch Hand personnel (n = 995) vs SEA veterans (n = 1,299)     Wolfe et al., 1990
Basal-cell carcinoma 78 1.5 (1.0–2.1)  
Squamous-cell carcinoma 6 1.6 (0.5–5.1)  
International Vietnam-Veteran Study
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters - 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
Validation Study (expected number of exposed cases)      
Men 6,936 nr CDVA, 1998a
Women 37 nr CDVA, 1998b
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
International Vietnam-Veteran Studies
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—“other skin” (C44) categorized high (n = 40) vs low (n = 38)   1.0 (0.6–1.6) Yi and Ohrr, 2014
OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates 4 0.9 (0.3–2.4)  
Mortality 1939–1992     Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 4 1.3 (0.3–3.2)
7,553 not exposed to highly chlorinated PCDDs 0 0.0 (0.0–3.4)  
British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)   MCPA  
Mortality through 1983 3 3.1 (0.6–9.0) Coggon et al., 1986
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Through 1994 (n = 1,517) 0 nr Burns et al., 2001
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
DENMARK
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Men
Self-employed 493 0.7 (p < 0.05)  
Employee 98 0.7 (p < 0.05)  
Women
Self-employed 5 0.3 (p < 0.05)  
Employee 10 0.9 (nr)  
Family worker 90 0.6 (p < 0.05)  
Danish gardeners—incidence from 3,156 male and 859 female gardeners (skin, ICD-7 190–191) 31 Herbicides
1.3 (0.9–1.8)
Hansen et al., 2007
25-yr follow-up (1975–2001)      
Born before 1915 (high exposure) 28 0.9 (0.6–1.4)  
Born 1915–1934 (medium exposure) 36 0.6 (0.4–0.9)  
Born after 1934 (low exposure) 5 0.3 (0.1–0.7)  
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 2000—melanoma, squamous-cell carcinoma, unknown skin cancer (mortality presumably attributable to melanoma) 5 3.6 (1.2–8.3) Swaen et al., 2004
ICELANDIC pesticide users (n = 2,449, 1,860 men and 589 women), 2,4-D used most often, little 2,4,5-T     Zhong and Rafnsson, 1996
Men 5 2.8 (0.9–6.6)  
Men, women combined 5 2.6 (0.8–6.1)  
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401) 3 0.6 (0.1–1.8) Torchio et al., 1994
SWEDEN
Incident melanoma cases 1961–1973 with agriculture as economic activity in 1960 census Swedish lumberjacks—Used phenoxys 1954–1967, Incidence 1958–1992 708 99% CI 1.1 (1.0–1.2) Wiklund, 1983 Thörn et al., 2000
Exposed (n = 154)      
Foremen (n = 15) 1 16.7 (0.2–92.7)  
Lumberjacks (n = 139) 0  
Unexposed lumberjacks (n = 241) 3 2.0 (0.4–5.8)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states (skin, including melanoma)   Herbicides
PCMRs
Blair et al., 1993
Men
Whites (n = 119,648) 425 1.1 (1.0–1.2)  
Nonwhites (n = 11,446) 13 1.0 (0.5–1.7)  
Women
Whites (n = 2,400) 6 1.0 (0.4–2.1)  
Nonwhites (n = 2,066) 3 1.8 (0.4–5.4)  
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group)   TCDD  
Incidence
20-yr follow-up to 1996—men and women     Pesatori et al., 2009
Zone A 3 1.4 (0.5–4.3)
Zone B 5 0.4 (0.2–0.9)  
Zone R 88 0.9 (0.8–1.2)  
10-yr follow-up to 1991—men     Bertazzi et al., 1993
Zone A 1 2.4 (0.3–17.2)
Zone B 2 0.7 (0.2–2.9)  
Zone R 20 1.0 (0.6–1.6)  
10-yr follow-up to 1991—women     Bertazzi et al., 1993
Zone A 1 3.9 (0.5–28.1)
Zone B 2 1.3 (0.3–5.1)  
Zone R 13 1.0 (0.6–1.9)  
Other International Environmental Study
Swedish fishermen (high consumption of fish with persistent organochlorines)   Organochlorine compounds Svensson et al., 1995
Incidence
East coast 22 2.3 (1.5–3.5)  
West coast 69 1.1 (0.9–1.4)  
Mortality
East coast 0 0.0 (0.0–15.4)  
West coast 5 3.1 (1.0–7.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
CASE-CONTROL STUDIES
International Case-Control Studies
Alberta, Canada residents—squamous-cell carcinoma—incidence   Herbicides Gallagher et al., 1996
All herbicide exposure 79 1.5 (1.0–2.3)  
Low herbicide exposure 33 1.9 (1.0–3.6)  
High herbicide exposure 46 3.9 (2.2–6.9)  
Alberta, Canada residents—basal-cell carcinoma   Herbicides Gallagher et al., 1996
All herbicide exposure 70 1.1 (0.8–1.7)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, 2-methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Clemens et al. (2014) reviewed clinical characteristics of 100 consecutive male patients with Fitzpatrick skin types I though IV who enrolled in the Agent Orange registry at the Veterans Affairs Hospital of Washington, DC, between August 2009 and January 2010. Because by design all participants were selected on the basis of being presumably exposed to Agent Orange and being diagnosed with non-melanotic invasive skin cancers, the committee deemed this analysis of no value with respect to examining relationships between the COIs.

Occupational, Environmental, and Case-Control Studies Since Update 2012, no additional occupational, environmental, or case-control studies of nonmelanoma skin cancers and exposure to the COIs have been published.

Biologic Plausibility

There are no new studies on animal models of skin cancers that are relevant to this update. TCDD has been shown to produce non-melanoma skin cancers in animal models (Wyde et al., 2004). As discussed elsewhere in this chapter, TCDD is a known tumor promoter and could act as a promoter for skin-cancer initiators,

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

such as UV radiation, but no experiments have been conducted specifically to support this potential mechanism.

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

In accord with the results of reports previously assessed, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and basal-cell or squamous-cell cancers.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and basal-cell or squamous-cell cancers.

BREAST CANCER

Breast cancer (ICD-9 174 for females, ICD-9 175 for males) is the second most common type of cancer (after non-melanoma skin cancers) in women in the United States. ACS estimated that 231,840 women would receive diagnoses of breast cancer in the United States in 2015 and that 40,290 would die from it (Siegel et al., 2015). Overall, those numbers represent about 29 percent of the new cancers and 14 percent of cancer deaths in women. Incidence data on breast cancer are presented in Table 8-20. In men and women, breast cancer incidence generally increases with age. In the age groups of most Vietnam veterans, the incidence in men is higher in blacks than in whites; in women the incidence in whites is generally higher (NCI, 2015).

Established risk factors for women other than age include a personal or family history of breast cancer, alcohol consumption, and some characteristics

TABLE 8-20 Average Annual Incidence (per 100,000) of Breast Cancer in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Men 3.0 2.9 4.5 5.0 5.0 7.4 6.0 6.1 8.1
Women 343.6 353.6 341.6 422.6 437.9 397.8 440.6 460.1 422.8

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

of reproductive history—specifically, early menarche, late onset of menopause, and either no pregnancies or a first full-term pregnancy after the age of 30 years (Kamińska et al., 2015). In a meta-analysis of studies on alcohol consumption and female breast cancer, Corrao et al. (2004) reported that, in comparison to those who never drank, light drinkers (≤ 1 drink/day or 12.5 g/day) had an elevated pooled relative risk (RR = 1.25, 95% CI 1.20–1.29), whereas the risk was more markedly increased (RR = 1.55, 95% CI 1.44–1.67) for heavy drinkers (≥ 4 drinks/day or 50 g/day). Other lifestyle risk factors for breast cancer include high body mass index/obesity and physical inactivity. In addition, breast cancer risk is increased by the prolonged use of hormone-replacement therapy, particularly preparations that combine estrogen and progestins, whereas estrogen-only therapy (only applied in women without a uterus) slightly decreased the risk (Anderson et al., 2004; Chlebowski et al., 2003). The potential of other personal behavioral and environmental factors (including the use of exogenous hormones) to affect breast cancer incidence is being studied extensively.

The roughly 10,000 female Vietnam veterans who were potentially exposed to herbicides in Vietnam by now would have reached menopause. Given the high incidence of breast cancer in older and postmenopausal women in general, it is expected on the basis of demographics alone that the breast cancer burden in female Vietnam veterans will be increasing in the near future.

The vast majority of breast cancer epidemiologic studies involve women. Although there has been an increase in breast cancer incidence in men over the past 30 years (Kamińska et al., 2015), the disease occurs rarely in men, with 2,350 new cases expected in 2015 (Siegel et al., 2015). Instances of male breast cancer are noted below when reported, but the committee’s conclusions are based on the studies in women.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and breast cancer. The additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. After consideration of a new study with positive findings on an association between 2,4-D exposure and breast cancer in female farm workers in California (Mills and Yang, 2005)—in conjunction with the earlier findings of Kang et al. (2000b), Kogevinas et al. (1997), Revich et al. (2001), and Warner et al. (2002)—the committee responsible for Update 2006 was unable to reach consensus as to whether there might be limited or suggestive evidence of an association between the COIs and breast cancer. An increase in the incidence of breast cancer in the residents of Zone A in Seveso may be emerging with greater latency (Pesatori et al., 2009), but in light of the null findings on mortality from breast cancer in the important cohorts of

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

female Vietnam-era veterans (Cypel and Kang, 2008) and Seveso residents (Consonni et al., 2008), all members of the committees for Update 2008 and Update 2010 concurred that breast cancer should remain in the category of inadequate or insufficient evidence to determine whether there is an association.

Update 2012, examined several occupational and environmental cohort studies that had investigated breast cancer incidence or mortality The strongest evidence came from the Hamburg cohort of 398 women employed at an insecticide/herbicide plant in Hamburg (Manuwald et al., 2012), which reported an increased breast cancer mortality (SMR = 1.86, 95% CI 1.12–2.91) relative to the general population. Follow-ups of workers from Dow’s Michigan cohort (Burns CJ et al., 2011) and from the NIOSH PCP cohort (Ruder and Yiin, 2011) found no increased rates of breast cancer; however, the number of women in these cohorts was relatively small. An update of the Seveso Women’s Health Study through 2009 reported a non-statistically significant 46 percent increase in breast cancer incidence (95% CI 0.89–2.33) with increasing serum TCDD concentrations (Warner et al., 2011). With stratification by decade since the industrial accident in 1976, the breast cancer risk was highest in the interval 11–20 years after explosion (HR = 2.23, 95% CI 1.09–4.56) and then subsided in the latest period, 21–32 years after the explosion (HR = 1.06, 95% CI 0.58–1.93). After careful consideration of the new evidence and the results in previous updates, the committee for Update 2012 did not change the previous category of association.

Table 8-21 summarizes the relevant research.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

Since Update 2012, Kang et al. (2014) updated vital status through 2010 for three sets of female US Vietnam-era veterans: 4,734 deployed to Vietnam, 2,062 deployed to countries near Vietnam, and 5,313 non-deployed. From the end of the Vietnam War in 1973 through 2010, 81, 34, and 89 deaths from breast cancer were observed among those who, respectively, served in Vietnam, served near Vietnam, or were non-deployed. Compared to the general population of US women, there were slight, although not statistically significant, increases in the risk of breast cancer mortality in those who served in Vietnam (SMR = 1.11, 95% CI 0.88–1.38) or who were non-deployed (SMR = 1.12, 95% CI 0.90–1.37), but there was no excess for those serving near Vietnam (SMR = 1.03, 95% CI 0.71–1.44). Internal comparison to the non-deployed era veterans found that breast cancer mortality was not associated with service in Vietnam (RR = 1.05, 95% CI 0.77–1.43) or

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-21 Selected Epidemiologic Studies—Breast Cancer (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Mortality
1965–2000 0 nr Boehmer et al., 2004
US VA Cohort of Female Vietnam-era Veterans served in Vietnam (n = 4,586); nurses only (n = 3,690); non-deployed (n = 5,325; nurses only (n = 3,282)   All COIs  
Incidence
Breast cancer 170 1.2 (0.9–1.5) Kang et al., 2000b
Mortality
Through 2010 170 1.1 (0.8–1.4) Kang et al., 2014
Vietnam nurses only 118 0.9 (0.6–1.3)
Through 2004 57 1.0 (0.7–1.4) Cypel and Kang, 2008
Vietnam nurses only 44 0.9 (0.6–1.4)
Through 1991 (Vietnam nurses not reported separately) 26 1.0 (0.6–1.8) Dalager et al., 1995a
Through 1987 (Vietnam nurses not reported separately) 17 1.2 (0.6–2.5) Thomas et al., 1991
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 7 0.9 (0.4–1.9) ADVA, 2005b
Navy 1 0.6 (0.0–3.3)  
Army 5 1.0 (0.3–2.2)  
Air Force 1 1.1 (0.0–6.3)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Validation Study   Expected number of exposed cases  
Women 17 5 (2–11) CDVA, 1998b
Mortality
All branches, return–2001 4 2.2 (0.6–5.4) ADVA, 2005a
Navy 1 2.5 (0.0–13.5)  
Army 3 2.5 (0.5–7.2)  
Air Force 0 0.0 (0.0–14.6)  
1980–1994 (men) 3 5.5 (1.0– > 10.0) CDVA, 1997a
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence
1982–2000 0 0.0 (0.0–2.4) ADVA, 2005c
Mortality
1966–2001 nr   ADVA, 2005c
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—breast cancer (C50) categorized high (n = 3) vs low (n = 5)   0.5 (0.1–2.3) Yi and Ohrr, 2014
OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Mortality 1939–1992 (13,831 exposed to highly chlorinated PCDDs vs 7,553 unexposed)   Phenoxy herbicides Kogevinas et al., 1997
Men 2 1.6 (0.2–2.1)  
Exposed to highly chlorinated PCDDs 2 2.6 (0.3–9.3)  
Not exposed to highly chlorinated PCDDs 0 nr  
Women 12 1.2 (0.6–2.1)  
Exposed to highly chlorinated PCDDs 9 2.2 (1.0–4.1)  
Not exposed to highly chlorinated PCDDs 3 0.5 (0.1–1.6)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort     Saracci et al., 1991
Men 2 3.5 (0.4–12.5)  
Women 1 0.3 (0.0–1.7)  
Mortality, incidence of women in production (n = 699) and spraying (n = 2) compared to national death rates and cancer incidence rates   TCDD Kogevinas et al., 1993
7 0.9 (0.4–1.9)  
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)   Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP  
Incidence 1943–1982 (women) 13 0.9 (nr) Lynge, 1985
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)   Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP  
Mortality 1952–2007     Manuwald et al., 2012
Women 19 1.9 (1.1–2.9)
Mortality 1952–1989—stats on men only, 1,184 (tables all for 1,148 men, not necessarily German nationals) vs national rates (also vs gas workers); same observation period as Becher et al., 1966 9 2.2 (1.0–4.1) Manz et al., 1991
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Ever-exposed workers 2 1.4 (0.2–5.0)
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)      
Mortality 1969–2000     ’t Mannetje et al., 2005
Phenoxy herbicide producers    
Men 1 32 (0.8–175)  
Women 1 1.3 (0.0–7.2)  
Phenoxy herbicide sprayers (> 99% men)      
Men 0 0.0 (0.0–214)  
Women 0 0.0 (0.0–86.0)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
1940–2005 (n = 2,122) 1 0.5 (0.0–2.9)  
PCP and TCP (n = 720) 0 nr  
PCP (no TCP) (n = 1,402) 1 0.6 (0.0–3.1)  
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3) 0 nr Burns CJ et al., 2011
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Never 21 0.9 (0.6–1.4)  
Ever 32 0.9 (0.6–1.3)  
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
DENMARK
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Men
Self-employed 5 0.5 (nr)  
Employee 3 1.4 (nr)  
Women
Self-employed 41 0.9 (nr)  
Employee 25 0.6 (p < 0.05)  
Family worker 429 0.8 (p < 0.05)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
SWEDEN
Incident breast cancer cases 1961–1973 with agriculture as economic activity in 1960 census     Wiklund, 1983
Men, women   99% CI  
  444 0.8 (0.7–0.9)  
Men nr 1.0 (nr)  
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Men
Whites (n = 119,648) 18 0.7 (0.4–1.2)  
Nonwhites (n = 11,446) 4 1.7 (0.5–4.4)  
Women
Whites (n = 2,400) 71 1.0 (0.8–1.3)  
Nonwhites (n = 2,066) 30 0.7 (0.5–1.0)  
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Private applicators 33 1.0 (0.7–1.3)
Commercial applicators 0 nr  
Spouses 770 1.0 (0.9–1.1)  
Enrollment through 2002     Alavanja et al., 2005
Private applicators 27 1.1 (0.7–1.6)
Spouses of private applicators (> 99% women) 474 1.0 (0.9–1.1)  
Commercial applicators 1 0.6 (0.1–3.5)  
Enrollment through 2001     Engel et al., 2005
Wives’ own use of phenoxy herbicides 41 0.8 (0.6–1.1)
2,4-D 41 0.8 (0.6–1.1)  
Husbands’ own use of phenoxy herbicides 110 1.1 (0.7–1.8)  
2,4-D 107 0.9 (0.6–1.4)  
2,4,5-T 44 1.3 (0.9–1.9)  
2,4,5-TP 19 2.0 (1.2–3.2)  
Mortality      
Enrollment through 2007, vs state rates     Waggoner et al., 2011
Applicators (n = 1,641) 11 0.9 (0.5–1.7)
Spouses (n = 676) 136 0.8 (0.7–0.9)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Enrollment through 2000, vs state rates     Blair et al., 2005a
Private applicators (men and women)
Spouses of private applicators (> 99% women)
3
54
0.9 (0.2–2.7)
0.9 (0.7–1.1)
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group)   TCDD  
Incidence
20-yr follow-up to 1996—men and women
Zone A 8 1.4 (0.7–2.9) Pesatori et al., 2009
15+ yrs after accident 5 2.6 (1.1–6.2)
10–14 yrs after accident 2 1.4 (0.4–5.7)  
5–9 yrs after accident 1 0.8 (0.1–5.7)  
Zone B 30 0.9 (0.6–1.2)  
Zone R 249 1.0 (0.9–1.2)  
10-yr follow-up to 1991—men     Bertazzi et al., 1993
Zone R 1 1.2 (0.1–10.2)
10-yr follow-up to 1991—women     Bertazzi et al., 1993
Zone A 1 0.5 (0.1–3.3)
Zone B 10 0.7 (0.4–1.4)  
Zone R 106 1.1 (0.9–1.3)  
Mortality
25-yr follow-up to 2001—men and women     Consonni et al., 2008
Zone A 2 0.6 (0.2–2.4)
Zone B 13 0.6 (0.3–1.2)  
Zone R 133 0.9 (0.7–1.1)  
20-yr follow-up to 1996     Bertazzi et al., 2001
Zones A and B—women 14 0.7 (0.4–1.3)
15-yr follow-up to 1991—women     Bertazzi et al., 1997
Zone A 1 0.6 (0.0–3.1)  
Zone B 9 0.8 (0.4–1.5)  
Zone R 67 0.8 (0.6–1.0)  
10-yr follow-up to 1986—women     Bertazzi et al., 1989a, b
Zone A 1 1.1 (0.1–7.5)  
Zone B 5 0.9 (0.4–2.1)  
Zone R 28 0.6 (0.4–0.9)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Seveso (Italy) Women’s Health Study—981 women who were infants to 40 yrs of age when exposed—incidence   TCDD  
HRs for 10-fold increase in TCDD [log10 lipid adjusted TCDD (ppt)]     Warner et al., 2011
1976–2009 33 1.4 (0.9–2.3)  
Years from accident to diagnosis
0–10 yrs (1976–1986) 3 2.9 (0.9–9.4)  
11–20 yrs (1987–1996) 10 2.2 (1.1–4.6)  
21–32 yrs (1997–2009) 20 1.1 (0.6–1.9)  
1976–1997 15 2.1 (1.0–4.6) Warner et al., 2002
Ecological Study of Residents of Chapaevsk, Russia   Dioxin Revich et al., 2001
Women
Regional (Samara) nr 50.7 (nr)  
National (Russia) nr 46.2 (nr)  
Mortality—1995–1998 (SMR vs regional rates)
Women 58 2.1 (1.6–2.7)  
FINLAND
Finnish fishermen (n = 6,410) and spouses (n = 4,260) registered between 1980 and 2002 compared to national statistics   Serum dioxin Turunen et al., 2008
Fisherman’s wives 18 0.8 (0.5–1.3)  
CASE-CONTROL STUDIES
US Case-Control Studies
California—Women undergoing breast biopsies in San Francisco area hospitals—79 breast cancer cases vs 52 controls with benign breasts conditions—incidence   PCDDs, PCDFs Reynolds et al., 2005
Total TEQs (pg/g) in adipose breast tissue
≤ 14.0 24 1.0  
14.1–20.9 22 0.7 (0.3–1.9)  
≤ 21.0 33 0.3 (0.3–2.0)  
    p-trend = 0.99  
California—Registry-based study of 128 Hispanic agricultural farm workers (women) diagnosed 1988–2001 and 640 cancer-free controls.   Herbicides Mills and Yang, 2005
Cancer diagnosis 1987–1994
Low 2,4-D use 12 0.6 (0.2–1.9)  
High 2,4-D use 8 0.6 (0.2–1.7)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Cancer diagnosis 1995–2001
Low 2,4-D use 19 2.2 (1.0–4.9)  
High 2,4-D use 21 2.1 (1.1–4.3)  
California Teachers Study Cohort—residential proximity to use of “endocrine disruptors” (including 2,4-D, cacodylic acid)   2,4-D, cacodylic acid Reynolds et al., 2004
Quartiles of use (lb/mi2)
< 1 1,027 1.0  
1–21 274 1.0 (0.8–1.1)  
22–323 114 0.9 (0.7–1.1)  
≥ 324 137 1.0 (0.9–1.3)  
California women (n = 146) receiving medical care in Woodland Hills (1995–1996), 73 breast cancer cases vs 73 controls undergoing mammoplasty 73 Organochlorines nr Bagga et al., 2000
New York—Population-based study of lifetime residential pesticide use in Long Island; 1,508 newly diagnosed cases and 1,556 matched controls (1996–1997)   Pesticides Teitelbaum et al., 2007
Used lawn and garden pesticides
Never 240 1.0  
Ever 1,254 1.3 (1.1–1.6)  
Product for weeds 1,109 1.4 (1.2–1.8)  
North Carolina—862 female farm workers, residents diagnosed 1993–1996 and 790 controls   Herbicides Duell et al., 2000
Used pesticides in garden 228 2.3 (0.7–3.1)  
Laundered clothes for pesticide user 119 4.1 (2.8–5.9)  
Connecticut patient at Yale–New Haven hospital   dl PCBs Holford et al., 2000
with breast-related surgery; dl congener 156 nr 0.9 (0.8–1.0)  
International Case-Control Studies
Canadian women in Quebec City—315 newly diagnosed breast cancer cases (and plasma concentrations) vs hospital- and population-based controls 314 Organochlorines, nr Demers et al., 2000
Denmark females with breast cancer in Copenhagen City Heart Study (n = 195), 2 blood samples taken (1976–1978, 1981–1983)   Organochlorines Overall survival RR Høyer et al., 2000
  195 2.8 (1.4–5.6)  
France—Besançon residents in zones of dioxin exposure around solid-waste incinerator (434 incident breast cancer cases; 2,170 randomly selected controls) (1996–2002)   Dioxin Viel et al., 2008a
Women, 20–59 yrs of age      
Very low 41 1.0  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Low 81 1.1 (0.7–1.6)  
Intermediate 64 1.3 (0.8–1.9)  
High 11 0.9 (0.4–1.8)  
Women, 20–59 yrs of age
Very low 50 1.0  
Low 111 0.9 (0.6–1.3)  
Intermediate 72 1.0 (0.7–1.4)  
High 4 0.3 (0.1–0.9)  
Greenland Inuit women with breast cancer (n = 31) vs 115 matched controls, 2000–2003   POPs, dl PCBs Bonefeld-Jorgensen and Long, 2011
dl PCBs in serum (mediam: cases vs controls)   56.8 vs 65.4 pg/g lipid  
    p = 0.0009  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophen-oxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,4,5-TP, 2 (2,4,5-trichlorophenoxy) propionic acid; 2,5-DCP, 2,5-dichlorophenol; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; dl, dioxin-like; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCDF, polychlorinated dibenzofurans; PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; pg/g, picogram per gram; POP, persistent organic pollutant; ppt, parts per trillion; RR, relative risk; SIR, standardized incidence ratio; SMR, standardized mortality rate; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; TEQ, toxicity equivalent; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

near Vietnam (RR = 0.93, 95% CI 0.62–1.39). Finally, when the analysis was restricted to nurses, who constitute the majority of female Vietnam-era veterans, those who served in Vietnam (RR = 0.88, 95% CI 0.61–1.27) or near Vietnam (RR = 0.79, 95% CI 0.47–1.31) had lower breast cancer mortality than non-deployed US nurses, although the effect was not statistically significant (Kang et al., 2014).

Yi and Ohrr (2014) reported on male breast cancer in the Korean Veterans Health Study. Eight incident cases of male breast cancer (of which three were in the high-exposure category) were ascertained during follow-up of this cohort. Comparing veterans with higher EOI scores to those in the group with lower scores, there was an inverse association with male breast cancer risk (HR = 0.53, 95% CI 0.12–2.26), although the confidence interval was wide and included the null, possibly because of the low number of incident cases.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Occupational and Environmental Studies

No occupational or environmental studies of exposure to the COIs and breast cancer have been published since Update 2012.

Case-Control Studies

El-Zaemey et al. (2014) conducted a population-based case-control study of 1,205 breast cancer cases in Western Australia that were diagnosed and ascertained from 2009 through 2011 along with 1,789 controls. Information on household pesticide exposure was collected from self-report questionnaires, whereas occupational exposure to pesticides was constructed based on occupational history and potential exposure to pesticides using job-specific modules. Women’s exposures to pesticides were not associated with an increased risk of breast cancer either for self-reported household use (OR = 1.10, 95% CI 0.86–1.37) or for occupational pesticide exposure (OR = 0.77, 95% CI 0.45–1.32). Although the sample size of the study was large, one limitation is that information on exposure was collected after the breast cancer diagnosis, and thus there was potential for recall bias. In addition, the results of this study were not specific to COI or herbicides, and thus are not considered relevant to the committee’s task.

Biologic Plausibility

The experimental evidence indicates that 2,4-D, 2,4,5-T, and TCDD are weakly genotoxic at most. However, TCDD is a demonstrated carcinogen in animals and is recognized as having carcinogenic potential in humans because of the mechanisms discussed in Chapter 4.

There is no evidence from carcinogenicity bioassays that TCDD causes breast cancer in laboratory animals (Baan et al., 2009; IARC, 2012c). However, studies performed in laboratory animals indicate that TCDD may modify the carcinogenic process in the mammary gland and that the effect of TCDD may depend on the age of the animal. For example, a single oral exposure of 50-day-old Sprague Dawley rats to 10 µg/kg TCDD 3 days prior to a single administration of the chemical carcinogen dimethylbenzanthracene (DMBA) was found to inhibit mammary-tumor induction (Holcombe and Safe, 1994), but a single 2.5 µg/kg dose of TCDD to 18-day-old rats slightly increased tumor induction when followed by a single injection of the carcinogen methylnitrosourea (MNU) at 21 days of age (Desaulniers et al., 2001).

Fenton (2009) recently reviewed the literature on TCDD and breast cancer and suggested a mechanism that may be related to endocrine disruption, which might indicate a close association between the development of mammary cancers and mammary gland differentiation. Agents capable of disrupting the ability of the normal mammary epithelial cell to enter or maintain its appropriate status (a

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

proliferative, differentiated, apoptotic state), to maintain its appropriate architecture, or to conduct normal hormone (estrogen) signaling are likely to act as carcinogens, co-carcinogens, or tumor promoters for the breast (Fenton, 2006; McGee et al., 2006). In that light, it is interesting that postnatal exposure of pregnant rats to TCDD has been found to alter the proliferation and differentiation of cells in the mammary gland (Birnbaum and Fenton, 2003; Vorderstrasse et al., 2004). There is evidence that TCDD directly targets mammary epithelial cells and the surrounding stromal fat cells during pregnancy-induced mammary gland differentiation; this points to interference with stromal–epithelial cross-talk as one of several underlying pathways (Lew et al., 2011). Jenkins et al. (2007) used a rat carcinogen-induced mammary cancer model to show that prenatal exposure to TCDD alters mammary gland differentiation and increases susceptibility to mammary cancers by altering the expression of estrogen-receptor (ER) genes and of genes involved in oxidative-stress defense. Thus, the effect of TCDD may depend on the timing of the exposure and on the magnitude of gene expression at the time of exposure; TCDD may influence mammary-tumor development only if exposure to it occurs during a specific window during breast development (Rudel et al., 2011). Susceptibility to breast cancer appears to peak in utero and at puberty, which would not be relevant for female Vietnam veterans, who were potentially exposed as adults. The breast is the only human organ that does not fully differentiate until it becomes ready for use; nulliparous women have less-differentiated breast lobules, which are presumably more susceptible to carcinogenesis, because pregnancy is protective, particularly if carried to full term.

Activation of the AHR by dioxin or by the non-dioxin ligand indole-3carbinol has also been shown to protect against experimental breast cancer by mechanisms that disrupt migration and metastasis (Bradlow, 2008; Hsu et al., 2007). Administration of TCDD to mice that harbored highly metastatic murine breast-cancer cells in the mammary fat pad reduced the rate of metastasis by 50 percent without suppressing primary tumor size—an indication that TCDD’s protective effects are selective to the metastatic process (Wang T et al., 2011). In addition, AHR agonists inhibit the formation of lung metastases by ER-negative breast cancer cells (Zhang et al., 2012). However, Spink et al. (2013), using clones derived from the MCF-7 human breast cancer cell line that express different levels of AHR, showed that in nude mice AHR expression is not necessary for proliferation, migration, invasion, or tumor growth of ER-positive MCF-7 cells, and that the knock-down of AHR in wild-type MCF-7 cells did not affect the anti-proliferative effect of TCDD (Yoshioka et al., 2012). Also, the knockdown of the AHR in triple receptor-negative MDA-MB-231 cells inhibited their in-vivo growth and metastases (Goode et al., 2013). Collectively, these findings suggest that there may be species differences, ER-specific mechanisms, ER-independent mechanisms, or carcinogenic process-specific effects of the AHR in breast carcinogenesis. It is possible that some protective effects may be mediated through the known cross-talk between the AHR and ERa, which has

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

been studied extensively at the molecular level for potential therapeutic benefit. There is evidence to indicate that AHR controls ERa-regulated gene expression through its effects on DNA methylation (Marques et al., 2013) or through the recruitment of receptor-interacting protein 140 (RIP140), which can both activate and repress ER actions (Madak-Erdogan and Katzenellenbogen, 2012). In the presence of dioxin, the AHR can repress specific estrogen-dependent genes in MCF-7 breast cancer cells (Labrecque et al., 2012) and in triple receptor-negative MDA-MB-231 cells (Goode et al., 2014). TCDD can also activate AHR-mediated G1cell-cycle arrest (Barhoover et al., 2010); however, in the presence of progesterone receptor, TCDD enriches the G2/M phase and stimulates the proliferation of MCF-7 cells (Chen YJ et al., 2012). Together, these results demonstrate a complicated interplay between the AHR and other nuclear transcription factors, including steroid hormone receptors, which can either stimulate or inhibit breast cancer growth in a manner that depends on cell context. The growth of MCF-7 cells as mammospheres appears to be negatively regulated by the AHR (Zhao et al., 2012), but in the context of an inflammatory microenvironment and HER2 overexpression, the opposite effect has been reported (Zhao et al., 2013).

TCDD may affect breast carcinogenesis by silencing the BRCA-1 tumor suppressor gene through promoter hypermethylation, thereby impairing DNA repair (Papoutsis et al., 2012). TCDD has also been shown to modulate the induction of DNA-chain breaks in human breast cancer cells by regulating the activity of the enzymes responsible for estradiol catabolism and generating more reactive intermediates, which might contribute to TCDD-induced carcinogenesis by altering the ratio of 4-OH-estradiol to 2-OH-estradiol, a marker of breast cancer risk (La Merrill et al., 2010; Lin et al., 2007, 2008). A similar imbalance in metabolite ratios has been observed in pregnant Taiwanese women, in whom the ratio of 4-OH-estradiol to 2-OH-estradiol decreased with increasing exposure to TCDD (Wang et al., 2006). The expression of CYP1B1, the cytochrome P450 enzyme responsible for 2-OH-estradiol formation, but not of CYP1A1, the one responsible for 4-OH-estradiol formation, was found to be highly increased in premalignant and malignant rat mammary tissues in which the AHR was constitutively active in the absence of ligand (Yang et al., 2008). On the basis of recent mechanistic data, it has been proposed that the AHR contributes to mammary-tumor cell growth by inhibiting apoptosis while promoting the transition to an invasive, metastatic phenotype (Marlowe et al., 2008; Schlezinger et al, 2006; Vogel et al., 2011). There is also evidence showing that AHR activation by TCDD in human breast and endocervical cell lines induces sustained high concentrations of the IL-6 cytokine, which has tumor-promoting effects in numerous tissues, including breast tissue, suggesting that TCDD might promote carcinogenesis in these tissues (DiNatale et al., 2010; Hollingshead et al., 2008). Similarly, TCDD induced IL-8 expression in an AHR-dependent manner and may contribute to inflammatory breast cancer (Vogel et al., 2011). Degner et al. (2009) have shown that AHR ligands

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

can upregulate the expression of COX-2, which may lead to a proinflammatory local environment that can support tumor development.

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

In the early 1990s, it was suggested that exposure to some environmental chemicals, such as organochlorine compounds, might play a role in the etiology of breast cancer through estrogen-related pathways. The relationship between organochlorines and breast cancer risk has been studied extensively, especially in the past decade; TCDD and dioxin-like compounds have been among the organochlorines so investigated.

Because of the concerns raised by a combination of a new study that had good exposure assessment and positive findings (Mills and Yang, 2005) and several earlier studies (Kang et al., 2000b; Kogevinas et al., 1997; Revich et al., 2001; Warner et al., 2002), some members of the committee responsible for Update 2006 believed that there was suggestive evidence of an association, but that committee was unable to reach a consensus. After reviewing new studies that had null findings on mortality from breast cancer in the important cohorts of female Vietnam-era veterans (Cypel and Kang, 2008) and Seveso residents (Consonni et al., 2008), the committee for Update 2008 readily reached a consensus that breast cancer should remain in the category of inadequate or insufficient evidence of an association. The committees for Update 2010 and Update 2012 reviewed follow-up studies of cancer incidence in Seveso (Pesatori et al., 2009; Warner et al., 2011). Pesatori et al. (2009) reported a marginally significant increase in breast cancer incidence that peaked 15 or more years after the accident in the women in Zone A (RR = 2.57, 95% CI 1.07–6.20). The updated report of Warner et al. (2011), however, suggested the risk of breast cancer (HR = 1.46, 95% CI 0.89–2.33) had abated somewhat since 1998 when Warner et al. (2002) reported a risk of borderline statistical significance (HR = 2.1, 95% CI 1.0–4.6). A marginal increase was observed in the Hamburg cohort (Manuwald et al., 2012), while the study of the Dow 2,4-D production workers had null findings (Burns CJ et al., 2011).

In the present update, the follow-up on mortality through 2010 in the cohort of female US Vietnam-era veterans showed no evidence of increased breast cancer mortality associated with service in Vietnam (Kang et al., 2014). These results were similar to previous findings of no increased breast mortality on this study population through 2004 (Cypel and Kang, 2008) and to findings in reports by Thomas et al. (1991) and Dalager et al. (1995b). The data on male breast cancer from the Korean study are very sparse and imprecise mainly due to the very low incidence of breast cancer in men.

Biological mechanistic data also do not clearly indicate whether exposure to TCDD or the other COIs increases the risk of breast cancer. The age at which

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TCDD exposure occurs as well as the exposure duration may be critical determinants of whether dioxin influences breast carcinogenesis, but there is no experimental evidence to support the hypothesis that TCDD by itself is a breast tissue carcinogen or enhances breast carcinogenesis.

Conclusion

Having considered the new evidence and the results of studies reviewed in previous updates, the present committee concludes that there is inadequate or insufficient evidence to determine whether there is an association (either positive or negative) between exposure to the COIs and breast cancer.

CANCERS OF THE FEMALE REPRODUCTIVE SYSTEM

This section addresses cancers of the cervix (ICD-9 180), endometrium (also referred to as the corpus uteri; ICD-9 182.0–182.1, 182.8), and ovary (ICD-9 183.0). Additional cancers of the female reproductive system that are infrequently reported separately are cancers of the uterus (ICD-9 179), placenta (ICD-9 181), fallopian tube and other uterine adnexa (ICD-9 183.2–183.9), and other female genital organs (ICD-9 184); findings on these cancers are included in this section. ACS estimates of the numbers of new female reproductive-system cancers in the United States in 2015 are presented in Table 8-22; they represent roughly 12 percent of new cancer cases and 11 percent of cancer deaths in women (Siegel et al., 2015).

Cervical cancer occurs more often in blacks than in whites, but endometrial and ovarian cancers occur more often in whites. The incidence of endometrial and ovarian cancers is higher in older women and in those who have family histories of these cancers. The use of unopposed (without progestogen) estrogen-hormone therapy and obesity, which increases endogenous concentrations of estrogen, both increase the risk of endometrial cancer. Human papilloma virus (HPV) infection, particularly infection with HPV types 16 and 18, is the most important risk factor for cervical cancer (McGraw and Ferrante, 2014).

TABLE 8-22 Estimates of New Cases of Deaths from Selected Cancers of the Female Reproductive System in the United States in 2015

Site New Cases Deaths
Cervix 12,900 4,100
Endometrium 54,870 10,170
Ovary 21,290 14,180
Vagina & other female genital 4,070 910

SOURCE: Adapted from Siegel et al., 2015.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and female reproductive cancers. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, Update 2010, and Update 2012 has not changed that conclusion.

Tables 8-23, 8-24, and 8-25 summarize the results of the relevant studies on, respectively, cancers of the cervix, uterus, and ovary.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

Since Update 2012, Kang et al. (2014) updated mortality from 1992 through 2010 for three cohorts of US female veterans who served in Vietnam (n = 4,734), US female veterans who served in countries near Vietnam (n = 2,062), and non-deployed US military women (n = 5,313) for mortality through December 31, 2010, and reported on female reproductive cancers. The following sections summarize the results for mortality from cervical, uterine, and ovarian cancers, separately.

Cervical Cancer Very few deaths from cervical cancer were observed in this study of female US Vietnam-era veterans: five among those who served in Vietnam, one among those who served near Vietnam, and six among those who were non-deployed. Compared to the general population of US women, overall there were fewer than expected cervical cancer deaths in each cohort (SMRs between 0.27 and 0.65), with wide CIs largely due to the small number of cervical cancer deaths. In comparison to non-deployed female Vietnam-era veterans, those who served in Vietnam had no excess cervical cancer mortality (RR = 1.01, 95% CI 0.30–3.46). A further analysis restricted to female nurses, again using the non-deployed cohort as the referent, yielded virtually the same risk of mortality from cervical cancer (RR = 1.16, 95% CI 0.26–5.22).

Uterine Cancer There were also very few observed uterine cancer deaths of women who served in Vietnam, served near Vietnam, or were non-deployed, with 9, 4, and 12 deaths, respectively. Overall, there were no excess risks of uterine cancer mortality in any of the three cohorts (SMRs of 0.95, 0.91, and 1.13, respectively) when compared to the general population. In the internal comparison to non-deployed Vietnam-era veterans, uterine cancer mortality was not associated with service in Vietnam (RR = 0.90, 95% CI 0.37–2.20) or near Vietnam (RR = 0.83, 95% CI 0.26–2.60). Similar results were observed in analysis restricted to the nurses (RR = 0.94, 95% CI 0.35–2.52 and RR = 0.58, 95% CI 0.12–2.71, respectively).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-23 Selected Epidemiologic Studies—Cervical Cancer (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS  
US Vietnam Veterans  
US VA Cohort of Female Vietnam-era Veterans who served in Vietnam (n = 4,586; nurses only = 3,690); non-deployed (n = 5,325; nurses only 3,282)      
Incidence   All COIs  
Female Vietnam veterans 57 1.1 (0.7–1.7) Kang et al., 2000b
Mortality   All COIs  
Through 2010 11 1.0 (0.3–3.5) Kang et al., 2014
Vietnam nurses only 7 1.2 (0.3–5.2)
International Vietnam-Veterans Studies  
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence   Expected number of exposed cases CDVA, 1998b
Validation Study      
Self-reported cervical cancer 8 1 (0–5)  
OCCUPATIONAL—INDUSTRIAL      
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates   Dioxin, phenoxy herbicides  
Mortality 1939–1992 3 1.1 (0.2–3.3) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 0 0.0 (0.0–3.8)
7,553 not exposed to highly chlorinated PCDDs 3 1.8 (0.4–5.2)  
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)   Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP  
Incidence 1943–1987 7 3.2 (1.3–6.6) Lynge, 1993
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Cervix uteri (ICD-10 C53) 0 0.0 (0.0–14.6)
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
DENMARK
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Self-employed 7 0.5 (p < 0.05)  
Employees 12 0.8 (nr)  
Family workers 100 0.5 (p < 0.05)  
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Incident cervical cancer cases 1961–1973 with agriculture as economic activity in 1960 census   99% CI Wiklund, 1983
82 0.6 (0.4–0.8)
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Women
Whites (n = 2,400) 6 0.9 (0.3–2.0)  
Nonwhites (n = 2,066) 21 2.0 (1.3–3.1)  
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821   TCDD  
Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)      
Incidence
20-yr follow-up to 1996—men and women      
Zone A 2 2.7 (0.7–10.8) Pesatori et al., 2009
Zone B 7 1.5 (0.7–3.1)  
Zone R 28 0.8 (0.6–1.3)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Ecological Study of Residents of Chapaevsk, Russia   Dioxin Revich et al., 2001
Incidence—Crude incidence rate in 1998 vs    
Regional (Samara) nr 11.7 (nr)  
National (Russia) nr 13.2 (nr)  
Mortality—1995–1998 (SMR vs regional rates) 13 1.8 (1.0–3.1)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophen-oxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; SMR, standardized mortality rate; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Ovarian Cancer Totals of 27, 12, and 21 deaths from ovarian cancer were observed among the female Vietnam-era veterans who, respectively, served in Vietnam, served near Vietnam, or were non-deployed. There were no meaningful differences in the risk of ovarian cancer mortality among those who served in Vietnam (SMR = 1.13, 95% CI 0.75–1.65), who served near Vietnam (SMR = 1.12, 95% CI 0.58–1.95), or were non-deployed (SMR = 0.82, 95% CI 0.51–1.26) in comparison with the general population of US women. In the internal comparison to the non-deployed veterans, ovarian cancer mortality was slightly increased among Vietnam veterans (RR = 1.57, 95% CI 0.87–2.85) and among women who served near Vietnam (RR = 1.60, 95% CI 0.77–3.13). An analysis restricted to nurses revealed similar patterns of increased (albeit not statistically significant) ovarian cancer mortality both for veterans who served in Vietnam (RR = 1.35, 95% CI 0.69–2.62) and for veterans who served near Vietnam (RR = 0.37, 95% CI 0.60–3.14) when compared with non-deployed US nurses (Kang et al., 2014).

Occupational, Environmental, and Case-Control Studies

No occupational or environmental studies or case-control studies of exposure to the COIs and female reproductive cancers have been published since Update 2012.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-24 Selected Epidemiologic Studies—Uterine Cancer (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans   All COIs  
US VA Cohort of Female Vietnam-era Veterans who served in Vietnam (n = 4,586; nurses only = 3,690); non-deployed (n = 5,325; nurses only 3,282)      
Incidence
Female Vietnam veterans 41 1.0 (0.6–1.6) Kang et al., 2000b
Mortality
Through 2010 21 0.9 (0.4–2.2) Kang et al., 2014
Vietnam nurses only 17 0.9 (0.4–2.5)  
Through 2004—US non-Vietnam veterans 5 0.8 (0.2–2.8) Cypel and Kang, 2008
vs non-Vietnam nurses 5 1.3 (0.3–5.0)
Through 1991—US Vietnam veterans 4 2.1 (0.6–5.4) Dalager et al., 1995a
International Vietnam-Veterans Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence   Expected number of exposed cases  
Validation Study    
Self-reported uterine cancer 4 1 (0–5) CDVA, 1998b
OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates   Dioxin, phenoxy herbicides  
Mortality 1939–1992 3 3.4 (0.7–10.0) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 1 1.2 (0.0–6.5)  
7,553 not exposed to highly chlorinated PCDDs 4 2.3 (0.6–5.9)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Corpus uteri (ICD-10 C54–C55) 0 0.0 (0.0–30.6)
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
DENMARK
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Self-employed 8 0.6 (nr)  
Employees 9 0.9 (nr)  
Family workers 103 0.8 (p < 0.05)  
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Incident NHL cases 1961–1973 with agriculture as economic activity in 1960 census 135 99% CI 0.9 (0.7–1.1) Wiklund, 1983
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Women
Whites (n = 2,400) 15 1.2 (0.7–2.1)  
Nonwhites (n = 2,066) 17 1.4 (0.8–2.2)  
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Private applicators 4 nr
Commercial applicators 1 nr  
Spouses 148 0.9 (0.8–1.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group)   TCDD  
Incidence
20-yr follow-up to 1996 (Uterus, ICD-9 179–182)
Zone A 4 2.3 (0.9–6.3) Pesatori et al., 2009
Zone B 10 0.9 (0.5–1.7)  
Zone R 61 0.8 (0.6–1.0)  
20-yr follow-up to 1996 (Endometrium, ICD-9 182)      
Zone A 1 1.2 (0.2–8.8)  
Zone B 3 0.6 (0.2–1.9)  
Zone R 27 0.7 (0.5–1.1)  
Mortality
25-yr follow-up to 2001      
Zone A 0 0 Consonni et al., 2008
Zone B 2 0.5 (0.1–1.9)
Zone R 41 1.3 (0.9–1.8)  
20-yr follow-up to 1996      
Zone A, B 2 0.5 (0.1–1.9) Bertazzi et al., 2001
15-yr follow-up to 1991      
Zone B 1 0.3 (0.0–2.4) Bertazzi et al., 1997, 1998
Zone R 27 1.1 (0.8–1.7)
CASE-CONTROL STUDIES      
International Case-Control studies
Swedish women—endometrial cancer and serum concentrations of chlorinated pesticides and PCB congeners   Pesticides, PCB congeners Weiderpass et al., 2000
154 1.0 (0.6–2.0)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; CATI, computer-assisted telephone interviewing; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-meth-ylphenoxy)butanoic acid; NHL, non-Hodgkin lymphoma; nr, not reported; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; SIR, standardized incidence ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-25 Selected Epidemiologic Studies—Ovarian Cancer (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans
US VA Cohort of Female Vietnam-era Veterans who served in Vietnam (n = 4,586; nurses only = 3,690); non-deployed (n = 5,325; nurses only 3,282)      
Incidence   All COIs  
Female Vietnam veterans 16 1.8 (0.7–4.6) Kang et al., 2000b
Mortality
Through 2010 48 1.6 (0.8–3.1) Kang et al., 2014
Vietnam nurses only 38 1.4 (0.7–2.6)
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence   Expected number of exposed cases  
Validation Study    
Self-reported uterine cancer 1 0 (0–4) CDVA, 1998b
OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates   Dioxin, phenoxy herbicides  
Mortality 1939–1992 1 0.3 (0.0–1.5) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 0 0.0 (0.0–2.6)
7,553 not exposed to highly chlorinated PCDDs 1 0.5 (0.0–2.5)  
Mortality, incidence of women in production (n = 699) and spraying (n = 2) compared to national death rates and cancer incidence rates   TCDD Kogevinas et al., 1993
1 0.7 (nr)
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Ovarian cancer (ICD-10 C56) 0 0.0 (0.0–9.5)
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
DENMARK
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Self-employed 12 0.9 (nr)  
Employees 5 0.5 (nr)  
Family workers 104 0.8 (p < 0.05)  
UNITED STATES
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010      
Incidence
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Private applicators 9 2.5 (1.1–4.7)
Commercial applicators 0 nr  
Spouses 58 0.7 (0.6–0.9)  
Enrollment through 2002     Alavanja et al., 2005
Private applicators (men, women) 8 3.0 (1.3–5.9)
Spouses of private applicators (> 99% women) 32 0.6 (0.4–0.8)  
Commercial applicators (men, women) 0 0.0 (0.0–16.0)  
Mortality
Enrollment through 2007, vs state rates     Waggoner et al., 2011
Applicators (n = 1,641) 5 1.6 (0.5–3.8)
Spouses (n = 676) 45 0.7 (0.5–0.9)  
Enrollment through 2000, vs state rates     Blair et al., 2005a
Private applicators (men, women) 4 3.9 (1.1–10.1)
Spouses of private applicators (> 99% women) 13 0.7 (0.4–1.2)  
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Incidence
20-yr follow-up to 1996 (Uterus, ICD-9 179–182)
Zone A 1 1.1 (0.2–7.9) Pesatori et al., 2009
Zone B 1 0.2 (0.0–1.3)
Zone R 45 1.1 (0.8–1.5)  
Mortality
25-yr follow-up to 2001
Zone A 1 1.2 (0.2–8.5) Consonni et al., 2008
Zone B 2 0.4 (0.1–1.6)
Zone R 37 1.0 (0.7–1.4)  
20-yr follow-up to 1996
Zone A, B 3 0.7 (0.2–2.0) Bertazzi et al., 2001
15-yr follow-up to 1991
Zone B 1 2.3 (0.3–16.5) Bertazzi et al., 1997, 1998
Zone R 21 1.0 (0.6–1.6)
CASE-CONTROL STUDIES
International Case-Control studies      
Italian women—hospital-based study of women with primary mesothelial ovarian tumors (n = 60) and 127 subjects with non-ovarian malignancies   Herbicides Donna et al., 1984
18 4.4 (1.9–16.1)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; CATI, computer-assisted telephone interviewing; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines; SIR, standardized incidence ratio; TCDD, 2,3,7,8-tetrachloro-dibenzo-p-dioxin; VA, US Department of Veterans Affairs.

aSubjects are female and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Biologic Plausibility

Yoshizawa et al. (2009) have shown that the chronic administration of TCDD and other AHR ligands to adult female Harlan Sprague Dawley rats results in chronic inflammation and increased incidences of reproductive-tissue preneoplasia and tumors, including cystic endometrial hyperplasia and uterine squamous-cell carcinoma. The mechanism of action might be related to endocrine disruption

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

and chronic inflammation. Qu et al. (2014) observed increased mRNA and protein expression of the AHR in human endometrial cancer tissue and human endometrial cancer cell lines (Ishikawa and ECC-1) compared with nonmalignant endometrium; increased AHR expression in human endometrial cancer tissue compared to nonmalignant tissue has also been reported by Li D et al. (2013). Qu et al. (2014) showed that a polycyclic hydrocarbon known to be an AHR ligand inhibited proliferation of Ishikawa and ECC-1 cells but that this was not mediated by the AHR. Wormke et al. (2000) reported that TCDD inhibited proliferation of Ishikawa endometrial cancer cells stimulated by estradiol and reduced estrogen receptor activity, but increased AHR-mediated gene expression in these cells, suggesting that the estrogen receptor, not the AHR, mediates the anti-proliferative effect of TCDD. Hollingshead et al. (2008) showed that TCDD activation of the AHR in human breast and endocervical cancer cell lines induces sustained high concentrations of the IL-6 cytokine. It is noteworthy that the effects of TCDD treatment differed between MCF-7 breast cancer cells and ECC-1 endometrial carcinoma cells with respect to the activation and repression of genes; this illustrates the role of cell context and organ specificity in responses to TCDD by cancer cells (Labrecque et al., 2012).

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

The results on female reproductive cancers considered in this update came from a follow-up study on mortality among female US Vietnam-era veterans. For both cervical and uterine cancers there was no evidence of increased mortality risk; however, the small observed number of deaths for these outcomes in all three cohorts limited the statistical power to determine whether risk was increased or decreased. With regard to ovarian cancer, there was some evidence of slightly elevated mortality in veterans who served either in or near Vietnam, but for both risks the CIs were large and their point estimates imprecise. However, because ovarian cancer mortality was similar between veterans who served in Vietnam (with potential exposure to Agent Orange and the related COIs) and those who served near Vietnam (who presumably were not so exposed), this evidence is equivocal for the purpose of this review. The results of mechanistic studies provide more plausibility for a reduced risk of female reproductive cancers than for an increased risk.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and uterine, ovarian, or cervical cancers.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

PROSTATE CANCER

ACS estimated that 220,800 new cases of prostate cancer (ICD-9 185; ICDO-3 C61.9) would be diagnosed in the United States in 2015 and that 27,540 men would die from it (Siegel et al., 2015). That makes prostate cancer the second-most common cancer in men (after non-melanoma skin cancers); it is expected to account for about 6 percent of new cancer diagnoses and 9 percent of cancer deaths in men in 2015. The average annual incidence of prostate cancer is shown in Table 8-26.

The incidence of and mortality from prostate cancer varies widely with age and race. The incidence rate of prostate cancer more than doubles from the ages of 50–54 years to the ages of 55–59 years, and it nearly doubles again from the ages of 55–59 years to the ages of 60–64 years. As a group, African American men have the highest recorded incidence of prostate cancer in the world (Jemal et al., 2011); their risk is roughly twice that of whites in the United States, 5 times that in Alaska natives, and nearly 8.5 times that in Korean Americans. Little is known about the causes of prostate cancer. Other than race and age, the risk factors include a family history of the disease both in first- and second-degree relatives (Bruner et al., 2003; Zeegers et al., 2003). and probably some elements of the Western diet, including high consumption of red meat and saturated fats, but these have not been conclusively identified. Of note, selenium and vitamin E supplementation did not reduce, but rather slightly increased, prostate cancer incidence in a large clinical trial (Klein et al., 2011; Kristal et al., 2014; Lippman et al., 2009), and soy protein supplementation did not prevent the recurrence of prostate cancer after surgical treatment in a randomized study (Bosland et al., 2013). The 5a-reductase inhibiting drugs finasteride and dutasteride, which are widely used to treat benign enlargement of the prostate, were found to decrease the prevalence of prostate cancer by about 25 percent in two major randomized trials (Andriole et al., 2010; Thompson et al., 2003); however, in the finasteride trial the risk of high-grade prostate cancer was increased. Finasteride acts by decreasing the formation of the potent androgen metabolite 5a-dihydrotestosterone in the prostate.

TABLE 8-26 Average Annual Incidence (per 100,000) of Prostate Cancer in the United Statesa

60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
518.6 493.4 856.2 788.1 753.0 1,207.3 835.4 800.7 1,167.8

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

The study of the incidence of and mortality from prostate cancer is complicated by various approaches to screening for the disease in different countries and populations. The widespread adoption of serum prostate-specific antigen (PSA) screening in the 1990s led to very large increases in prostate cancer incidence in the United States, which have recently subsided as exposure to screening has become saturated. PSA screening has recently come under scrutiny and is no longer uniformly recommended or consistently applied in the United States following a D grade recommendation from the US Preventive Service Task Force in 2012 (Moyer et al., 2012). The long-term influence of PSA screening on incidence and mortality in any country or population is difficult to predict and will depend on the rapidity with which the PSA screening tool was adopted, its differential use in men of various ages, and the aggressiveness of tumors detected early with this test (Gann, 1997). Because exposure to PSA testing is such a strong determinant of prostate cancer incidence, epidemiologic studies must be careful to exclude differential PSA testing as a potential explanation of differences in risk observed between two groups.

Prostate cancer tends not to be fatal in many cases, particularly for screening-detected (i.e., localized stage/well-differentiated grade) prostate cancer, so mortality studies may miss an increase in incidence of the disease and thus potentially misclassify the outcome. In addition, findings that show an association between an exposure and prostate cancer mortality should be examined closely to determine whether the exposed group might have had poorer access to screening or treatment that would have decreased the likelihood of survival.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to the COIs and prostate cancer, based on positive associations observed in occupational and environmental studies. Additional information from various epidemiologic studies (available to the committees responsible for subsequent updates) has not changed that conclusion.

Table 8-27 summarizes results of the relevant studies, including both morbidity and mortality studies. The results from studies new to this update are shaded.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

Since Update 2012, there have been two publications concerning prostate cancer among veterans at VA medical facilities and two international cohort studies of male Vietnam veterans from New Zealand and Korea have recently reported on cancer incidence and mortality for prostate cancer.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-27 Selected Epidemiologic Studies—Prostate Cancer (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)   All COIs  
Incidence
2,516 veterans (1,019 Ranch Hand, 1,497 SEA veterans) who participated in ≥ 1 physical examination and had recorded serum TCDD measurements     Pavuk et al., 2006
20-yr cumulative TCDD (ppt-yr)
Comparison group 81 1.0  
Ranch Hand low (≤ 434 ppt-yr) 31 1.0 (0.7–1.6)  
Ranch Hand high (> 434 ppt-yr) 28 1.2 (0.8–1.9) p-trend = 0.42  
Last tour in SEA before 1969 (heavy spraying)      
Yes
Comparison group 17 1.0  
Ranch Hand low (≤ 434 ppt-yr) 9 1.0 (0.4–2.3)  
Ranch Hand high (> 434 ppt-yr) 15 2.3 (1.1–4.7) p-trend = 0.04  
No
Comparison group 64 1.0  
Ranch Hand low (≤ 434 ppt-yr) 22 1.1 (0.7–1.8)  
Ranch Hand high (> 434 ppt-yr) 13 0.9 (0.5–1.6) p-trend = 0.75  
Less than 2 yrs served in SEA
Yes
Comparison group 16 1.0  
Ranch Hand low (≤ 434 ppt-yr) 20 1.9 (1.0–3.7)  
Ranch Hand high (> 434 ppt-yr) 14 2.2 (1.0–4.5) p-trend = 0.03  
No
Comparison group 65 1.0  
Ranch Hand low (≤ 434 ppt-yr) 11 0.8 (0.4–1.5)  
Ranch Hand high (> 434 ppt-yr) 14 1.1 (0.6–1.9) p-trend = 0.89  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
1982–2003—White SEA comparison veterans only (n = 1,482). Serum TCDD (pg/g) based on model with exposure variable loge(TCDD)     Pavuk et al., 2005
Per unit increase of –loge(TCDD) (pg/g) Quartiles (pg/g): 83 1.1 (0.7–1.5)  
0.4–2.6 13 1.0  
2.6–3.8 24 1.7 (0.8–3.3)  
3.8–5.2 24 1.5 (0.7–2.9)  
> 5.2 22 1.2 (0.6–2.4)  
Number of years served in SEA (per year of service) 83 1.1 (1.0–1.2)  
Quartiles (years in SEA):
0.8–1.3 8 1.0  
1.3–2.1 11 1.3 (0.5–3.2)  
2.1–3.7 28 2.2 (1.0–4.9)  
3.7–16.4 36 2.4 (1.1–5.2)  
Through 1999—White subjects vs national rates     Akhtar et al., 2004
Ranch Hand veterans (n = 1,189) 36 1.5 (1.0–2.0)  
With tours between 1966–1970 34 1.7 (1.2–2.3)  
SEA comparison veterans (n = 1,776) 54 1.6 (1.2–2.1)  
With tours between 1966–1970 42 1.6 (1.2–2.2)  
White AFHS subjects who spent at most 2 yrs in SEA      
Per unit increase of –loge(TCDD) 28 1.5 (0.9–2.4)  
Comparison group 7 1.0  
Ranch Hand— < 10 TCDD pg/g in 1987 10 1.5 (0.5–4.4)  
Ranch Hand— < 118.5 TCDD pg/g at end of service 6 2.2 (0.7–6.9)  
Ranch Hand— > 118.5 TCDD pg/g at end of service 5 6.0 (0.4–24.6)  
Only Ranch Hands with 100% service in Vietnam and comparisons with no service in Vietnam      
Per unit increase of –loge(TCDD) 20 1.1 (0.6–1.8)  
Comparison group 3 1.0  
Ranch Hand— < 10 TCDD pg/g in 1987 9 2.5 (0.4–16.1)  
Ranch Hand— < 118.5 TCDD pg/g at end of service 4 2.4 (0.4–16.0)  
Ranch Hand— > 118.5 TCDD pg/g at end of service 4 4.7 (0.8–29.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality
Through 1999—White subjects vs national rates     Akhtar et al., 2004
Ranch Hand veterans (n = 1,189) 2 0.7 (0.1–2.3)  
SEA comparison veterans (n = 1,776) 3 0.8 (0.2–2.1)  
US VA Cohort of Army Chemical Corps—Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 non-deployed) serving during Vietnam era (July 1, 1965–March 28, 1973)   All COIs  
Mortality—Prostate cancers
Through 2005     Cypel and Kang, 2010
Deployed veterans (2,872) vs non-deployed (2,737) 5 vs 2 1.0 (0.2–5.6)
ACC veterans vs US men      
Vietnam cohort 5 1.1 (0.3–2.5)  
Non-Vietnam cohort 2 1.0 (0.1–3.4)  
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Mortality
1965–2000 1 0.4 (nr) Boehmer et al., 2004
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1988     Watanabe and Kang, 1996
Army, deployed (n = 27,596 ) vs non-deployed (n = 31,757 ) 58 0.9 (nr)
Marine Corps, deployed (n = 6,237) vs non-deployed (n = 5,040) 9 0.8 (nr)  
1965–1982     Breslin et al.,1986, 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 30 0.9 (0.6–1.2)
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 5 1.3 (0.2–10.3)  
State Studies of US Vietnam Veterans
US VA Hospital Medical Records—VVs who underwent radial prostatectomy between 2005 and 2009 (n = 93); dioxin levels (TEQs) measured in subcutaneous adipose tissue   All COIs (supposed AO exposure) Li et al., 2013
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Proportion of TEQ levels for AO-exposed (self-reported) vs unexposed   27% vs 20%  
  p = 0.68  
Proportion of higher TEQ levels vs lower TEQs   28% vs 17%  
  p = 0.23  
Veterans with radical prostatectomies examined in VA Healthcare facilities (California, Georgia, North Carolina)     Shah et al., 2009
AO-exposed veterans with biochemical progression nr 1.5 (1.1–2.0)  
Northern California—prostate cancer (self-reported [before diagnosis] of AO exposed vs not)   All COIs Chamie et al., 2008
239 2.9 (2.3–3.6)
Massachusetts veterans aged 35–65 years in 1993—prostate cases diagnosed 1988–1993 vs gastrointestinal cancers 15 All COIs 0.8 (0.4–1.6) Clapp, 1997
Michigan Vietnam veterans using the VA Medical Center in Ann Arbor, MI (n = 47); 142 frequency-matched controls   All COIs Giri et al., 2004
Cases reporting AO exposure 11 OR 2.1 (0.8–5.2)  
Cases in white veterans reporting AO exposure nr OR 2.7 (0.9–8.2)  
Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs non-deployed   All COIs Vistainer et al., 1995
Male genital system 19 1.1 (0.6–1.7) Clapp, 1997
923 White male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans 0 All COIs nr Anderson et al., 1986a,b
Oregon: A cohort of 2,720 veterans who underwent biopsy at Portland VA Medical Center (896 prostate cancers)   All COIs (supposed AO exposure) Ansbaugh et al., 2013
All prostate cancer 74 1.5 (1.1–2.1)  
High grade prostate cancer (Gleason score > 7) 40 1.8 (1.1–2.7)  
Gleason score > 8 prostate cancer nr 2.1 (1.2–3.6)  
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Incidence
All branches, 1982–2000 692 1.3 (1.2–1.3) ADVA, 2005b
Navy 137 1.2 (1.0–1.4)  
Army 451 1.3 (1.2–1.4)  
Air Force 104 1.3 (1.0–1.5)  
Validation Study   Expected number of exposed cases AIHW, 1999
  212 147 (123–171)  
Men 428 147 (123–171) CDVA, 1998a
Mortality
All branches, return–2001 107 1.2 (1.0–1.5) ADVA, 2005a
Navy 22 1.3 (0.8–1.8)  
Army 65 1.2 (0.9–1.5)  
Air Force 19 1.4 (0.8–2.1)  
Sample of 1,000 Male Australian Vietnam Veterans–prevalence   All COIs  
450 interviewed 2005–2006 vs respondents to 2004–2005 national survey     O’Toole et al., 2009
nr 1.3 (0.3–6.7)
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence
1982–2000 65 1.2 (0.9–1.5) ADVA, 2005c
Mortality
1966–2001 0 0.0 (0.0–0.7) ADVA, 2005c
1982–1994 36 1.5 (1.0–2.0) CDVA, 1997b
Other Australian Vietnam veterans   All COIs  
606 prostate cancer cases in Western Australia     Leavy et al., 2006
Vietnam service 25 2.1 (0.9–5.1)
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008) 136 1.2 (1.0–1.4)  
Mortality (1988–2008) 13 1.0 (0.6–1.8)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—prostate cancer (C61) categorized high (n = 53) vs low (n = 71) 53 0.7 (0.5–1.0) Yi and Ohrr, 2014
Mortality (1992–2005)—prostate cancer (C61) categorized high (n = 17) vs low (n = 21)   0.7 (0.4–1.3) Yi et al., 2014b
HR per unit of log EOI (n = 180,639) 38 0.9 (0.8–1.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Mortality 1939–1992 68 1.1 (0.9–1.4) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 43 1.1 (0.8–1.5)  
7,553 not exposed to highly chlorinated PCDDs 25 1.1 (0.7–1.6)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort     Saracci et al., 1991
30 1.1 (0.8–1.6)
British MCPA Plant—production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)   MCPA  
Mortality through 1983 18 1.3 (0.8–2.1) Coggon et al., 1986
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)   Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP  
Mortality 1955–2006 14 1.1 (0.8–1.5) Boers et al., 2012
Incidence 1943–1982 9 0.8 (nr) Lynge, 1985
Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)   Dioxins, 2,4,5-T, 2,4,5-TCP  
Mortality 1955–2006 (HRs for lagged TCDD plasma levels) 8 1.3 (0.9–1.9) Boers et al., 2012
Mortality 1955–2006 6 vs 2 2.9 (0.6–14.2) Boers et al., 2010
Mortality 1955–1985 2 2.2 (0.3–7.8) Bueno de Mesquita et al., 1993
Dutch production workers in Plant B (414 men exposed during production 1965–1986; 723 unexposed) (in IARC cohort)   2,4-D; MCPA; MCPP; highly chlorinated dioxins unlikely  
Mortality 1965–2006 4 vs 2 2.7 (0.5–14.9) Boers et al., 2010
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality 1965–1986 1 4.8 (0.1–26.5) Bueno de Mesquita et al., 1993
German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 mo in 1951–1976) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4,5-TCP  
Mortality 1951–1992 1 1.5 (0.0–8.5) Becher et al., 1996
German Production Workers at Bayer Plant in Dormagen (520 men working > 1 mo in 1965–1989) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Mortality 1965–1989 0 Becher et al., 1996
German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 mo in 1957–1987) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Mortality 1956–1989 1 0.7 (0.0–3.7) Becher et al., 1996
BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)   Focus on TCDD  
Incidence
1960–1992     Ott and Zober, 1996a
TCDD < 0.1 µg/kg of body weight 3 2.5 (0.5–7.4)
TCDD 0.1–0.99 µg/kg of body weight 1 1.1 (0.0–5.9)  
TCDD > 1.0 µg/kg of body weight 0 0.0 (0.0–2.5)  
Mortality
1953–1992     Ott and Zober, 1996a
TCDD < 0.1 µg/kg of body weight 0 0.0 (0.0–5.7)
TCDD 0.1–0.99 µg/kg of body weight 0 0.0 (0.0–7.5)  
TCDD > 1.0 µg/kg of body weight 0 0.0 (0.0–4.6))  
Through 1987   90% CI Zober et al., 1990
  0 0.0 (0.0–6.1)
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working >1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)   Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality 1952–2007 19 1.4 (0.8–2.1) Manuwald et al., 2012
Mortalilty 1952–1989 7 1.5 (0.6–3.0) Becher et al., 1996
Mortality 1952–1989—stats on men only, 1,184 (tables all for 1,148 men, not necessarily German nationals) vs national rates (also vs gas workers); same observation period as Becher et al., 1966 7 1.4 (0.6–2.9) Manz et al., 1991
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Ever-exposed workers 1 0.2 (0.0–1.2)
Never-exposed workers 2 1.9 (0.2–6.7)  
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)      
Mortality 1969–2000 1 0.4 (0.0–2.1) ’t Mannetje et al., 2005
Sprayers (697 men and 2 women on register of New Zealand applicators, 1973–1984)      
Mortality 1973–2000 2 0.6 (0.1–2.2) ’t Mannetje et al., 2005
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Through 1993 28 1.2 (0.8–1.7) Steenland et al., 1999
Through 1987 17 1.2 (0.7–2.0) Fingerhut et al., 1991
≥ 1-yr exposure, ≥ 20-yr latency 9 1.5 (0.7–2.9)
Mortality—754 Monsanto workers, among most highly exposed workers from Fingerhut et al. (1991) 9 1.6 (0.7–3.0) Collins et al., 1993
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (in IARC and NIOSH cohorts)   2,4,5-T; 2,4,5-TCP  
1942–2003 (n = 1,615)     Collins et al., 2009b
  21 1.4 (0.9–2.2)
1940–1994 (n = 2,187 men)     Bodner et al., 2003
  nr 1.7 (1.0–2.6)
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
1940–2005 (n = 2,122) 26 1.0 (0.7–1.5)  
PCP and TCP (n = 720) 8 1.1 (0.5–2.1)  
PCP (no TCP) (n = 1,402) 18 1.0 (0.6–1.6)  
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3) 51 0.8 (0.6–1.0) Burns CJ et al., 2011
Through 1994 (n = 1,517) 7 1.3 (0.5–2.8) Burns et al., 2001
Through 1982 (n = 878) 1 1.0 (0.0–5.8) Bond et al., 1988
Dow PCP Production Workers (1937–1989 in Midland, MI) ( not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP)     Collins et al., 2009c
8 1.0 (0.4–1.9)
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Never 117 0.9 (0.7–1.0)  
Ever 84 0.9 (0.7–1.2)  
New Hampshire pulp and paper workers, 883 white men working ≥ 1 yr, mortality through July 1985 9 1.0 (0.5–1.9) Henneberger et al., 1989
United Paperworkers International, 201 white men employed ≥ 10 yr and dying 1970–1984 4 1.1 (0.3–2.9) Solet et al., 1989
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Northwestern US paper and pulp workers—5 mills in Washington, Oregon, and CA, 3,523 worked ≥ 1 yr 1945–1955, mortality through March 1977 17 90% CI 1.2 (0.7–1.7) Robinson et al., 1986
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
CANADA
Canadian Farm Operator Study—156,242 men farming in Manitoba, Saskatchewan, and Alberta in 1971; mortality from prostate cancer June 1971–Dec 1987   Herbicides Morrison et al., 1993
Herbicides sprayed on ≥ 250 acres vs 0 acres 20 2.2 (1.3–3.8)  
Sawmill Workers in British Columbia—23,829 workers for ≥ 1 yr at 11 mills using chlorophenates 1940–1985   Chlorophenates, not TCDD  
Incidence 1969–1989 282 1.0 (0.9–1.1) Hertzman et al., 1997
Hertzman et al., 1997 116 1.2 (1.0–1.4)  
DENMARK
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Men
Self-employed 399 0.9 (p < 0.05)  
Employee 63 0.8 (p < 0.05)  
Danish gardeners—incidence from 3,156 male and 859 female gardeners     Hansen et al., 2007
25-year follow-up (1975–2001)   Herbicides  
Born before 1915 (high exposure) 39 1.3 (1.0–1.8)  
Born 1915–1934 (medium exposure) 35 0.9 (0.6–1.2)  
Born after 1934 (low exposure) 3 0.4 (0.1–1.3)  
10-year follow-up (1975–1984) of male gardeners 20 1.2 (0.7–1.8) Hansen et al., 1992
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 2000 6 1.0 (0.4–2.2) Swaen et al., 2004
Through 1987 1 1.3 (0.0–7.3) Swaen et al., 1992
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
FINNISH Phenoxy Herbicide Sprayers (1,909 men working 1955–1971 ≥ 2 wks) not IARC   Phenoxy herbicides  
Incidence 6 0.4 (0.1–0.8) Asp et al., 1994
Mortality 1972–1989 5 0.8 (0.3–1.8)  
ICELAND
Icelandic men (1,860), women (859) exposed to agricultural pesticides, primarily 2,4-D (other endocrine organs, ICD-9 194)—incidence 10 2,4-D 0.7 (0.3–1.3) Zhong and Rafnsson, 1996
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401) 66 1.0 (0.7–1.2) Torchio et al., 1994
Italian rice growers with documented phenoxy use (n = 1,487)   Phenoxy herbicides Gambini et al., 1997
  19 1.0 (0.6–1.5)  
NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of incident prostate cancer cases vs remainder of 19,904 men with any incident cancer   Herbicides Reif et al., 1989
Forestry workers (n = 134) 12 0.7 (0.4–1.3)  
SWEDEN
Swedish Cancer-Environment Registry—National cancer registry linked to census   Herbicides Sharma-Wagner et al., 2000
36,269 incident prostate cancer cases 1961–1979 with 1960 census occupation of:      
Agriculture, stock raising 6,080 (1.0–1.1) (p < 0.01)  
Farmers, foresters, gardeners 5,219 (1.0–1.1) (p < 0.01)  
Paper-mill workers 304 0.9 (0.8–1.0)  
Pulp grinding 39 1.4 (1.0–1.9) (p < 0.05)  
Incident prostate cancer cases 1961–1973 with agriculture as economic activity in 1960 census 3,890 99% CI 1.0 (0.9–1.0) Wiklund, 1983
Licensed Swedish Pesticide Sprayers—Incidence of prostate cancer   Phenoxy herbicides Dich and Wiklund, 1998
  401 1.1 (1.0–1.2)
Born 1935 or later 7 2.0 (0.8–4.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Born before 1935 394 1.1 (1.0–1.2)  
Swedish lumberjacks—Used phenoxys 1954–1967, Incidence 1958–1992     Thörn et al., 2000
Exposed (n = 154)
Foremen (n = 15) 2 4.7 (nr)  
Lumberjacks (n = 139) 3 0.9 (nr)  
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Men
Whites (n = 119,648) 3,765 1.2 (1.1–1.2)  
Nonwhites (n = 11,446) 564 1.1 (1.1–1.2)  
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Private applicators 1,719 1.2 (1.1–1.3)  
Commercial applicators 73 1.3 (1.0–1.6)  
Spouses 7 1.1 (0.4–2.2)  
Enrollment through 2002     Samanic et al., 2006
Dicamba—lifetime days exposure    
None 343 1.0  
1– < 20 106 1.0 (0.8–1.3)  
20– < 56 102 0.9 (0.7–1.2)  
56– < 116 76 1.0 (0.7–1.3)  
≥ 116 67 (0.8–1.5)  
    p-trend 0.45  
Enrollment through 2002     Alavanja et al., 2005
Private applicators 1.046 1.3 (1.2–1.3)
Spouses of private applicators (> 99% women) 5 1.2 (0.4–2.8)  
Commercial applicators 41 1.4 (1.0–1.9)  
Enrollment through 1999 (n = 55,332) 566 1.1 (1.1–1.2) Alavanja et al., 2003
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality
Enrollment through 2007, vs state rates     Waggoner et al., 2011
Applicators (n = 1,641) 171 0.8 (0.7–1.0)
Enrollment through 2000, vs state rates     Blair et al., 2005a
Private applicators (men and women) Spouses of private applicators (> 99% women) 48 0 0.7 (0.5–0.8) 0.0 (0.0–1.6)
US Agricultural Health Study—Nested CC study (776 cases vs 1,444 controls)   Herbicides Karami et al., 2013
2,4 D (ever exposed) 617 0.8 (0.7–1.1) (supplemental Table S1)
2,4 D (high exposure) 295 0.8 (0.6–1.1)
2,4,5 T (ever exposed) 229 0.9 (0.7–1.1)  
2,4,5 T (high exposure) 56 0.7 (0.5–0.9)  
2,4,5 TP (ever exposed) 64 0.8 (0.6–1.1)  
2,4,5 TP (high exposure) 11 0.6 (0.3–1.1)  
US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 of prostate cancer   Herbicides  
Agricultural extension agents nr 1.0 (0.7–1.5) Alavanja et al., 1988
Forest conservationists   p-trend < over yrs worked Alavanja et al., 1989
  nr p < 0.05  
Soil conservationists nr p < 0.26  
Florida Licensed Pesticide Applicators (common phenoxy use assumed but not documented; had been listed by Blair et al., 1983)   Herbicides  
30,155 white men licensed 1975–1993      
Incidence 1975–1993 353 1.9 (1.7–2.1) Fleming et al., 1999a
Mortality 1975–1993 64 2.4 (1.8–3.0) Fleming et al., 1999b
Pesticide applicators in Florida licensed 1965–1966 (n = 3,827)—mortality through 1976   Herbicides Blair et al., 1983
Any pesticide (dose–response by length of licensure)   Expected number of exposed cases  
  2 3.8 (nr)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
> 30 yrs old when died     Burmeister et al., 1983
1964–1978—case-control 4,827 1.2 (p < 0.05)
H0: only for “modern methods” → born after 1900      
Born before 1880 1,539 1.5 (nr)  
Born 1980–1900 2,081 1.3 (nr)  
Born after 1900 1,207 0.8 (nr)  
> 20 yrs old when died 1971–1978—PMR 1,138 1.1 (p < 0.01) Burmeister, 1981
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Incidence
20-yr follow-up to 1996—men and women
Zone A 0   Pesatori et al., 2009
Zone B 7 0.9 (0.5–2.0)
Zone R 39 0.8 (0.5–1.1)  
10-yr follow-up to 1991—men     Bertazzi et al., 1993
Zone R 16 0.9 (0.5–1.5)
Mortality
25-yr follow-up to 2001—men and women     Consonni et al., 2008
Zone A 1 0.9 (0.1–6.2)
Zone B 8 0.9 (0.4–1.8)  
Zone R 65 1.1 (0.8–1.4)  
20-yr follow-up to 1996     Bertazzi et al., 2001
Zones A, B—men 8 1.1 (0.5–2.2)
15-yr follow-up to 1991—men     Bertazzi et al., 1997
Zone B 6 1.2 (0.5–2.7)
Zone R 39 1.2 (0.8–1.6)  
10-yr follow-up to 1986—men     Bertazzi et al., 1989b
Zone B 3 2.2 (0.7–6.9)
Zone R 16 1.6 (0.9–2.7)  
Other International Environmental Studies
FINLAND
Finnish fishermen (n = 6,410) and spouses (n = 4,260) registered between 1980 and 2002 compared to national statistics   Serum dioxin Turunen et al., 2008
Fisherman 36 1.0 (0.7–1.4)  
Spouses  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
SWEDEN
Swedish fishermen (high consumption of fish with persistent organochlorines)   Organochlorine compounds Svensson et al., 1995a
Incidence
East coast 38 1.1 (0.8–1.5)  
West coast 224 1.0 (0.9–1.1)  
Mortality
East coast 12 1.0 (0.5–1.8)  
West coast 123 1.1 (0.9–1.3)  
CASE-CONTROL STUDIES
CANADA—1,516 prostate cancer patients identified in the British Columbia Cancer Registry vs 4,994 matched controls; estimated lifetime exposure to:   Pesticides Band et al., 2011
2,4-D 11 2.7 (1.1–6.6)  
2,4-DB 24 1.8 (1.0–3.0)  
MCPA 14 1.8 (1.0–3.2)  
Dicamba 22 2.0 (1.0–4.2)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DB, 4-(2,4-dichlorophenoxy)butyric acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; ACC, Army Chemical Corps; AFHS, Air Force Health Study; AO, Agent Orange; CATI, computer-assisted telephone interviewing; CC, case-control; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; MOS, military occupation specialty; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; pg/g, picogram per gram; PM, proportionate mortality; PMR, proportionate mortality ratio; ppt, parts per trillion; SEA, Southeast Asia; SIR, standardized incidence ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; TEQ, (total) toxic equivalent; VA, US Department of Veterans Affairs; VV, Vietnam veteran.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

A Vietnam-veteran cohort study conducted in Oregon State evaluated a possible relationship between herbicide exposure and the incidence of more aggressive cases of prostate cancer in a cohort of veterans undergoing prostate biopsies diagnosed with this cancer. Ansbaugh et al. (2013) conducted a retrospective cohort analysis among 2,720 veterans (94 percent Caucasian) who were referred

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

to the Portland VA Medical Center with an elevated serum PSA and underwent an initial prostate biopsy. A total of 896 incident prostate cancers were diagnosed in this cohort, of which 459 were intermediate- to high-grade tumors (Gleason scores ≥ 7). Herbicide exposure, as classified within the VA electronic medical records, was determined during the patients’ enrollment into the VA hospital. In addition, all veterans completed a questionnaire that collected demographic and anthropometric factors, as well as a medical history and family history of prostate cancer. Of the 2,720 veterans, 203 (7.5 percent) were classified as having herbicide exposure. There was a statistically significant positive association between herbicde exposure and the overall risk of prostate cancer (OR = 1.52, 95% CI 1.07–2.13) after adjustment for age and receipt of PSA or digital rectal exam screening. Stratified analyses by tumor characteristics found a stronger association between herbicide exposure and intermediate- to high-grade prostate cancer (OR = 1.75, 95% CI 1.12–2.74) and an even stronger association with more aggressive (Gleason scores 8–10) prostate cancer (OR = 2.10; 95% CI 1.22–3.61). Although this study had a relatively large sample size and included a large number of incident prostate cancers, several limitations should be considered carefully when interpreting the results. First, potential selection/referral bias is a major issue because men who were referred for prostate biopsy probably had an elevated PSA and could possibly have had better access to health care in comparison to other veterans. In addition, the referring physician may have acted because he or she knew that the veteran could have had herbicide exposure. However, the authors argue, correctly, that the likelihood of this selection/referral bias was low and that the study physicians did not take such exposure into account at the time of the biopsy referral. The indication of herbicide exposure in the VA database is likely to have introduced exposure misclassification, because VA does not have accurate information on the extent to which individual Vietnam veterans were exposed to herbicides.

Q Li et al. (2013) recently published a small study conducted among 93 veterans who underwent radical prostatectomy between 2005 and 2009; the goal of the study was to determine the relationship between herbicide exposure and biochemical recurrence of prostate cancer during an average of 5.3 years of follow-up after the prostatectomy. Herbicide exposure was determined from the VA administrative databases, as had been done in the study by Ansbaugh et al. (2013). According to the study authors, herbicide exposure was determined by self-report and military records confirming that Vietnam veterans had served in an area in which herbicides had been sprayed. In this study, however, subcutaneous adipose tissue obtained during prostatectomy was assayed for dioxin. The measured TEQ levels of the 37 men with self-reported herbicide exposure were higher than those of the 56 purportedly unexposed men (medians 22.3 and 15.0 pg/g, respectively; p < 0.001). The proportions of men with biochemical recurrence were very modestly higher both for the veterans with self-reported herbicide exposure versus those said to be unexposed (27 percent and 20 percent, respectively; p = 0.68) and for those with higher TEQ levels compared with those with lower TEQ levels

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

(28 percent and 17 percent, respectively; p = 0.23); there were few recurrences in the groups categorized as exposed by the two criteria (8 and 13, respectively). Of note, in neither this study nor the previous publication of the same cohort (see Shah et al., 2009) was it clear how herbicide exposure was ascertained or defined.

McBride et al. (2013) followed 2,783 male veterans from New Zealand who had served in Vietnam between 1964 and 1972 and were still alive as of 1988. This cohort, which was followed for cancer incidence and mortality from 1988 through 2008, included 84 percent of all 3,322 New Zealand veterans who returned from service in Vietnam. Standardized incidence and mortality ratios were generated by comparing the observed incident cases and deaths in this cohort with the corresponding expected numbers of new cases and deaths from the general male population of New Zealand. A total of 136 incident cases and 13 deaths from prostate cancers were identified in this cohort. When compared to the general male population of New Zealand, there was a modest excess risk of prostate cancer incidence (SIR = 1.17, 95% CI 0.98–1.39), but no excess prostate cancer–specific mortality (SMR = 1.03, 95% CI 0.55–1.76). A limitation of this study was that information on prostate cancer incidence and mortality in the time period immediately following service in Vietnam (i.e., between 1973 and 1998) was not available. Moreover, there was no information on potential confounding factors, including a family history of prostate cancer; however, it is unlikely that family history would differ between men with and without herbicide exposure.

Several recent publications examined prostate cancer incidence (Yi, 2013; Yi and Ohrr, 2014) and cancer-specific mortality (Yi et al., 2014b) in the Korean Veterans Health Study. A total of 125 incident cases and 53 deaths from prostate cancer were identified in this cohort during follow-up. When compared to the general Korean population, there was a statistically significant excess prostate cancer risk (SIR = 1.22, 95% CI 1.02–1.46) in the entire cohort (Yi, 2013), which was mostly due to a significant 2.5-fold elevated prostate cancer incidence among officers (SIR = 2.49, 95% CI 1.93–3.21; based on 59 incident cases). By contrast, both enlisted soldiers and non-commissioned officers had lower incidence rates of prostate cancer (SIR = 0.85 and 0.81, respectively) relative to the general population, although the 95% confidence intervals for both risk estimates were large and the differences were not statistically significant. However, in the internal comparison analysis, Yi and Ohrr (2014) reported an inverse association between the EOI scores and prostate cancer incidence (RR = 0.70, 95% CI 0.49–1.00, when comparing high- versus low-exposure), which was based on 53 cases in the high-exposure category. It should be noted, however, that Yi and Ohrr (2014) did not stratify incident prostate cancer cases according to tumor characteristics (low- versus high-grade tumors) as is usually done in studies of prostate cancer incidence. With regard to exposure potential and prostate cancer–specific mortality, Yi et al. (2014b) reported a similar inverse association (RR = 0.68, 95% CI 0.36–1.31) when comparing high- versus low-exposure groups, which had 17 and 21 prostate cancer deaths, respectively.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Occupational Studies

Karami et al. (2013) recently evaluated the interactions between 41 pesticides and 152 single-nucleotide polymorphisms (SNPs) in nine vitamin D pathway genes among 776 prostate cancer cases and 1,444 male controls in a nested case-control study of Caucasian pesticide applicators within the AHS. In the main effect analysis of this study, the associations between pesticide use and prostate cancer risk were largely null. With regard to the COIs, the authors examined association between prostate cancer risk and ever-exposed or high exposures to 2,4-D, 2,4,5-T, and 2,4,5-TP. Most of the associations had ORs ranging from 0.6 to 0.8, with large CIs that included the null. However, for high exposure to 2,4,5-T there was a statistically significant inverse association with prostate cancer (OR = 0.67, 95% CI 0.48–0.93), based on 56 exposed cases. The AHS has been generating valuable information on the COIs for a number of years, but some of its results are not herbicide-specific and so cannot be regarded fully informative for the committee’s task.

Environmental and Case-Control Studies

No environmental cohort studies or case-control studies of exposure to the COIs and prostate cancer have been published since Update 2012.

Biologic Plausibility

In prostate cells and prostate cancer cell lines TCDD can lead to the induction of various genes, including those involved in drug metabolism. Simanainen et al. (2004) used different rat lines (TCDD-resistant Hannover/Wistar and TCDD-sensitive Long Evans) and found that TCDD treatment resulted in a significant decrease in the weight of prostate lobes; the effect did not appear to be rat strain–specific. Different responses to TCDD in the human prostate cancer cell lines LNCaP and PC3 have been reported, including increased proliferation or no growth and stimulation or repression of AHR activity, which may be a function of coactivator–corepressor concentrations in the cells (Kollara and Brown, 2009, 2010). In addition AHR activation has been shown to interfere with androgen receptor binding to androgen response elements in LNCaP cells via the upregulation of AP-1, resulting in a reduced expression of PSA (Kizu et al., 2003). However, the number of CAG repeats in the androgen receptor gene, which affects androgen receptor activity, did not significantly affect the induction of CYP1A1 by TCDD in androgen receptor–negative prostate cells transfected with androgen receptor constructs with different CAG repeat lengths (Björk and Giwercman, 2013). In that study, TCDD altered androgen receptor activity in a CAG repeat length–dependent manner in PC-3 cells, but not in a non-tumorigenic, immortalized epithelial prostate cell line. The AHR is

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

upregulated in androgen receptor–negative, hormone-independent prostate cancer cells compared to androgen receptor–positive, hormone-dependent LNCaP cells, and treatment of these cells (PC3, PC3M, and DU145) with an AHR agonist suppressed their growth (Richmond et al., 2014). In contrast, even though the AHR is upregulated in castration-resistant C4-2 cells compared with the LNCaP cells from which they have been derived, silencing of the AHR caused a growth inhibition of these cells, perhaps because they retained androgen-receptor expression and are androgen-sensitive (Tran et al., 2013). TCDD suppressed expression of genes associated with cell-cycle progression in LNCaP cells but also suppressed DNA-repair genes and increased Wnt5a concentrations; these effects could lead to divergent responses with regard to prostate cancer progression (Hruba et al., 2011). AHR overexpression and activation reduced induction of the expression of vascular endothelial growth factor in PC3 cells, raising the possibility of interference with angiogenesis by AHR ligands (Wu PY et al., 2013). Transforming growth factor (TGF)-β suppressed AHR expression via SMAD4 and possibly also interfered with AHR signaling in a non-tumorigenic, but immortalized, epithelial prostate cell line (BPH-1) (Staršíchová et al., 2012); whether this also occurs in prostate cancer cells and has a bearing on prostate carcinogenesis is not known. In utero and lactational exposure to TCDD increases aging-associated cribiform hyperplasia in the murine prostate, which may be a pre-cancerous lesion (Fritz et al., 2005). In a follow-up, progeny of a genetic cross between AHR-null mice and the transgenic adenocarcinoma of the mouse-prostate (TRAMP) strain that models prostate cancer showed that the presence of the AHR inhibited the formation of prostate tumors that have a neuroendocrine phenotype (Fritz et al., 2008). As with breast cancer, these studies suggest that the timing of an exposure may be critical, with early-life exposures increasing prostate cancer susceptibility and adult AHR activation reducing it. Because male Vietnam veterans were exposed to herbicides after adolescence, toxicologic findings concerning early-life exposure are not particularly relevant to this population, although their exposure to herbicides could potentially influence risk of the prostate cancer later in life.

Taken together, there is some in vivo and in vitro laboratory evidence in support of a role of the AHR in prostate cancer and suggesting that dioxin exposure could affect processes involved in prostate carcinogenesis or prostate cancer growth and progression. However, there is no substantial understanding of the importance of these mechanisms and how they could affect prostate cancer risk. The general biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

This update describes several newly published studies involving prostate cancer in Vietnam veterans in the Korea, New Zealand, and United States; however, the results of these studies were inconsistent. The study of US veterans, all of

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

whom had been referred to the Portland VA Medical Center for prostate biopsies, reported a statistically significant positive association between herbicide exposure and the overall risk of prostate cancer and a two-fold increased risk for high-grade (Gleason score 8–10) prostate cancer. Although the study took into consideration the issues of screening and potential for referral/filter bias, the definition of herbicide exposure based on the VA database might have introduced potential exposure misclassification because VA does not have accurate information on Vietnam veterans who were exposed to herbicides. On the other hand, the two international studies of Vietnam veterans in New Zealand and Korea reported no association or else an inverse association between herbicide exposure and prostate cancer. The study of Vietnam veterans in New Zealand reported a modest, non-significant excess risk of prostate cancer incidence, but no excess prostate cancer–specific mortality relative to the general population. However, the number of prostate cancer cases in this cohort was small and the fact of deployment served as a proxy for herbicide exposure. The Korean study, which was very large, examined the risk of prostate cancer incidence and mortality with exposure estimates based on an EOI score developed by Stellman et al. (2003b). Internal comparison analyses found a marginally significant 30 percent reduction in the risk of prostate cancer, comparing groups with high and low EOI scores, as well as a 32 percent reduction in the risk of prostate cancer–specific mortality. Because the Stellman exposure opportunity model has not been validated or used in other epidemiologic studies, it is difficult to determine the reliability of this exposure metric.

Despite the above conflicting evidence from the new Vietnam veterans studies, the increased risks of prostate cancer reported from the earlier studies among US Air Force Ranch Hand troops and Australian Vietnam veterans, along with the positive associations reported from several occupational studies and the case-control study of specific agricultural exposures in British Columbia (Band et al., 2011) support the notion of an association between exposure to the herbicides used in Vietnam and prostate cancer.

The existing body of epidemiologic evidence supporting an association between exposure to the COIs and prostate cancer is robust enough and biologically plausible enough that this committee finds no justification for reversing the conclusion of prior VAO committees that there is limited or suggestive evidence of an association.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there remains limited or suggestive evidence of an association between exposure to at least one of the COIs and prostate cancer.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TESTICULAR CANCER

ACS estimated that 8,430 men would receive diagnoses of testicular cancer (ICD-9 186.0–186.9) in the United States in 2014 and that 380 men would die from it (Siegel et al., 2015). Other cancers of the male reproductive system that are infrequently reported separately are cancers of the penis and other male genital organs (ICD-9 187). The average annual incidence of testicular cancer is shown in Table 8-28.

Testicular cancer occurs most often in men between the ages of 25–29. On a lifetime basis, the risk in white men is about five times higher than in black men (Stevenson and Lowrance, 2015). Known risk factors for testicular cancer include cryptorchidism (undescended testes) and having a previous occurrence of testicular cancer. Several other hereditary, medical, and environmental risk factors have been suggested, but the results of research are inconsistent (Mikuz, 2015; Stevenson and Lowrance, 2015).

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and testicular cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, Update 2010, and Update 2012 did not change that conclusion.

Table 8-29 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran, Environmental, and Case-Control Studies

There have been no studies of US Vietnam veterans evaluating exposure to the COIs and testicular cancer since Update 2012. Furthermore, the study of Vietnam veterans from New Zealand (McBride et al., 2013) did not report results on testicular cancer.

TABLE 8-28 Average Annual Incidence (per 100,000) of Testicular Cancer in the United Statesa

60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
2.0 2.4 0.5 1.3 1.3 0.7 1.1 1.2 0.4

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-29 Selected Epidemiologic Studies—Testicular Cancer (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans
US VA Cohort of Army Chemical Corps—Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 non-deployed) serving during Vietnam era (July 1, 1965–March 28, 1973)   All COIs  
Mortality
Through 2005     Cypel and Kang, 2010
Deployed veterans (2,872) vs non-deployed (2,737) 2  
Through 1991 2 4.0 (0.5–14.5) Dalager and Kang, 1997
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1988     Watanabe and Kang, 1996
Army, deployed (n = 27,596) vs non-deployed (n = 31,757) 114 1.1 (nr)
Marine Corps, deployed (n = 6,237) vs non-deployed (n = 5,040) 28 1.0 (nr)  
1965–1984     Watanabe et al., 1991
Army, deployed (n = 24,145) vs non-deployed (n = 27,917) 109 1.2 (ns)
Served in I Corps (n = 6,668) 12 2.6 (1.1–6.2) Bullman et al., 1990
Marine Corps, deployed (n = 5,501 ) vs non-deployed (n = 4,505) 28 0.8 (ns) Watanabe et al., 1991
1965–1982     Breslin et al., 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 90 1.1 (0.8–1.5)
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 26 1.3 (0.5–3.6)  
State Studies of US Vietnam Veterans
District of Columbia patients (18–42 yrs of age) in 3 hospitals, diagnosed with testicular cancer (1976–June 30, 1981) 31 2.3 (1.0–5.5) Tarone et al., 1991
Massachusetts Vietnam-era veterans
Veterans aged 35–65 years in 1993—cases diagnosed 1988–1993 vs gastrointestinal cancers 30 1.2 (0.4–3.3) Clapp, 1997
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
923 White male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans 9 1.0 (0.5–1.9) Anderson et al., 1986a,b
International Vietnam-Veterans Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 54 0.9 (0.6–1.1) ADVA, 2005b
Navy 17 1.2 (0.7–1.8)
Army 34 0.8 (0.5–1.0)  
Air Force 3 0.8 (0.2–2.3)  
Validation Study   Expected number of exposed cases AIHW, 1999
  59 110 (89–139)  
Men 151 110 (89–131)  
Mortality
All branches, return–2001 14 0.9 (0.4–1.4) ADVA, 2005a
Navy 3 0.8 (0.2–2.4)  
Army 10 0.9 (0.4–1.7)  
Air Force 0 0.0 (0.0–3.3)  
1980–1994 4 ns CDVA, 1997a
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence
1982–2000 17 0.7 (0.4–1.2) ADVA, 2005c
Mortality      
1966–2001 4 0.8 (0.2–2.0) ADVA, 2005c
1982–1994 1 1.3 (nr) CDVA, 1997b
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)     Yi and Ohrr, 2014
Penis (C60) categorized high (n = 0) vs low (n = 1)   0.0 (NR)
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Testes (C62) categorized high (n = 2) vs low (n = 3)   0.5 (0.1–3.3)  
Other male genital organs (C63) categorized high (n = 1) vs low (n = 2)   1.0 (0.1–15.1)  
OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Mortality 1939–1992 68 1.1 (0.9–1.4) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 43 1.1 (0.8–1.5)
7,553 not exposed to highly chlorinated PCDDs 25 1.1 (0.3–1.6)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort 7 2.3 (0.9–4.6) Saracci et al., 1991
British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)   MCPA  
Mortality through 1983 4 2.2 (0.6–5.7) Coggon et al., 1986
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Ever-exposed workers 0 0.0 (0.0–15.6)
Never-exposed workers      
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (in IARC and NIOSH cohorts)   2,4,5-T; 2,4,5-TCP  
1942–2003; testes and other male genital (n = 1,615) 1 1.6 (0.0–8.9) Collins et al., 2009b
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Through 1994 (n = 1,517) 1 2.2 (0.0–12.5) Burns et al., 2001
Through 1982 (n = 878) 1 4.6 (0.0–25.7) Bond et al., 1988
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP); testes and other male genital     Collins et al., 2009c
0 0.0 (0.0–12.5)
Mortality 1940–1989 (n = 770) 0 nr Ramlow et al., 1996
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Never 2 1.1 (0.1–4.1)  
Ever 5 3.6 (1.2–8.4)  
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
CANADA
Sawmill Workers in British Columbia—23,829 workers for ≥ 1 yr at 11 mills using chlorophenates 1940–1985   Chlorophenates, not TCDD  
Incidence 1969–1989 18 1.0 (0.6–1.4) Hertzman et al., 1997
Mortality 1950–1989 (male genital cancers) 116 1.0 (0.8–1.1)
DENMARK
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Men
Self-employed 74 0.9 (nr)  
Employee 23 0.6 (p < 0.05)  
ICELANDIC men (1,860), women (859) exposed to agricultural pesticides, primarily 2,4-D—incidence   2,4-D Zhong and Rafnsson, 1996
2 1.2 (0.1–4.3)
NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of 339 incident testicular cancer cases vs remainder of 19,904 men with any incident cancer   Herbicides Reif et al., 1989
Forestry workers (n = 134) 6 1.0 (0.4–2.6)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
SWEDEN
Incident testicular cancer cases 1961–1973 with agriculture as economic activity in 1960 census 101 99% CI 1.0 (0.7–1.2) Wiklund, 1983
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Men
Whites (n = 119,648) 32 0.8 (0.6–1.2)  
Nonwhites (n = 11,446) 6 1.3 (0.5–2.9)  
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Private applicators 32 1.0 (0.7–1.4)
Commercial applicators 6 1.2 (0.5–2.6)  
Spouses 0 nr  
Enrollment through 2002     Alavanja et al., 2005
Private applicators 23 1.1 (0.7–1.6)
Spouses of private applicators (> 99% women) nr 0.0 (0.0–50.2)  
Commercial applicators 4 1.2 (0.3–3.2)  
Mortality
Enrollment through 2000, vs state rates     Blair et al., 2005a
Private applicators (men and women) 0 nr
Spouses of private applicators (> 99% women) 0 nr  
Florida Licensed Pesticide Applicators (common phenoxy use assumed but not documented; had been listed by Blair et al., 1983)   Herbicides  
Mortality 1975–1993 23 2.5 (1.6–3.7) Fleming et al., 1999b
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Incidence
20-yr follow-up to 1996—men and women
Zone A 0   Pesatori et al., 2009
Zone B 2 0.8 (0.2–3.3)
Zone R 22 1.4 (0.9–2.3)  
10-yr follow-up to 1991—men     Bertazzi et al., 1993
Zone B 1 1.0 (0.1–7.5)
Zone R 9 1.4 (0.7–3.0)  
Mortality
20-yr follow-up to 1996     Bertazzi et al., 2001
Zones A, B—men 17 1.0 (0.6–1.7)
15-yr follow-up to 1991—men     Bertazzi et al., 1998
Zone B 10 1.0 (0.5–1.8)
Zone R 73 1.0 (0.8–1.3)  
CASE-CONTROL STUDIES
International Case-Control Studies
Swedish Cancer Registry (1989–1992)—testicular cancer patients (20–75 yrs old) (n = 148)   Herbicides Hardell et al., 1998
Exposed to herbicides 4 0.3 (0.1–1.0)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; CATI, computer-assisted telephone interviewing; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MOS, military occupation specialty; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; ns, not statistically significant; PCDD, polychlorinated dibenzo- p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; SIR, standardized incidence ratio; TCDD, 2,3,7,8-tetrachlorodibenzo- p-dioxin; TCP, trichlorophenol; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

In a follow-up through 2003, the Korean Veterans Health Study identified only five incident cases of testicular cancers of which two cancers occurred among veterans with high exposure. Overall, no difference in the incidence of testicular cancer was seen in this cohort in comparison with the Korean general population (SIR = 1.05, 95% CI 0.42–2.63) (Yi, 2013). In the internal comparison analysis of high- versus low-exposure opportunity scores, Yi and Ohrr (2014) reported no association for testicular cancer (RR = 0.51, 95% CI 0.08–3.27);

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

however, this analysis was underpowered because it was based on only two cases in the higher herbicide category. Yi et al. (2014b) did not report results for testicular cancer mortality in the Korean Veterans Health Study.

Occupational, Environmental, and Case-Control Studies

No occupational, environmental, or case-control studies of exposure to the COIs and testicular cancer have been published since Update 2012.

Biologic Plausibility

No animal studies of the incidence of testicular cancer after exposure to any of the COIs have been published since Update 2012. That is undoubtedly due to the lack of a valid animal model of testicular cancer. SNPs of uncertain functional significance in the human AHR gene (11 SNPs) and the AHR repressor (AHRR) gene (18 SNPs) were studied in a case-control study of 278 Swedish men and 89 Danish men with testicular germ cell cancers (mean age 31 years) and 214 Swedish men without testicular cancer (mean age 18 years) (Brokken et al., 2013). There was no association between risk of testicular germ cell cancer and any of the SNPs analyzed, but four SNPs in the AHRR gene were significant associated with risk of metastatic cancer compared to localized cancer. The general biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

The evidence from epidemiologic studies is inadequate to link herbicide exposure and testicular cancer. The relative rarity of this cancer makes it difficult to develop risk estimates with any precision. Most cases occur in men 25–35 years old, and men who have received such a diagnosis could have been excluded from military service; this could explain the slight reduction in risk observed in some veteran studies.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and testicular cancer.

BLADDER CANCER

Urinary bladder cancer (ICD-9 188) is the most common urinary tract cancer. Cancers of the urethra, and paraurethral glands and other or unspecified urinary

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

cancers (ICD-9 189.3–189.9) are infrequently reported separately; any findings on these cancers would be reported in this section. ACS estimated that 56,320 men and 17,680 women would receive a diagnosis of bladder cancer in the United States in 2015 and that 11,510 men and 4,490 women would die from it (Siegel et al., 2015). In males, in whom this cancer is about twice as common as it is in females, those numbers represent about 7 percent of new cancer diagnoses and 3 percent of cancer deaths. Overall, bladder cancer is fourth in incidence in men in the United States.

Bladder cancer risk rises rapidly with age. In men in the age groups that characterize most Vietnam veterans, bladder cancer incidence is about twice as high in whites as in blacks. The average annual incidence of urinary bladder cancer is shown in Table 8-30. The most important known risk factor for bladder cancer is tobacco smoke inhalation, which accounts for about one-half of the bladder cancers in men and one-third of them in women (Cumberbatch et al., 2015; Ferris et al., 2013a). Occupational exposure to hair dyes, aromatic amines (also called arylamines), polycyclic aromatic hydrocarbons, and some other organic chemicals used in the aluminum, rubber, leather, textile, paint-products, and printing industries is associated with higher incidence (Ferris et al., 2013a,b). In some parts of Africa and Asia, infection with the parasite Schistosoma haematobium contributes to the high incidence (Ferris et al., 2013a).

Exposure to inorganic arsenic is also a risk factor for bladder cancer. Although cacodylic acid is a metabolite of inorganic arsenic, as discussed in Chapter 4, the data are insufficient to conclude that studies of inorganic-arsenic exposure are directly relevant to exposure to cacodylic acid, so the literature on inorganic arsenic is not considered in this section. Cacodylic acid constituted about 30 percent of the approximately 4 million liters of Agent Blue mixtures sprayed in Vietnam (see Table 3-1), as compared with approximately 44 million liters of 100 percent phenoxy herbicide mixtures with various degrees of TCDD contamination. Moreover, other than studies of exposure in Vietnam, there have been no occupational or environmental epidemiologic studies investigating bladder cancer incidence or mortality involving direct exposure to cacodylic acid.

TABLE 8-30 Average Annual Incidence (per 100,000) of Bladder Cancer in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Men 70.5 77.0 47.0 123.1 134.9 75.2 182.9 200.7 112.4
Women 19.5 21.7 12.8 31.1 33.5 24.7 43.1 47.7 31.9

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was limited or suggestive evidence of no association between exposure to the COIs and urinary bladder cancer. The conclusion of no increased risk of bladder cancer was based largely on the null results (SMR = 0.8, 95% CI 0.4–1.4) from the overarching IARC cohort study of phenoxy herbicide production workers and sprayers (Saracci et al., 1991) and consistently inconclusive results from studies of additional occupationally exposed cohorts, environmentally exposed populations, and two small studies of Vietnam veterans. An almost statistically significant finding on bladder cancer mortality (SMR = 1.4, 95% CI 0.9–2.1) in the IARC cohort, augmented with 12 additional cohorts and updated through 1992 (Kogevinas et al., 1997) led the committee responsible for Update 1998 to move bladder cancer to the default category of inadequate or insufficient information to determine whether there is an association. The committees responsible for subsequent updates did not change that conclusion.

Table 8-31 summarizes the results of the relevant studies; entries from primary epidemiologic publications new to this update are shaded.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

There have been no US Vietnam-veteran studies addressing bladder cancer since Update 2012, and neither bladder cancer incidence nor mortality was reported for the cohort of male veterans from New Zealand (McBride et al., 2013).

The prospective cohort of Korean veterans included 185,265 male veterans who had served in Vietnam from 1964 until 1973, were alive in 1992, and were followed for cancer incidence from 1992 through 2003 (Yi, 2013; Yi and Ohrr, 2014) and for mortality through 2005 (Yi et al., 2014b). A total of 264 incident cases and 61 deaths from bladder cancer were identified in this cohort during follow-up. The internal comparison analysis of the groups with high- versus low-exposure opportunity scores (Yi and Ohrr, 2014) revealed no difference in the risk of bladder cancer diagnosis (RR = 0.99, 95% CI 0.77–1.28), based on a large number of cases (122 in the low-exposure category and 133 in the high-exposure category). By contrast, Yi et al. (2014b) reported a statistically significant two-fold increase in bladder cancer–specific mortality (RR = 2.04, 95% CI 1.17–3.55) comparing the high- and low-exposure groups without adjustment for smoking; these results were based on 42 deaths from bladder cancer in the high category.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-31 Selected Epidemiologic Studies—Urinary Bladder Cancer (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)   All COIs  
Incidence
Through 1999—White subjects vs national rates     Akhtar et al., 2004
Ranch Hand veterans (n = 1,189) 14 1.1 (0.6–1.7)  
With tours between 1966–1970 14 1.3 (0.7–2.1)  
SEA comparison veterans (n = 1,776) 8 0.4 (0.2–0.8)  
With tours between 1966–1970 4 0.3 (0.1–0.7)  
Mortality
Through 1999—White subjects vs national rates      
Ranch Hand veterans 1 0.9 (nr)  
SEA comparison veterans 1 0.6 (nr)  
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Mortality
1965–2000 1 nr Boehmer et al., 2004
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1982     Breslin et al., 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 9 0.6 (0.3–1.2)
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 4 2.4 (0.1–66.4)  
State Studies of US Vietnam Veterans
Massachusetts Vietnam-era veterans
Veterans served 1958–1973—cases diagnosed 1988–1993 (served in Vietnam) (updates Clapp et al., 1991) 80 0.6 (0.2–1.3) Clapp, 1997
923 White male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans (includes lymphosarcoma, reticulosarcoma) 1 nr Anderson et al., 1986a,b
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 164 1.0 (0.9–1.2) ADVA, 2005b
Navy 34 1.0 (0.7–1.4)  
Army 104 1.0 (0.8–1.2)  
Air Force 26 1.3 (0.8–1.8)  
Mortality      
All branches, return–2001 22 0.7 (0.4–1.0) ADVA, 2005a
Navy 4 0.6 (0.2–1.6)  
Army 13 0.7 (0.3–1.1)  
Air Force 5 1.1 (0.4–2.5)  
1980–1994 11 1.1 (0.6–1.9) CDVA, 1997a
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence—1982–2000 19 0.7 (0.4–1.1) ADVA, 2005c
Mortality
1966–2001 1 0.3 (0.0–1.7)  
1982–1994 1 0.6 (nr) CDVA, 1997b
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—bladder cancer (C67) categorized high (n = 133) vs low (n = 122)   1.0 (0.8–1.3) Yi and Ohrr, 2014
Mortality (1992–2005)—bladder cancer (C67) categorized high (n = 85,809) vs low (n = 42)   2.0 (1.2–3.6) Yi et al., 2014b
HR per unit of log EOI score (n = 19) 61 1.1 (1.0–1.3)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates   Dioxins, phenoxy herbicides  
Mortality 1939–1992 34 1.0 (0.7–1.5) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 24 1.4 (0.9–2.1)
7,553 not exposed to highly chlorinated PCDDs 10 0.7 (0.3–1.2)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort 13 0.8 (0.4–1.4) Saracci et al., 1991
British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)   MCPA  
Mortality through 1983 8 0.9 (0.4–1.7) Coggon et al., 1986
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)   Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP  
Incidence 1943–1982 (men only) 11 0.8 (nr) Lynge, 1985
Mortality 1955–2006 15 1.1 (0.8–1.4) Boers et al., 2012
TCDD plasma level (HRs, by tertile)    
Background (≤ 0.4) 4 nr  
Low (0.4–4.1) 10 2.4 (0.8–8.3)  
Medium (4.1–20.1) 7 4.0 (1.1–14.3)  
High (≥ 20.1) 2 3.1 (0.6–17.0)  
Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)   Dioxins, 2,4,5-T, 2,4,5-TCP  
Mortality 1955–2006 (HRs for lagged TCDD plasma levels) 11 1.0 (0.7–1.5) Boers et al., 2012
Mortality 1955–2006 9 vs 2 2.3 (0.5–10.3) Boers et al., 2010
Mortality 1955–1991 4 3.7 (1.0–9.5) Hooiveld et al., 1998
Accidentally exposed subcohort 1 2.8 (0.1–15.5)
Mortality 1955–1985 1 1.5 (0.0–8.8) Bueno de Mesquita et al., 1993
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Dutch production workers in Plant B (414 men exposed during production 1965–1986; 723 unexposed) (in IARC cohort)   2,4-D; MCPA; MCPP; highly chlorinated dioxins unlikely  
Mortality 1965–2006 2 vs 2 1.1 (0.2–7.2) Boers et al., 2010
Mortality 1965–1986 0 0.0 (0.0–20.5) Bueno de Mesquita et al., 1993
German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 mo in 1957–1987) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)   Focus on TCDD  
Incidence
1960–1992     Ott and Zober, 1996a
TCDD < 0.1 µg/kg of body weight 1 0.7 (0.0–4.0)
TCDD 0.1–0.99 µg/kg of body weight 3 3.0 (0.6–8.9)  
TCDD > 1.0 µg/kg of body weight 1 0.8 (0.0–4.4)  
Mortality
1960–1992      
TCDD < 0.1 µg/kg of body weight 0 0.0 (0.0–5.7)  
TCDD 0.1–0.99 µg/kg of body weight 2 4.1 (0.5–14.7)  
TCDD > 1.0 µg/kg of body weight 0 0.0 (0.0–5.4)  
Through 1987   90% CI Zober et al., 1990
  0 nr (0.0–15.0)
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)   Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP  
Mortality 1952–2007 13 1.8 (1.0–3.1) Manuwald et al., 2012
Men 11 1.8 (0.9–3.3)
Women 2 1.8 (0.2–6.6)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Ever-exposed workers 0 0.0 (0.0–2.9)
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)      
Mortality 1969–2000 0 nr ’t Mannetje et al., 2005
Sprayers (697 men and 2 women registered any time 1973–1984)      
Mortality 1973–2000 0 nr ’t Mannetje et al., 2005
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Through 1993 16 2.0 (1.1–3.2) Steenland et al., 1999
Chloracne subcohort (n = 608) 6 3.0 (1.4–8.5)
Through 1987 (bladder, other) 9 1.6 (0.7–3.0) Fingerhut et al., 1991
≥ 1-yr exposure, ≥ 20-yr latency 4 1.9 (0.5–4.8)
Mortality—754 Monsanto workers, among most highly exposed workers from Fingerhut et al. (1991) 16 6.8 (3.9–11.1) Collins et al., 1993
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (in IARC and NIOSH cohorts)   2,4,5-T; 2,4,5-TCP  
1942–2003 (n = 1,615) 6 1.2 (0.5–2.7) Collins et al., 2009b
1940–1994 (n = 2,187 men) nr 0.7 (0.1–2.0) Bodner et al., 2003
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
1940–2005 (n = 2,122) (bladder and other urinary organs, ICD-9 188, 189.3, 189.9) 8 1.1 (0.5–2.1)  
PCP and TCP (n = 720) 1 0.4 (0.0–2.3)  
PCP (no TCP) (n = 1,402) 7 1.4 (0.6–2.9)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3) 19 1.2 (0.7–1.9) Burns CJ et al., 2011
Through 1994 (n = 1,517) 1 0.5 (0.1–2.8) Burns et al., 2001
Through 1982 (n = 878) 0 nr (0.0–7.2) Bond et al., 1988
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) 2 0.7 (0.1–2.7) Collins et al., 2009c
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Never 50 1.0 (0.7–1.3)  
Ever 43 1.1 (0.8–1.5)  
New Hampshire pulp and paper workers, 883 white men working ≥ 1 yr, mortality through July 1985 4 1.2 (0.3–3.2) Henneberger et al., 1989
Pulp and Paper cohorts independent of IARC cohort      
Northwestern US paper and pulp workers—5 mills in Washington, Oregon, and California, 3,523 worked ≥ 1 yr 1945–1955, mortality through March 1977 8 90% CI
1.2 (0.6–2.6)
Robinson et al., 1986
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)
CANADA
Sawmill Workers in British Columbia—23,829 workers for ≥ 1 yr at 11 mills using chlorophenates 1940–1985   Chlorophenates, not TCDD  
Incidence 1969–1989 33 0.9 (0.7–1.2) Hertzman et al., 1997
Mortality 1950–1989 94 1.0 (0.8–1.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Herbicide sprayers routinely exposed to herbicides for 6 mos or more (1950–1982)   Phenoxy herbicides Green, 1991
Diseases of genitourinary system 1 1.0 (0.0–5.6)  
DENMARK
Danish gardeners (n = 3,124) exposed to pesticides 59 0.8 (0.6–1.1) Kenborg et al., 2012
Danish farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Men
Self-employed 300 0.6 (p < 0.05)  
Employee 70 0.7 (p < 0.05)  
Women
Self-employed 1 0.2 (nr)  
Employee 2 0.6 (nr)  
Family worker 25 0.6 (p < 0.05)  
Danish gardeners—incidence from 3,156 male and 859 female gardeners (urinary system, ICD-7 180–181)     Hansen et al., 2007
25-yr follow-up (1975–2001)   Herbicides  
Born before 1915 (high exposure) 25 1.1 (0.7–1.6)  
Born 1915–1934 (medium exposure) 23 0.5 (0.4–0.8)  
Born after 1934 (low exposure) 1 0.2 (0.0–1.1)  
10-yr follow-up (1975–1984) of male gardeners 18 0.9 (0.7–1.8) Hansen et al., 1992
(lymphohematopoietic, ICD-7 200–2005)      
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 2000 2 0.7 (0.1–2.4) Swaen et al., 2004
FINNISH Phenoxy Herbicide Sprayers (1,909 men working 1955–1971 ≥ 2 wks) not IARC   Phenoxy herbicides  
Incidence     Asp et al., 1994
No latency 12 1.6 (0.8–2.8)  
10-yr latency 11 1.7 (0.8–3.0)  
Mortality
No latency 1 0.5 (0.0–2.6)  
10-yr latency 1 0.5 (0.0–3.0)  
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401) 31 0.5 (0.4–0.8) Torchio et al., 1994
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Italian rice growers with documented phenoxy use (n = 1,487) 12 Phenoxy herbicides Gambini et al., 1997
    1.0 (0.5–1.8)  
NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of incident stomach cancer cases vs remainder of 19,904 men with any incident cancer     Reif et al., 1989
Forestry workers (n = 134)   Herbicides  
  4 0.7 (0.3–1.8)  
UNITED STATES
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Private applicators 191 0.6 (0.5–0.7)  
Commercial applicators 16 0.2 (0.7–1.9)  
Spouses 29 0.6 (0.4–0.9)  
Enrollment through 2002     Samanic et al., 2006
Dicamba—lifetime days exposure    
None 43 1.0  
1– < 20 6 0.5 (0.2–1.3)  
20– < 56 9 0.7 (0.3–1.4)  
56– < 116 6 0.6 (0.3–1.5)  
≥ 116 8 0.8 (0.4–1.9)  
    p-trend = 0.66  
Enrollment through 2002     Alavanja et al., 2005
Private applicators 184 0.7 (0.6–0.8)
Spouses of private applicators (> 99% women) 17 0.7 (0.4–1.1)  
Commercial applicators 13 1.1 (0.6–1.8)  
Mortality
Enrollment through 2007, vs state rates     Waggoner et al., 2011
Applicators (n = 1,641) 35 0.6 (0.4–0.8)
Spouses (n = 676) 9 0.8 (0.4–1.6)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Enrollment through 2000, vs state rates     Blair et al., 2005a
Private applicators (men and women) 7 0.4 (0.1–0.7)
Spouses of private applicators (> 99% women) 2 0.8 (0.1–2.7)  
US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 of NHL   Herbicides  
Agricultural extension agents 8 0.7 (0.4–1.4) Alavanja et al., 1988
Forest conservationists   p-trend < over years worked Alavanja et al., 1989
  8 0.8 (0.3–1.6)  
Florida Licensed Pesticide Applicators (common phenoxy use assumed but not documented; had been listed by Blair et al., 1983)   Herbicides  
Pesticide applicators in Florida licensed 1965–1966 (n = 3,827)—mortality through 1976   Herbicides Blair et al., 1983
Any pesticide (dose-response by length of licensure)   Expected exposed cases  
  3 1.6 (nr)  
White Male Residents of Iowa—NHL cancer on death certificate, usual occupation: farmers vs not   Herbicides  
> 20 yrs old when died 1971–1978—PMR 274 0.9 (nr) Burmeister, 1981
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Incidence
20-yr follow-up to 1996—men and women
Zone A 3 1.4 (0.5–4.5) Pesatori et al., 2009
Zone B 17 1.3 (0.8–2.2)
Zone R 84 0.9 (0.8–1.2)  
10-yr follow-up to 1991—men     Pesatori et al., 1992
Zone A, B 10 1.6 (0.9–3.1)
Zone R 39 1.0 (0.7–1.4)  
10-yr follow-up to 1991—women      
Zone A, B 1 0.9 (0.1–6.8)  
Zone R 4 0.6 (0.2–1.5)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality
25-yr follow-up to 2001—men and women     Consonni et al., 2008
Zone A 1 1.0 (0.2–7.4)
Zone B 6 0.9 (0.4–2.0)  
Zone R 42 0.9 (0.6–1.2)  
20-yr follow-up to 1996     Bertazzi et al., 2001
Zones A and B—men 6 1.2 (0.5–2.7)
15-yr follow-up to 1991—men     Bertazzi et al., 1998
Zone B 1 2.4 (0.3–16.8)
Zone R 21 0.9 (0.6–1.5)  
15-yr follow-up to 1991—women     Bertazzi et al., 1998
Zone B 3 0.9 (0.3–3.0)
Zone R 4 0.6 (0.2–1.8)  
Ecological Study of Residents of Chapaevsk, Russia   Dioxin Revich et al., 2001
Mortality—1995–1998 (SMR vs regional rates)
Men 31 2.6 (1.7–3.6)  
Women 17 0.8 (0.5–1.3)  
Other International Environmental Studies
FINLAND
Finnish community exposed to chlorophenol contamination (men and women)—incidence 14 Chlorophenol
1.0 (0.6–1.9)
Lampi et al., 1992
SWEDEN
Swedish fishermen (high consumption of fish with persistent organochlorines)   Organochlorine compounds Svensson et al., 1995a
Incidence
East coast 10 0.7 (0.4–1.3)  
West coast 55 0.9 (0.7–1.1)  
Mortality
East coast 5 1.3 (0.4–3.1)  
West coast 20 1.0 (0..6–1.6)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; CATI, computer-assisted telephone interviewing; CC, case-control; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job-exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; NHL, non-Hodgkin lymphoma; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo- p-dioxin (highly chlorinated, if four or more chlorines); PCP, pentachlorophenol; PMR, proportional mortality ratio; SEA, Southeast Asia; SIR, standardized incidence ratio; SMR, standardized mortality rate; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Occupational and Environmental Studies

No occupational or environmental studies of exposure to the COIs and bladder cancer have been published since Update 2012.

Case-Control Studies

Matic et al. (2014) conducted a hospital-based case-control study of bladder cancer in Serbia. A total of 143 cases and 114 matched controls were recruited in this study, and information on pesticide use was collected via self-reports. An increased risk of bladder cancer (OR = 3.5, 95% CI 0.9–12.9) was found to be associated with self-reported use of pesticides; however, the results were based on 15 exposed cases. Limitations include the potential for selection bias and recall bias because information on pesticide exposure was collected after bladder cancer diagnosis. In addition, exposure characterization was not specific to the COIs, so its results are not fully relevant to committee’s task.

Biologic Plausibility

Cacodylic acid (DMAIII and DMAV) is carcinogenic and has been shown to induce urinary bladder cancer in F344 rats (Arnold et al., 2006; Cohen et al., 2007b; Wang A et al., 2009; Wei et al., 2002; Yamamoto et al., 1995).

No studies have reported an increased incidence of urinary bladder cancer in TCDD- or 2,4-D-treated animals. Working with tissues from urothelial cancer patients, Ishida et al. (2010) found that activation of the AHR pathway by TCDD enhanced bladder cancer cell invasion by upregulated expression of matrix metalloproteinases 1 and 9 and that reduced expression of AHR resulted in the inhibition of invasive behavior of urothelial cancer cells. They also found that the level of nuclear AHR expression in human upper urinary tract urothelial cancers was positively associated with cancer grade and stage and that it predicted poor prognosis. In contrast, transgenic mice that have deletion of the AHR exhibit immune-cell infiltration in bladder submucosa and loss of e-cadherin in some epithelial cells in aged mice (Butler et al., 2012); although direct studies with TCDD were not undertaken, these findings suggest a protective effect of AHR signaling in bladder cancer.

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

Many of the available analyses of an association between exposure to the COIs and bladder cancer risk are characterized by low precision because of the small numbers of exposed cases, low exposure specificity, and a lack of ability

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

to control for confounding, particularly cigarette smoking, which is a major risk factor for bladder cancer. However, there are some studies with considerable numbers of bladder cancer cases.

Because of the large sample size of the Korean Vietnam Veterans Health Study and a correspondingly ample number of incident cases, the observed absence of an association between herbicide exposure and incident bladder cancer cannot be considered a meaningful finding. In contrast, there was a statistically significant two-fold increase in mortality from bladder cancer among veterans in the high-exposure-opportunity group relative to those in the low-exposure group. Because information on smoking was not available in the cancer incidence and mortality publications (Yi and Ohrr, 2014; Yi et al., 2014b), it might be hypothesized that the results for bladder cancer mortality could be explained in part by uncontrolled confounding. However, self-reported information on smoking among surviving Korean veterans (Yi et al., 2013b) revealed that the distribution of smoking habits was similar, regardless of exposure opportunity score, indicating that the results for bladder cancer mortality are unlikely to have been majorly confounded by smoking.

The evidence for bladder cancer mortality found in the Korean Vietnam Veterans Health Study is consistent with some previous mortality studies in occupationally exposed cohorts that had reasonable numbers of cases and exposure assessments. When augmented with 12 additional subcohorts and updated through 1992, the IARC cohort had an almost statistically significant finding for deaths from bladder cancer (SMR = 1.4, 95% CI 0.9–2.1) among those workers exposed to highly chlorinated PCDDs (Kogevinas et al., 1997). Subsequently, follow-up reports on mortality after 1992 in several of the IARC subcohorts found elevations in bladder cancer mortality. For the NIOSH subcohort, Steenland et al. (1999) reported significant increases in mortality through 1993 due to bladder cancer in the entire cohort (SMR = 2.0, 95% CI 1.1–3.2) and a stronger result in the subgroup with chloracne (SMR = 3.0, 95% CI 1.4–8.5). Manuwald et al. (2012) reported a marginally significant increase in bladder cancer mortality through 2007 (SMR = 1.8, 95% CI 1.0–3.1) in the Hamburg cohort, and Boers et al. (2010) also reported increased mortality through 2006 (HR = 2.3, 95% CI 0.5–10.3, n = 9 versus 2) in Plant A of the Dutch subcohort. However, updates of Plant B of the Dutch subcohort (Boers et al., 2010), the Dow PCP cohort through 2005 (Ruder and Yiin, 2011), and the Dow 2,4-D cohort through 2007 (Burns CJ et al., 2011) found minimal increases in bladder cancer mortality, and the update of mortality in the New Zealand subcohort through 2004 still found no deaths from bladder cancer (McBride et al., 2009a). In addition, Revich et al. (2001) also reported an increase in bladder cancer mortality (SMR = 2.6, 95% CI 1.7–3.6, based on 31 deaths) during 1995–1998 among male residents of Chapaevsk, Russia, in comparison with the general population, possibly because of dioxin exposure from a local chemical plant.

Mortality data for bladder cancer are considered to be of more importance than incidence data because the majority of bladder cancers are detected early or

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

incidentally, when they are non-invasive and therefore can be treated curatively (ACS, 2015). Investigations of bladder cancer incidence evaluated in VAO updates have not stratified cases based on tumor invasiveness, and thus any positive association there might have been with invasive tumors could have been masked.

The toxicologic information on cacodylic acid is consistent with findings of an increase in bladder cancer among Vietnam veterans exposed to herbicides, but there are no occupational or environmental epidemiologic studies investigating bladder cancer incidence or mortality in relation to cacodylic acid exposure. The evidence from mortality studies in populations occupationally exposed to TCDD or the phenoxy herbicides, however, do suggest the possibility of increased risk of death from bladder cancer. The new data on bladder cancer mortality in the Korean Vietnam veterans reviewed in this update add to the existing epidemiologic evidence suggesting a possible increased risk of bladder cancer mortality associated with herbicide exposure based on a large number of bladder cancer deaths in the high-exposure category. An increase may have become evident only recently because of the long latency of most fatal bladder cancers. Although the results of this study lack adjustment for smoking and other potential confounders, as do other occupational studies, it is unlikely that smoking prevalence differed by exposure category.

After careful consideration and discussion, the VAO committee determined that the available data and scientific literature, taken as a whole, are sufficiently consistent to conclude that there is limited or suggestive evidence for an association of bladder cancer with exposure to the COIs.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to the COIs and bladder cancer.

RENAL CANCERS

Cancers of the kidney other than the renal pelvis (ICD-9 189.0) and cancer of the renal pelvis (ICD-9 189.1) are often grouped in epidemiologic studies; cancer of the ureter (ICD-9 189.2) is sometimes also included. Although diseases of these organs have different characteristics and could have different risk factors, there is some logic to grouping them: the structures are all exposed to filterable chemicals, such as polycyclic aromatic hydrocarbons, that appear in urine. ACS estimated that 38,270 men and 23,290 women would receive diagnoses of renal cancer (ICD-9 189.0, 189.1) in the United States in 2015 and that 9,070 men and 5,010 women would die from it (Siegel et al., 2015).Those figures represent 2 to 4 percent of all new cancer diagnoses and cancer deaths. The average annual incidence of renal cancers is shown in Table 8-32.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-32 Average Annual Incidence (per 100,000) of Kidney and Renal Pelvis Cancers in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Men 61.1 61.6 79.0 83.3 84.7 108.0 94.5 98.2 107.5
Women 28.7 29.4 35.7 39.6 40.3 52.7 46.8 48.0 59.2

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

Renal cancers are twice as common in men as in women. In the age groups that include most Vietnam veterans, black men have a higher incidence than white men. With the exception of Wilms tumor, which is more likely to occur in children, renal cancers are more common in people over 50 years old.

Tobacco use is a well-established risk factor for renal cancers (Qayyum et al., 2013). Obesity is also another risk factor for renal cell carcinoma, and a recently published meta-analysis of 21 cohort studies reported an elevated risk for renal cancers (RR = 1.77, 95% CI 1.68–1.87) when comparing obese to normal weight participants (Wang and Xu, 2014). Some rare syndromes—notably, von Hippel–Lindau syndrome and tuberous sclerosis—are associated with an elevated risk of renal cancer. Other potential risk factors include acetaminophen or non-aspirin non-steroidal anti-inflammatory drug use, organic solvents, or a history of kidney stones in men (Cheungpasitporn et al., 2015; Choueiri et al., 2014; Qayyum et al., 2013). Firefighters, who are routinely exposed to numerous pyrolysis products, have a significantly increased mortality risk after 20 or more years of employment (Youakim, 2006).

Conclusions from VAO and Previous Updates

The committee responsible for Update 1998 VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and renal cancers. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, Update 2010, and Update 2012 did not change that conclusion.

Table 8-33 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran, Environmental, and Case-Control Studies

There have been no studies of US Vietnam veterans that addressed renal cancers since Update 2012. In addition, the study of male veterans from New Zealand (McBride et al., 2013) did not report on renal cancer incidence or mortality.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-33 Selected Epidemiologic Studies—Renal Cancers (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veteran
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Mortality
1965–2000 1 nr Boehmer et al., 2004
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1982     Breslin et al., 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 55 0.9 (0.5–1.5)
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 13 0.9 (0.5–1.5)  
State Studies of US Vietnam Veterans
Massachusetts Vietnam veterans diagnosed 1972–1983 9 1.8 (1.0–3.5) Kogan and Clapp, 1988
Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs non-deployed 923 White male Vietnam veterans 21 1.4 (0.9–2.2) Visintainer et al., 1995
Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans (includes lymphosarcoma, reticulosarcoma) 2 nr Anderson et al., 1986a,b
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 125 1.0 (0.8–1.2) ADVA, 2005b
Navy 34 1.3 (0.9–1.7)  
Army 77 0.9 (0.7–1.1)  
Air Force 14 1.1 (0.6–1.8)  
Mortality
All branches, return–2001 50 1.0 (0.7–1.2) ADVA, 2005a
Navy 12 1.1 (0.6–1.9)  
Army 33 0.9 (0.6–1.3)  
Air Force 5 0.8 (0.3–1.8)  
1980–1994 22 1.2 (0.7–1.8)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence—1982–2000 19 0.7 (0.4–1.0) ADVA, 2005c
Mortality
1966–2001 4 0.4 (0.1–1.1)  
1982–1994 3 3.9 (nr) CDVA, 1997b
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—categorized high (n = 85,809) vs low (n = 94,442)     Yi and Ohrr, 2014
Kidney cancer (C64) categorized high (n = 79) vs low (n = 102)   0.7 (0.6–1.0)  
Renal pelvis cancer (C65) categorized high (n = 11) vs low (n = 12)   1.1 (0.4–2.5)  
Ureter cancer (C66) categorized high (n = 11) vs low (n = 8)   1.3 (0.5–3.2)  
Mortality (1992–2005)—renal cancer (C64–C66) categorized high (n = 30) vs low (n = 33)   0.9 (0.5–1.5) Yi et al., 2014b
HR per unit of EOI scores (n = 180,639) 63 1.0 (0.9–1.1)  
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates   Dioxin, phenoxy herbicides  
Mortality 1939–1992 29 1.1 (0.7–1.6) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 26 1.6 (1.1–2.4)
7,553 not exposed to highly chlorinated PCDDs 3 0.3 (0.1–0.9)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort 11 1.0 (0.5–1.7) Saracci et al., 1991
British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)   MCPA  
Mortality through 1983 5 1.0 (0.3–2.3) Coggon et al., 1986
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)   Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP  
Incidence 1943–1982 (men only) 3 0.6 (nr) Lynge, 1985
Mortality 1955–2006 8 1.2 (0.8–1.6) Boers et al., 2012
Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)   Dioxins, 2,4,5-T, 2,4,5-TCP  
Mortality 1955–2006 (HRs for lagged TCDD plasma levels) 8 0.8 (0.5–1.5) Boers et al., 2012
Mortality 1955–2006 8 HR = “infinitively large” Boers et al., 2010
Mortality 1955–1991 4 3.7 (1.0–9.5) Hooiveld et al., 1998
Total cohort—kidney cancer 4 4.1 (1.1–10.4)
Total cohort—“urinary organs” 8 3.9 (0.7–7.6)  
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)   Dioxins; 2,4,5-T; 2,4,5-TCP; 2,5-DCP  
Mortality 1952–2007 (kidney and other and unspecified urinary organs) 9 2.1 (0.9–3.9) Manuwald et al., 2012
Men 7 2.0 (0.8–4.1)  
Women 2 2.3 (0.3–8.1)  
Mortality 1952–1989—stats on men only, 1,184 (tables all for 1,148 men, not necessarily German nationals) vs national rates (also vs gas workers); same observation period as Becher et al., 1966 3 1.6 (0.3–4.6) Manz et al., 1991
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Ever-exposed workers 3 2.3 (0.5–6.7)
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)      
Mortality 1969–2000 1 1.2 (0.0–6.6) ’t Mannetje et al., 2005
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Sprayers (697 men and 2 women registered any time 1973–1984)      
Mortality 1973–2000 3 2.7 (0.6–8.0) ’t Mannetje et al., 2005
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Through 1993 13 1.6 (0.8–2.7) Steenland et al., 1999
Through 1987 (bladder, other) 8 1.4 (0.6–2.8) Fingerhut et al., 1991
≥ 1-yr exposure, ≥ 20-yr latency 2 1.1 (0.1–3.8)
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (in IARC and NIOSH cohorts)   2,4,5-T; 2,4,5-TCP  
1942–2003 (n = 1,615) 2 0.4 (0.1–1.5) Collins et al., 2009b
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
1940–2005 (n = 2,122) (kidney, ICD-9 189.0–189.2) 8 1.2 (0.5–2.4)  
PCP and TCP (n = 720) 4 1.8 (0.5–4.6)  
PCP (no TCP) (n = 1,402) 4 0.9 (0.3–2.3)  
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3) (kidney, renal pelvis) 5 0.8 (0.3–1.8) Burns CJ et al., 2011
Through 1994 (n = 1,517) 2 0.9 (0.1–3.3) Burns et al., 2001
Through 1982 (n = 878) 0 nr (0.0–6.2) Bond et al., 1988
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) 4 1.7 (0.5–4.4) Collins et al., 2009c
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Never 41 0.9 (0.7–1.3)  
Ever 18 0.5 (0.3–0.8)  
New Hampshire pulp and paper workers, 883 white men working ≥ 1 yr, mortality through July 1985 3 1.5 (0.3–4.4) Henneberger et al., 1989
Pulp and Paper cohorts independent of IARC cohort      
Northwestern US paper and pulp workers—5 mills in Washington, Oregon, and California, 3,523 worked ≥ 1 yr 1945–1955, mortality through March 1977 6 90% CI
1.2 (0.5–3.0)
Robinson et al., 1986
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
DENMARK
Danish farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Men
Self-employed 141 0.6 (p < 0.05)  
Employee 18 0.4 (p < 0.05)  
Women
Self-employed 4 0.9 (nr)  
Employee 3 1.0 (nr)  
Family Worker 30 0.8 (nr)  
Danish gardeners—incidence from 3,156 male and 859 female gardeners (urinary system, ICD-7 180–181)     Hansen et al., 2007
25-yr follow-up (1975–2001)   Herbicides  
Born before 1915 (high exposure) 25 1.1 (0.7–1.6)  
Born 1915–1934 (medium exposure) 23 0.5 (0.4–0.8)  
Born after 1934 (low exposure) 1 0.2 (0.0–1.1)  
10-yr follow-up (1975–1984) of male gardeners 18 0.9 (0.7–1.8) Hansen et al., 1992
(lymphohematopoietic, ICD-7 200–2005)      
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 2000 4 1.3 (0.4–3.4) Swaen et al., 2004
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401) 16 0.6 (0.4–1.0) Torchio et al., 1994
NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of incident stomach cancer cases vs remainder of 19,904 men with any incident cancer     Reif et al., 1989
Forestry workers (n = 134)   Herbicides  
  2 0.6 (0.2–2.3)  
SWEDEN
Incident cancer cases 1961–1973 with agriculture as economic activity in 1960 census (male, female) 775 99% CI
0.8 (0.7–0.9)
Wiklund, 1983
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Men
Whites (n = 119,648) 522 1.1 (1.0–1.2)  
Nonwhites (n = 11,446) 30 0.8 (0.5–1.1)  
Women
Whites (n = 2,400) 6 0.8 (0.3–1.7)  
Nonwhites (n = 2,066) 6 1.4 (0.5–3.1)  
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Private applicators 148 0.8 (0.7–1.0)  
Commercial applicators 2 nr  
Spouses 39 0.7 (0.5–1.0)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality
Enrollment through 2007, vs state rates     Waggoner et al., 2011
Applicators (n = 1,641) 71 0.9 (0.7–1.1)
Spouses (n = 676) 12 0.6 (0.3–1.1)  
US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 of NHL   Herbicides  
Agricultural extension agents nr 1.7 (0.9–3.3) Alavanja et al., 1988
Forest conservationists   p-trend < over years worked Alavanja et al., 1989
  2.3 0.1  
Soil conservationists 2.1 0.6  
Florida Licensed Pesticide Applicators (common phenoxy use assumed but not documented; had been listed by Blair et al., 1983)   Herbicides  
Pesticide applicators in Florida licensed 1965–1966 (n = 3,827)—mortality through 1976 1 0.5 (nr) Blair et al., 1983
White Male Residents of Iowa—NHL cancer on death certificate, usual occupation: farmers vs not   Herbicides  
> 20 yrs old when died 1971–1978—PMR 178 1.1 (ns) Burmeister, 1981
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Incidence
20-yr follow-up to 1996—men and women     Pesatori et al., 2009
Zone B 6 0.9 (0.4–2.0)
Zone R 43 0.9 (0.7–1.2)  
10-yr follow-up to 1991 (kidney, other urinary organs)     Bertazzi et al., 1993
Zone R—men 10 0.9 (0.4–1.7)  
Zone R—women 7 1.2 (0.5–2.7)  
10-yr follow-up to 1991—men     Pesatori et al., 1992
Zone A, B 0 nr
Zone R 11 0.9 (0.5–1.7)  
10-yr follow-up to 1991—women      
Zone A, B 1 1.1 (0.2–8.1)  
Zone R 7 1.2 (0.5–2.6)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality
25-yr follow-up to 2001—men and women     Consonni et al., 2008
Zone A 0 nr
Zone B 3 0.6 (0.2–2.0)  
Zone R 39 1.2 (0.8–1.6)  
20-yr follow-up to 1996     Bertazzi et al., 2001
Zones A and B—men 3 0.8 (0.3–2.6)
Zones A and B—women 3 1.8 (0.6–5.8)  
CASE-CONTROL STUDIES
International Case-Control Studies
Danish Cancer Registry patients (n = 365) and 396 referents, occupational herbicide exposure   Herbicides Mellemgaard et al., 1994
Men 13 1.7 (0.7–4.3)  
Women 3 5.7 (0.6–58.0)  
UK men, 18–35 yrs of age from counties with particular chemical manufacturing—mortality   Herbicides, Chlorophenols Magnani et al., 1987
Herbicides nr 1.3 (0.6–3.1)  
Chlorophenols nr 0.9 (0.4–1.9)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job—exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; NHL, non-Hodgkin lymphoma; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; PM, proportionate mortality; PMR, proportional mortality ratio; SIR, standardized incidence ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; VA, US Department of Veterans Affairs.

aSubjects are male, and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

The Korean Veterans Health Study, a prospective study of a of more than 180,000 Korean male veterans, examined renal cancer incidence from 1992 through 2003 (Yi, 2013; Yi and Ohrr, 2014) and mortality through 2005 (Yi et al., 2014). Results were reported separately for kidney cancer (ICD-10 C64) and renal pelvis cancer (ICD-10 C65). During the follow-up period, 186 incident cases of kidney cancers and 23 cases of renal pelvis cancers were identified. Compared

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

to the general Korean population, there was no excess cancer risk for the kidney (SIR = 1.09, 95% CI 0.94–1.27) or renal pelvis (SIR = 1.24, 95% CI 0.81–1.89) in the entire cohort (Yi, 2013). From internal comparisons of high- versus low-exposure opportunity scores, Yi and Ohrr (2014) reported an inverse association for renal cancer risk (HR = 0.74, 95% CI 0.55–1.00) based on 79 cases in the high exposure category, but no association for cancer of the renal pelvis (HR = 1.05, 95% CI 0.44–2.50), based on 11 cases in the high exposure category. A non-significant increased risk of ureter cancer (ICD-10 C66) was also reported (HR = 1.26, 95% CI 0.50–3.18).

For cancer-specific mortality, Yi et al. (2014) reported results combined for kidney cancer (ICD-10 C64), renal pelvis cancer (ICD-10 C65), and ureter cancer (ICD-10 C66), giving a total of 63 deaths. A comparison of the high- and low-exposure groups revealed no excess cancer mortality for the three types of renal cancers combined (HR = 0.88, 95% CI 0.53–1.47), based on 30 deaths in the high-exposure group. Comparability of the incidence and mortality risks for renal cancers is obscured by the different groupings used for reporting the results. Moreover, information on smoking or other lifestyle habits was not available for this cohort during follow-up through 2003, and thus the modest associations could be due to confounding by smoking or obesity.

Occupational, Environmental, and Case-Control Studies

No occupational studies, environmental studies, or case-control studies of exposure to the COIs and renal cancers have been published since Update 2010.

Biologic Plausibility

Cacodylic acid (DMAIII and DMAV) is carcinogenic and has been shown to induce renal cancer. In F344/DuCrj rats treated with a mixture of carcinogens for 4 weeks, subsequent exposure to DMA (not indicated whether this was DMAIII or V) via the drinking water for 24 weeks caused tumor promotion in the kidney, liver, urinary bladder, and thyroid gland but inhibited induction of tumors of the nasal passages (Yamamoto et al., 1995). Recent studies have also found that oral exposure of adult mice to 200 ppm DMAV in addition to fetal arsenic exposure can act as a promoter of renal and hepatocellular carcinoma, markedly increasing tumor incidence beyond that produced by fetal arsenic exposure alone (Tokar et al., 2012).

No animal studies with exposure to the other COIs have reported an increased incidence of renal cancers.

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Synthesis

The available analyses of an association between exposure to the COIs and renal cancer risk are limited by the small number of cases and a lack of exposure specificity. The Korean Vietnam veterans study reviewed in this update had a relatively large number of incident renal cases; however no association was observed for either renal cancer incidence or mortality with herbicide exposure index. One challenge was the comparability of results for renal cancer incidence and mortality because data on cancer incidence was reported separately for cancers of the kidney and renal pelvis, whereas results were combined for mortality. The renal cell carcinoma and renal pelvis cancers are histologically different, and thus herbicide exposure could potentially affect them differently. The new data reviewed in this update were not sufficient to alter the committee’s conclusion that the evidence is inadequate or insufficient to determine whether there is an association between the COIs and renal cancers.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and renal cancers.

BRAIN CANCER

Nervous-system cancers (ICD-9 191–192) involve the central nervous system (CNS) and include tumors of the brain and spinal cord, the cranial nerves, and the meninges (the outer coverings of the brain and spinal cord). Any of the cell types in the CNS can develop into cancer. Tumors of the peripheral nervous system and autonomic nervous system are considered soft-tissue tumors (ICD-9 171). Most cancers that are found in the CNS are not primary tumors arising from nervous system tissues, but instead originated from tissues in other parts of the body, such as the lung or breast, and metastasized to the brain or spinal cord. This section focuses on cancers that originate in the CNS.

Cancer of the eye (ICD-9 190) was considered in Update 2006, but the present committee decided that findings concerning cancer of the eye would be tracked with the results on brain cancer because when cancer of the eye is reported, it is often grouped with brain cancer.

The average annual incidence of primary CNS cancers is shown in Table 8-34. About 95 percent of cases originate in the brain, cranial nerves, and cranial meninges. In people over 45 years old, about 90 percent of tumors that originate in the brain are gliomas—astrocytoma, ependymoma, oligodendroglioma, or glioblastoma multiforme. Glioblastoma multiforme is the most common brain tumor and has the worst prognosis (Muth et al., 2015). Meningiomas make up 20 to 40

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-34 Average Annual Incidence (per 100,000) of Brain and Other Nervous System Cancers in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Men 15.9 17.8 9.0 19.5 21.4 13.0 23.4 25.9 13.0
Women 11.1 12.6 6.4 13.3 14.9 8.2 15.1 16.8 8.6

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

percent of CNS cancers; they tend to occur in middle age and are more common in women than in men. Most meningiomas are benign and can be removed surgically.

ACS estimated that about 12,900 men and 9,950 women would receive diagnoses of brain and other nervous-system cancers in the United States in 2015 and that 8,940 men and 6,380 women would die from them (Siegel et al., 2015). Those numbers represent about 1 percent of new cancer diagnoses and 3 percent of cancer deaths. ACS estimated that 1,360 men and 1,220 women would receive diagnoses of cancers of the eye and orbit in the United States in 2015 and that 140 men and 130 women would die from them (Siegel et al., 2015).

In reviewing the descriptive epidemiology of these cancers, it is important to recognize the variation with which specific cancers are included in published reports, many of which distinguish between benign and malignant tumors. Another variation is whether cancers derived from related tissues (such as the pituitary or the eye) are included with CNS cancers. Various types of cancer are usually grouped; although this may bias results in unpredictable ways, the most likely consequence is a dilution of risk estimates toward the null.

The only well-established environmental risk factor for brain tumors is exposure to high doses of ionizing radiation (ACS, 2012b; Wrensch et al., 2002). Other environmental exposures—such as to petroleum products, electromagnetic fields, and cell-phone use—are unproved as risk factors (Gomes et al., 2011; Ostrom et al., 2015). The causes of most cancers of the brain and other portions of the nervous system are not known.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was limited or suggestive evidence of no association between exposure to the COIs and brain cancer. The committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion.

The committee responsible for Update 2006 changed the classification for brain cancer (formally expanding it to include cancers of the eye and orbit) to inadequate or insufficient evidence to determine whether there is an association

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

between exposure to the COIs and brain cancer. That committee considered one study that suggested a relationship between phenoxy acid herbicides and adult gliomas (Lee et al., 2005), studies that reported slightly but not statistically significantly higher risks of brain cancer in deployed versus non-deployed Australian Vietnam-era veterans (ADVA, 2005a,b) and in pesticide applicators in the AHS (Alavanja et al., 2005), and several studies that had essentially neutral findings (Carreon et al., 2005; Magnani et al., 1987; McLean et al., 2006; Ruder et al., 2004; Torchio et al., 1994). Overall, the studies discussed in Update 2006 suggested that a conclusion of no association between exposure to the COIs and brain cancer had been too definitive.

The committee for Update 2008 agreed, after review of two new studies, that brain cancer should remain in the inadequate or insufficient category. The relevance of the largely null findings on the association with occupational exposure to herbicides from a case-control study of gliomas and meningiomas (Samanic et al., 2008) was limited in that no specific compounds were addressed. In evaluating mortality through 2001 in the Seveso cohort, Consonni et al. (2008) found no increase in mortality from brain cancer in any of the three exposure zones with increasing exposure and no indication of a dose–response relationship.

Update 2010 considered several new studies. A study of Vietnam War–era ACC veterans found no difference in brain cancer rates between deployed and non-deployed veterans (Cypel and Kang, 2010), and studies of TCP and 2,4,5-T production workers in two settings also found no difference in brain cancer incidence (Collins et al., 2009b) or mortality (Collins et al., 2009c; McBride et al., 2009a) compared with general population rates. A 20-year follow-up of brain cancer after the Seveso exposure incident found a statistically non-significantly increased rate of brain cancer in those in the closest zone (RR = 2.43, 95% CI 0.60–9.79), but not in Zones B and R (Pesatori et al., 2009). Update 2012 reviewed several studies relevant to the possibility of an association between the COIs and brain cancer, including cohort and case-control studies. Most of the recent studies did not identify a relationship between exposure to the COIs and the development of brain cancers. A few studies were somewhat suggestive of an association, but they had limited exposure specificity or limited precision because of small sample sizes. The committee concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and brain cancer or other nervous system cancers.

Table 8-35 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran and Environmental Studies

Since Update 2012, Kang et al. (2014) performed a retrospective study of three cohorts of US military women—4,734 who served in Vietnam, 2,062 who

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-35 Selected Epidemiologic Studies—Brain Tumors (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)   All COIs  
Incidence
Through 1999—White subjects vs national rates (brain and nervous system)     Akhtar et al., 2004
Ranch Hand veterans (n = 1,189) 5 1.8 (0.7–4.1)  
With tours between 1966–1970 5 2.2 (0.8–4.8)  
SEA comparison veterans (n = 1,776) 2 0.5 (0.1–1.8)  
With tours between 1966–1970 2 0.7 (0.1–2.3)  
Mortality
Through 1999—White subjects vs national rates     Akhtar et al., 2004
Ranch Hand veterans (n = 1,189) 3 1.3 (0.3–3.6)  
SEA comparison veterans (n = 1,776) 1 0.3 (nr)  
US VA Cohort of Army Chemical Corps—Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 non-deployed) serving during Vietnam era (7/1/1965–3/28/1973)   All COIs  
Mortality—brain tumors
Through 2005     Cypel and Kang, 2010
Deployed veterans (2,872) vs non-deployed (2,737) 4 vs 2 1.7 (0.3–10.2)
ACC veterans vs US men      
Vietnam cohort 4 0.9 (0.2–2.2)  
Non-Vietnam cohort 2 0.5 (0.1–2.0)  
Through 1991 2 1.9 (nr) Dalager and Kang, 1997
894 ACC members assigned to Vietnam in 1966–1971 through 1987 2 nr Thomas and Kang, 1990
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Mortality
1965–2000 (meninges, brain, other CNS) 9 1.2 (0.4–3.2) Boehmer et al., 2004
Post-service–1983 3 nr Boyle et al., 1987
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1982     Breslin et al., 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 116 1.0 (0.3–3.2)
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 25 1.1 (0.2–7.1)  
US VA Cohort of Female Vietnam-era Veterans who served in Vietnam (n = 4,586; nurses only = 3,690); non-deployed (n = 5,325; nurses only 3,282)   All COIs  
Mortality—brain or other nervous system
Through 2010 22 2.3 (0.9–5.7) Kang et al., 2014
Vietnam nurses only 16 4.6 (1.3–16.8)
Through 2004 (all female Vietnam veterans) 8 2.0 (0.7–5.9) Cypel and Kang, 2008
Vietnam veteran nurses only 8 3.6 (0.9–14.5)
Through 1991 4 1.4 (0.4–3.7) Dalager et al., 1995a
State Studies of US Vietnam Veterans
Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs non-deployed 36 1.1 (0.8–1.5) Vistainer et al., 1995
New York
—deployed vs non-deployed (brain, CNS) 4 0.5 (0.2–1.5) Lawrence et al., 1985
923 White male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans 8 0.8 (0.3–1.5) Anderson et al., 1986a,b
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 (brain) 97 1.1 (0.9–1.2) ADVA, 2005b
Navy 24 1.2 (0.7–1.7)  
Army 63 1.0 (0.8–1.3)  
Air Force 10 1.1 (0.6–2.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality
All branches, return–2001 (brain, CNS) 99 1.0 (0.8–1.1) ADVA, 2005a
Navy 23 1.0 (0.6–1.4)  
Army 66 0.9 (0.7–1.2)  
Air Force 9 0.9 (0.4–1.6)  
1980–1994 39 1.1 (0.7–1.4) CDVA, 1997a
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence (brain, CNS)
1982–2000 23 1.4 (0.7–2.6) ADVA, 2005c
Mortality (brain, CNS)
1966–2001 27 1.6 (0.9–3.1) ADVA, 2005c
1982–1994 13 1.4 (nr) CDVA, 1997b
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—brain cancer (C70–C72) categorized high (n = 32) vs low (n = 30)   1.0 (0.6–1.7) Yi and Ohrr, 2014
Mortality (1992–2005)—CNS cancer (C70–C72) categorized high (n = 36) vs low (n = 37)   0.9 (0.6–1.4) Yi et al., 2014b
HR per unit of log EOI score (n = 180,639) 73 1.0 (0.9–1.1)  
OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Mortality 1939–1992 22 0.7 (0.4–1.0) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 12 0.6 (0.3–1.1)
7,553 not exposed to highly chlorinated PCDDs 10 0.8 (0.4–1.5)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort 6 0.4 (0.1–0.8) Saracci et al., 1991
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)   MCPA  
Mortality through 1983 (brain, CNS) 11 1.2 (0.6–2.2) Coggon et al., 1986
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)   Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP  
Incidence 1943–1982 4 0.7 (nr) Lynge, 1985
German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 mo in 1951–1976) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4,5-TCP  
Mortality 1951–1992 0 Becher et al., 1996
German Production Workers at Bayer Plant in Dormagen (520 men working > 1 mo in 1965–1989) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Mortality 1965–1989 0 Becher et al., 1996
German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 mo in 1957–1987) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Mortality 1956–1989 0 Becher et al., 1996
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)   Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP  
Mortalilty 1952–1989 3 2.3 (0.5–6.8) Becher et al., 1996
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality 1969–2004     McBride et al., 2009a
Ever-exposed workers 4 2.0 (0.6–5.2)
Never-exposed workers 0 0.0 (0.0–5.5)  
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)      
Mortality 1969–2000 1 0.8 (0.0–4.6) ’t Mannetje et al., 2005
Sprayers (697 men and 2 women on register of New Zealand applicators, 1973–1984)      
Mortality 1973–2000 1 0.6 (0.0–3.4) ’t Mannetje et al., 2005
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Through 1993 (brain, CNS) 8 0.8 (0.4–1.6) Steenland et al., 1999
Through 1987 (brain, CNS)     Fingerhut et al., 1991
≥ 1-yr exposure, ≥ 20-yr latency 2 1.1 (0.1–3.8)
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, Michigan) (in IARC and NIOSH cohorts)   2,4,5-T; 2,4,5-TCP  
1942–2003 (n = 1,615) 3 0.6 (0.1–1.7) Collins et al., 2009b
1940–1994 (n = 2,187 men) nr 0.6 (0.1–1.8) Bodner et al., 2003
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
1940–2005 (n = 2,122) (brain, other nervous system) 6 0.9 (0.3–1.9)  
PCP and TCP (n = 720) 1 0.4 (0.0–2.4)  
PCP (no TCP) (n = 1,402) 5 1.1 (0.4–2.6)  
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3) (brain, other CNS) 3 1.1 (0.2–3.2) Burns CJ et al., 2011
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Through 1994 (n = 1,517) 3 1.1 (0.1–3.2) Burns et al., 2001
Through 1982 (n = 878) (brain, other system tissues) 0 nr (0.0–4.1) Bond et al., 1988
Dow PCP Production Workers (1937–1989 in Midland, Michigan) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) Mortality 1940–1989 (n = 770) 1 0.4 (0.0–2.3) Collins et al., 2009c
0-yr latency 1 nr Ramlow et al., 1996
15-yr latency 1 nr  
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Never 44 1.0 (0.7–1.4)  
Ever 28 0.8 (0.5–1.2)  
New Hampshire pulp and paper workers, 883 white men working ≥ 1 yr, mortality through July 1985 2 1.2 (0.1–4.2) Henneberger et al., 1989
Northwestern US paper and pulp workers—5 mills in Washington, Oregon, and California, 3,523 worked ≥ 1 yr 1945–1955, mortality through March 1977 4 0.6 (0.2–2.1) Robinson et al., 1986
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
CANADA
Canadian Farm Operator Study—156,242 men farming in Manitoba, Saskatchewan, and Alberta in 1971; mortality from brain cancer June 1971–Dec 1987      
210 histologically confirmed deaths attributed to brain cancer in farmers ≥ 35 yrs of age     Morrison et al., 1992
Herbicides sprayed on ≥ 250 acres vs 0 acres 24 0.8 (0.5–1.2)  
70,000 male Saskatchewan farmers identified in 1971 census data linked to mortality records (brain) 96 1.0 (0.8–1.3) Wigle et al., 1990
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
DENMARK
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Men
Self-employed 194 1.1 (nr)  
Employee 39 0.9 (nr)  
Women
Self-employed 5 1.0 (nr)  
Employee 2 0.5 (nr)  
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 2000 4 1.6 (0.4–4.1) Swaen et al., 2004
Through 1987 3 3.2 (0.6–9.3) Swaen et al., 1992
FINNISH Phenoxy Herbicide Sprayers (1,909 men working 1955–1971 ≥ 2 wks) not IARC (eye, brain)   Phenoxy Herbicides  
Incidence 3 0.7 (0.1–2.0) Asp et al., 1994
Mortality 1972–1989 3 1.2 (0.3–3.6)  
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401)     Torchio et al., 1994
Brain, nervous system 15 0.5 (0.3–0.9)
Eye 4 2.4 (0.7–6.1)  
Italian rice growers with documented phenoxy use (n = 1,487) (brain, CNS)   Phenoxy herbicides Gambini et al., 1997
  4 0.9 (0.2–2.3)  
NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of incident brain cancer cases vs remainder of 19,904 men with any incident cancer   Herbicides Reif et al., 1989
Forestry workers (n = 134) (brain, CNS) 4 1.2 (0.4–3.3)  
SWEDEN
Swedish lumberjacks—Used phenoxys 1954–1967, Incidence 1958–1992     Thörn et al., 2000
Exposed (n = 154) 0  
Foremen (n = 15) 0  
Lumberjacks (n = 139) 0  
Unexposed lumberjacks (n = 241) 1 0.9 (0.0–5.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Men
Whites (n = 119,648)
Brain 447 1.2 (1.1–1.3)  
Eye 17 1.6 (0.9–2.5)  
Nonwhites (n = 11,446) (brain) 16 1.0 (0.6–1.6)  
Women
Whites (n = 2,400) (brain) 9 1.1 (0.5–2.1)  
Nonwhites (n = 2,066) (brain) 1 0.4 (0.0–2.1)  
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Private applicators 51 0.8 (0.6–1.0)  
Commercial applicators 5 1.2 (0.4–2.8)  
Spouses 26 0.9 (0.6–1.4)  
Enrollment through 2002     Alavanja et al., 2005
Private applicators 33 0.8 (0.6–0.8)
Spouses of private applicators (> 99% women) 15 0.9 (0.5–1.4)  
Commercial applicators 5 1.9 (0.6–4.3)  
Mortality
Enrollment through 2007, vs state rates     Waggoner et al., 2011
Applicators (n = 1,641) (brain, other nervous system) 59 0.8 (0.6–1.0)
Spouses (n = 676) 25 0.8 (0.5–1.2)  
Enrollment through 2000, vs state rates     Blair et al., 2005a
Private applicators (men and women) 19 0.7 (0.4–1.1)
Years handled pesticides      
≤ 10 yrs 5 0.9 (ns)  
> 10 yrs 12 0.6 (ns)  
Spouses of private applicators (> 99% women) 11 1.1 (0.5–1.8)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 of brain cancer   Herbicides  
Agricultural extension agents nr 1.0 (0.4–2.4) Alavanja et al., 1988
Forest conservationists 6 1.7 (0.6–3.7) Alavanja et al., 1989
Soil conservationists
Pesticide applicators in Florida licensed 1965–1966 (n = 3,827)—mortality through 1976 5 Herbicides 2.0 (nr) Blair et al., 1983
White Male Residents of Iowa—brain cancer on death certificate, usual occupation: farmers vs not   Herbicides  
> 20 yrs old when died 1971–1978—PMR 111 1.1 (ns) Burmeister, 1981
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Incidence
20-yr follow-up to 1996—men and women
Zone A 2 2.4 (0.6–9.8) Pesatori et al., 2009
Zone B 4 0.8 (0.3–2.1)
Zone R 37 1.0 (0.7–1.5)  
10-yr follow-up to 1991—men     Bertazzi et al., 1993
Zone R 6 0.6 (0.3–1.4)
10-yr follow-up to 1991—women     Bertazzi et al., 1993
Zone R 6 1.4 (0.6–3.4)
Mortality      
25-yr follow-up to 2001—men and women     Consonni et al., 2008
Zone A 0 nr
Zone B 3 0.7 (0.2–2.1)  
Zone R 34 1.1 (0.8–1.6)  
20-yr follow-up to 1996     Bertazzi et al., 2001
Zones A, B—men 1 0.4 (0.1–3.0)
Zones A, B—women 3 1.9 (0.6–6.0)  
15-yr follow-up to 1991—men     Bertazzi et al., 1998
Zone B 1 0.8 (0.1–5.5)
Zone R 12 1.3 (0.7–2.5)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
15-yr follow-up to 1991—women     Bertazzi et al., 1998
Zone B 3 3.2 (1.0–10.3)
Zone R 8 1.1 (0.5–2.4)  
10-yr follow-up to 1986—men     Bertazzi et al., 1989a
Zone A, B, R 5 1.2 (0.4–3.1)
10-yr follow-up to 1986—women     Bertazzi et al., 1989a
Zone A, B, R 5 2.1 (0.8–5.9)
Other International Environmental Studies      
SWEDEN      
Swedish fishermen (high consumption of fish with persistent organochlorines)   Organochlorine compounds Svensson et al., 1995
Incidence
East coast 3 0.5 (0.1–1.5)  
West coast 24 0.9 (0.6–1.4)  
Mortality
East coast 2 0.6 (0.1–2.1)  
West coast 15 1.1 (0.6–1.7)  
CASE-CONTROL STUDIES
US Case-Control Studies
NIOSH UMHS—farm pesticide exposure and glioma risk in adults (18–80 yrs of age) living in Iowa, Michigan, Minnesota, Wisconsin (glioma cases diagnosed 1995–January 1997   Arsenicals, phenoxy herbicides, 2.4-D  
798 glioma cases vs 1,175 population-based controls (excluding proxy, 438 vs 1,141)     Yiin et al., 2012
Herbicide use—including proxy (160 vs 265)   0.8 (0.6–1.0)  
Herbicide use—excluding proxy (90 vs 260)   0.8 (0.6–1.1)  
341 female glioma cases vs 528 population-based controls     Carreon et al., 2005
Arsenicals 13 1.0 (0.5–1.9)  
Phenoxy herbicides 25 0.9 (0.5–1.5)  
2,4-D 24 0.9 (0.5–1.6)  
457 male glioma cases vs 648 population-based controls     Ruder et al., 2004
Arsenicals 15 0.7 (0.4–1.4)  
Phenoxy herbicides 67 0.9 (0.6–1.2)  
2,4-D nr nr  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
US hospital-based study of 462 glioma and 195 meningioma patients vs 765 patient controls; cumulative lifetime occupational exposure to herbicides vs unexposed   Herbicides Samanic et al., 2008
Gliomas
Men 65 0.9 (0.6–1.3)  
Low quartile 20 1.0 (0.5–1.9)  
Second quartile 16 1.0 (0.5–2.1)  
Third quartile 12 0.6 (0.3–1.3)  
Fourth quartile 17 0.8 (0.4–1.6)  
    p-trend = 0.50  
Women 35 1.3 (0.8–2.0)  
Below median 23 1.5 (0.8–2.7)  
Above median 12 1.0 (0.5–2.1)  
    p-trend = 0.91  
Meningiomas (women only) 33 2.4 (1.4–4.3)  
Below median 16 2.1 (1.0–4.4)  
Above median 17 2.9 (1.3–6.2)  
    p-trend = 0.01  
Nebraska men and women diagnosed with gliomas between 1988 and 1993; association between farming and pesticide use (251 cases vs 498 controls)     Lee et al., 2005
Phenoxy herbicides—combined reports (identical with results for 2,4-D specifically) 32 1.8 (1.0–3.3)  
By self 7 0.6 (0.2–1.6)  
By proxy 25 3.3 (1.5–7.2)  
2,4,5-T—combined reports 7 1.3 (0.5–3.6)  
By self 2 0.4 (0.1–2.3)  
By proxy 5 2.7 (0.7–9.8)  
International Case-Control Studies
Irish farmers and farm workers   Herbicides Dean, 1994
Men 195 nr  
Women 72 nr  
Italian hospital-based study of 240 brain glioma patients vs 742 controls   Herbicides Musicco et al., 1988
Male, female farmers 61 1.6 (1.1–2.4)  
French hospital-based study of 125 brain glioma patients vs 238 controls   Herbicides Cordier et al., 1988
Woodworkers   OR = 1.6
(p > 0.05)
 
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
UK men, 18–35 yrs of age from counties with particular chemical manufacturing—mortality   Herbicides, Chlorophenols Magnani et al., 1987
Herbicides nr 1.2 (0.7–2.1)  
Chlorophenols nr 1.1 (0.7–1.8)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DCP, 2,4-dichlorophenol; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; ACC, Army Chemical Corps; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; CNS, central nervous system; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; MOS, military occupation specialty; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; ns, not statistically significant; OR, odds ratio; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; PM, proportionate mortality; PMR, proportional mortality ratio; SEA, Southeast Asia; SIR, standardized incidence ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; UMHS, Upper Midwest Health Study; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

served in countries near Vietnam, and 5,313 who served primarily in the United States—and evaluated mortality outcomes. Overall, there was no association between cohort and brain or nervous system cancers. The adjusted RR for the Vietnam cohort versus the US cohort was 2.27, with a 95% CI of 0.91–5.65. The near-Vietnam cohort versus the US cohort was 1.67, with a 95% CI of 0.57–4.89. In a sub-analysis, nurses who served in Vietnam had an almost five-fold higher risk of brain cancer death than nurses who served in the United States (adjusted RR = 4.61, 95% CI = 1.27–16.83). In that sub-analysis, nurses who served near Vietnam did not have an elevated risk (adjusted RR = 2.12, 95% CI = 0.42–10.83). The study is problematic because of the issue of multiple comparisons and the possibility of Type I statistical error (i.e., false positives).

In the Korean Veterans Health Study, the National Cancer Incidence Database and death records from the National Statistical Office were screened to determine cancer incidence in 1992–2003 (Yi and Ohrr, 2014) and mortality in 1992–2005 (Yi et al., 2014b). The herbicide exposure index was based on the proximity of the veteran’s unit to herbicide-sprayed areas. For CNS cancers (C70–C72), a comparison of the low- and high-exposure groups showed no difference for either incidence (HR = 1.01, 95% CI = 0.60–1.68) or mortality (HR = 0.88, 95% CI = 0.55–1.40).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Occupational, Environmental, and Case-Control Studies

No occupational, environmental, or case-control studies of exposure to the COIs and brain cancer have been published since Update 2012.

Biologic Plausibility

No animal studies have reported an association between exposure to the COIs and brain cancer. The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

Since Update 2012, two studies relevant to the possibility of an association between the COIs and brain cancer were published. One of these reported no association. The second provides somewhat suggestive evidence of an association; however, this was not in the main analysis but only in a sub-analysis. With such a large cohort and scores of comparisons, the study is prone to false positive associations, further weakening the conclusions that may be drawn from a particular positive finding.

Conclusion

On the basis of the epidemiologic evidence from new and previously reported studies of populations that had potential exposure to the COIs, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and brain cancer or other nervous system cancers.

ENDOCRINE CANCERS

Cancers of the endocrine system as grouped by the Surveillance, Epidemiology, and End Results program (see Table C-2 in Appendix C) have a disparate group of ICD codes: thyroid cancer (ICD-9 193) and other endocrine cancers (ICD-9 194).

ACS estimated that 15,220 men and 47,230 women would receive diagnoses of thyroid cancer in the United States in 2015 and that 870 men and 1,080 women would die from it, and it estimated that 1,300 men and 1,110 women would receive diagnoses of other endocrine cancers in 2015 and that 480 men and 460 women would die from them (Siegel et al., 2015). Incidence data on cancers of the endocrine system are presented in Table 8-36.

Thyroid cancer is the most prevalent endocrine cancer. Several types of tumors can develop in the thyroid, most of them benign. The thyroid contains two main

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-36 Average Annual Incidence (per 100,000) of Endocrine System Cancers in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Men 17.1 18.2 9.4 19.6 20.2 14.0 20.3 21.0 18.5
Women 33.9 34.4 29.0 36.7 37.2 28.5 33.6 34.0 25.6

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

types of cells: follicular cells, which make and store thyroid hormones and make thyroglobulin, and C cells, which make the hormone calcitonin, which helps to regulate calcium metabolism. Different cancers of varied severity can develop from each kind of cell, and the classification of thyroid cancer is still evolving (Liu et al., 2006; Nikiforov, 2011). Papillary carcinoma is the most common type and usually affects women of childbearing age; the most common variant of papillary carcinoma is the follicular sub-type (also known as mixed papillary–follicular variant), which metastasizes slowly and is the least malignant type of thyroid cancer. Follicular carcinoma (or follicular adenocarcinoma), which is associated with inadequate dietary iodine intake, accounts for about 10 percent of all cases and has greater rates of recurrence and metastasis. Medullary carcinoma, cancer of parafollicular cells in the thyroid, is less common (4 percent of all cases) and tends to occur in families. Anaplastic carcinoma (also called giant-cell cancer and spindle-cell cancer) is rare but is the most aggressive form of thyroid cancer; it does not respond to radioiodine therapy and metastasizes quickly, invading such nearby structures as the trachea and causing compression and breathing difficulties.

Thyroid cancer can occur in all age groups. As radiation exposure is recognized as a risk factor for thyroid cancer, increased incidence is being observed in people who received radiation therapy directed at the neck (a common treatment in the 1950s for enlarged thymus, adenoids, and tonsils and for skin disorders) or who were exposed to iodine-125, for example, from the Chernobyl nuclear power-plant accident. If the radiation exposure occurred in childhood, then the risk of thyroid cancer is further increased. Other risk factors are a family history of thyroid cancer and chronic goiter.

Small thyroid tumors are common incidental findings, as are tumors of the pituitary and adrenal glands, which are far less common tumor types than malignant thyroid tumors and are rarely malignant. Malignant thymus tumors are exceedingly rare.

Conclusions from VAO and Previous Updates

The committees responsible for VAO, Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not consider endocrine cancers

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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separately and therefore reached no conclusion as to whether there was an association between exposure to the COIs and endocrine cancers. The committees responsible for Update 2006, Update 2008, Update 2010, and Update 2012 did consider endocrine cancers separately and concluded that there was inadequate or insufficient evidence to determine whether there is an association between the COIs and endocrine cancers.

Table 8-37 summarizes the pertinent results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

Several recent publications of Vietnam-veteran studies of exposure to the COIs and thyroid have been published since Update 2012 regarding incidence (Yi, 2013; Yi and Ohrr, 2014) and cancer-specific mortality (Yi et al., 2014b) in the Korean Veterans Health Study. A total of 84 incident cases and 11 deaths from thyroid cancer were identified in this cohort during follow-up. When compared to the general Korean population, there was no statistically significant excess thyroid cancer risk (SIR = 1.05, 95% CI 0.84–1.31) in the entire cohort (Yi, 2013). In an internal comparison of the high- versus low-exposure groups, Yi and Ohrr (2014), did not find an association between exposure and thyroid cancer incidence (RR = 1.05, 95% CI 0.67–1.65), based on 41 cases in the high-exposure category. In contrast, Yi et al. (2014b) reported a statistically significant association between exposure and thyroid cancer–specific mortality both when analyzed in terms of log increments in the exposure opportunity scores (HR = 2.88, 95% CI 1.12–7.39) and when comparing high- versus low-exposure groups (HR = 11.31, 95% CI 1.33–96.55). However, the number of thyroid cancer deaths was low (n = 10) in the highest exposure category and very low (n = 1) in the low-exposure category, which reduces the reliability of these results from Yi et al. (2014b).

Occupational, Environmental, and Case-Control Studies

No occupational, environmental studies, or case-control studies of exposure to the COIs and thyroid or other endocrine cancers have been published since Update 2012.

Biologic Plausibility

The NTP conducted carcinogenesis bioassays in Osborne-Mendel rats and B6C3F1 mice that were exposed to TCDD by gavage (NTP, 1982a). The incidence of follicular-cell adenoma, but not of carcinoma, increased with increasing TCDD dose in male and female rats; the increase was significant in male but not in female rats. There was a significant increase in follicular-cell adenoma in

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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TABLE 8-37 Selected Epidemiologic Studies—Endocrine Cancers (Thyroid, Thymus, and Other) (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1982 (thyroid and other endocrine, ICD-9 193–194)     Breslin et al., 1986, 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 15 0.6 (0.3–1.2)  
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 4 0.6 (0.1–3.4)  
State Studies of US Vietnam Veterans
Massachusetts Vietnam-era veterans
Veterans aged 35–65 years in 1993—cases diagnosed 1988–1993 vs thyroid cancer 4 1.2 (0.3–4.5) Clapp, 1997
International Vietnam-Veterans Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence—thyroid
All branches, 1982–2000 17 0.6 (0.3–0.9) ADVA, 2005b
Navy 3 0.5 (0.1–1.3)  
Army 11 0.5 (0.3–1.0)  
Air Force 3 1.2 (0.2–3.5)  
Mortality—thyroid      
All branches, return–2001 2 0.5 (0.0–1.8) ADVA, 2005a
Navy 1 1.2 (0.0–6.5)  
Army 1 0.4 (0.0–2.0)  
Air Force 0 0.0 (0.0–7.8)  
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence—thyroid
1982–2000 4 0.6 (0.1–2.2) ADVA, 2005c
Mortality—thyroid      
1966–2001 1 1.2 (0.0–91.7) ADVA, 2005c
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—thyroid cancer (C73) categorized high (n = 41) vs low (n = 43)   1.1 (0.7–1.7) Yi and Ohrr, 2014
Mortality (1992–2005)—thyroid cancer (C73) categorized high (n = 10) vs low (n = 1)   11.3 (1.3–96.6) Yi et al., 2014b
HR per unit of log EOI scores (n = 180,639) 11 2.9 (1.1–7.4)  
OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Mortality 1939–1992     Kogevinas et al., 1997
Thyroid (ICD-9 193) 4 1.7 (0.5–4.3)
13,831 exposed to highly chlorinated PCDDs 2 1.4 (0.2–4.9)  
7,553 not exposed to highly chlorinated PCDDs 2 2.2 (0.3–7.9)  
Other endocrine organs (ICD-9 194) 5 3.6 (1.2–8.4)  
13,831 exposed to highly chlorinated PCDDs 2 2.3 (0.3–8.1)  
7,553 not exposed to highly chlorinated PCDDs 3 6.4 (1.3–18.7)  
British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)   MCPA  
Mortality through 1983 (thyroid) 1 1.8 (0.4–9.8) Coggon et al., 1986
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004 (thyroid, other endocrine)     McBride et al., 2009a
Ever-exposed workers 0 0.0 (0.0–19.8)
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)      
Mortality 1969–2000 0 nr ’t Mannetje et al., 2005
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Sprayers (697 men and 2 women registered any time 1973–1984)      
Mortality 1973–2000 0 nr ’t Mannetje et al., 2005
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Through 1982 (n = 878) 0 nr Bond et al., 1988
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–1989 (n = 770) 0 nr Ramlow et al., 1996
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
CANADA      
Herbicide sprayers routinely exposed to herbicides for 6 mos or more (1950–1982)   Phenoxy Green, 1991
1 herbicides
    nr  
DENMARK
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Men
Self-employed 13 0.7 (nr)  
Employee 5 1.1 (nr)  
Women
Self-employed 1 1.3 (nr)  
Employee 1 1.4 (nr)  
Family worker 15 1.7 (p < 0.05)  
FINNISH Phenoxy Herbicide Sprayers (1,909 men working 1955–1971 ≥ 2 wks), not IARC   Phenoxy herbicides  
Incidence (thyroid, other endocrine)     Asp et al., 1994
No latency 2 1.9 (0.3–7.0)  
10-yr latency 2 2.4 (0.3–8.6)  
15-yr latency 2 3.4 (0.4–12.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality (thyroid)
No latency 1 3.8 (0.1–21.3)  
10-yr latency 1 4.7 (0.1–26.4)  
15-yr latency 1 6.5 (0.2–36.2)  
ICELANDIC men (1,860), women (859) exposed to agricultural pesticides, primarily 2,4-D (other endocrine organs, ICD-9 194)—incidence 2 2,4-D
1.3 (0.1–4.7)
Zhong and Rafnsson, 1996
SWEDEN
Swedish pesticide applicators—incidence 6 1.1 (0.4–2.4) Wiklund et al., 1989a
Incident NHL cases 1961–1973 with agriculture as economic activity in 1960 census   99% CI Wiklund, 1983
Thyroid 126 0.9 (0.7–1.1)  
Other endocrine gland 117 0.7 (0.5–0.9)  
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Men
Whites (n = 119,648) 39 1.3 (1.0–1.8)  
Nonwhites (n = 11,446) 1 0.6 (0.0–3.0)  
Women
Whites (n = 2,400) 1 0.8 (0.0–4.4)  
Nonwhites (n = 2,066) 1 1.1 (0.0–6.4)  
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Private applicators 39 1.0 (0.7–1.3)
Commercial applicators 5 1.4 (0.5–3.3)  
Spouses 49 0.9 (0.7–1.2)  
Enrollment through 2002 (thyroid, other endocrine)     Alavanja et al., 2005
Private applicators 29 1.3 (0.8–1.8)  
Spouses of private applicators (> 99% women) 24 0.9 (0.5–1.4)  
Commercial applicators 3 1.6 (0.3–5.0)  
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality
Enrollment through 2007, vs state rates     Waggoner et al., 2011
Applicators (n = 1,641) 8 1.5 (0.7–3.0)
Spouses (n = 676) 1 nr  
Enrollment through 2000, vs state rates (thyroid)     Blair et al., 2005a
Private applicators (men and women) 3 1.8 (0.4–5.3)  
Spouses of private applicators (> 99% women) 0 0.0 (0.0–2.2)  
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Incidence
20-yr follow-up to 1996—men and women
Zone A 1 2.6 (0.4–18.9) Pesatori et al., 2009
Zone B 4 1.6 (0.6–4.4)
Zone R 19 1.2 (0.7–1.9)  
Seveso population (1976–1996); incidence cases identified by hospital discharge records      
Zone A (prolactinoma) 1 6.2 (0.9–45.5) Pesatori et al., 2008
Zone B (nonfunctioning pituitary tumors) 2 1.9 (0.5–7.7)
Zone R (2 nonfunctioning pituitary adenomas and 3 prolactinomas) 5 0.7 (0.3–1.8)  
Mortality
15-yr follow-up to 1991—men     Bertazzi et al., 1997, 1998
Zone B 1 4.9 (0.6–39.0)
Zone R 0 nr
15-yr follow-up to 1991—women     Bertazzi et al., 1997, 1998
Zone B 1 3.2 (0.4–24.5)
Zone R 2 0.8 (0.2–3.6)
CASE-CONTROL STUDIES
International Case-Control Studies
Sweden—male, female thyroid cancers from Swedish Cancer Registry, 1980–1989   Phenoxy herbicides, chlorophenols Hallquist et al., 1993
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Phenoxy herbicide exposure 3 0.5 (0.0–2.0)  
Chlorophenols 4 2.8 (0.5–18.0)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; CATI, computer-assisted telephone interviewing; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, 2-methyl-4-chloro-phenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; NHL, non-Hodgkin lymphoma; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; SIR, standardized incidence ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

female but not in male mice. More recently, the NTP carried out a similar study in female Sprague Dawley rats (NTP, 2006), and Walker et al. (2006) compared the data from that study and the results of the Dow Chemical assessment of TCDD carcinogenicity (Kociba et al., 1978). In the NTP and Dow studies, the incidence of C-cell adenoma and carcinoma decreased with increasing dose of TCDD. However, an increased incidence of slight thyroid follicular-cell hypertrophy was noted in rats that were given TCDD at 22 ng/kg of body weight or more. A more recent 2-year NTP study (Yoshizawa et al., 2010) treated female Sprague Dawley rats with TCDD, 2,3,4,7,8-pentachlorodibenzofuran, dioxin-like PCB congeners (PCB 126 or 118), a non–dioxin-like PCB (PCB 153), or mixtures of these chemicals; it did not find any increases in either thyroid adenoma or carcinoma. Thus, although human and animal studies showed that dioxin and dioxin-like compounds alter thyroid hormones (Chapter 13 on other health effects) and increase follicular-cell hyperplasia, there is little evidence of an increase in thyroid cancer.

There are some reports of therapeutic treatment with arsenic trioxide and later development of thyroid cancer (Au et al., 2014; Firkin, 2014), raising the possibility of an association between arsenic and a risk of this malignancy. DMA treatment via the drinking water for 24 weeks caused increases in the incidence of thyroid hyperplasia and adenoma, but not adenocarcinoma, in male F344/DuCrj rats that were first exposed for 4 weeks to a mixture of five carcinogens to induce tumor initiation in a wide range of tissues (Yamamoto et al., 1995). These increases were statistically significant at DMA doses of 200 and 400 ppm, but not at 50 or 100 ppm. Animals treated with 200 and 400 ppm DMA but not

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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given the carcinogens did not develop thyroid lesions, which is consistent with the absence of elevated incidences of endocrine organ tumors in other bioassays with DMA (see Chapter 4).

As indicated in Chapter 4, 2,4-D and 2,4,5-T are at most weakly mutagenic or carcinogenic, and no studies that addressed a possible association between exposure to those herbicides and thyroid cancer in animal models have been identified.

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

The studies reviewed previously did not provide sufficient evidence to determine whether there is an association between exposure to the COIs and cancers of the endocrine organs. The results from the Korean Vietnam Veterans Study reviewed in this update did not alter this conclusion. Consequently, the present committee retained the categorization for endocrine cancers assigned by previous VAO committees.

Conclusion

On the basis of the epidemiologic evidence reviewed here, the committee concludes that there is insufficient evidence to determine whether there is an association between exposure to the COIs and thyroid or other endocrine cancers.

LYMPHOHEMATOPOIETIC CANCERS

Lymphohematopoietic cancers (LHCs) constitute a heterogeneous group of clonal hematopoietic and lymphoid-cell disorders, including leukemias, lymphomas, and multiple myeloma. They are among the most common types of cancer induced by environmental and therapeutic agents. As in the case of other cancers that are subject to evolving and complex grouping in reports of the results of epidemiologic studies (notably, head and neck cancers and gastrointestinal cancers), the conclusions that the VAO committees have drawn about associations between herbicide exposure to the COIs and specific LHCs have been complicated and curtailed by the lack of specificity and by inconsistencies in groupings in the available evidence. For LHCs, that has been a function not only of epidemiologists’ seeking to combine related cancers to produce categories that have enough cases to permit statistical analysis but also of continuous alterations in the prevailing system used by the medical community to classify these malignancies. The categorization of cancers of the lymphatic and hematopoietic systems has changed over time, guided by growing information about gene expression and

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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the lineage of the clonal cancer cells that characterize each of a broad spectrum of neoplasms arising in these tissues (Jaffe, 2009). The World Health Organization (WHO) categorization presented in the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue (WHO, 2008) bases its primary partition on whether the cancer cells are of myeloid or lymphoid origin (see Figure 8-1). This classification is to be updated in 2015.

Stem cells arising in the bone marrow generate two major lineages of leukocytes: myeloid and lymphoid. Myeloid cells include monocytes and three types of granulocytes (neutrophils, eosinophils, and basophils). Lymphoid cells include T and B lymphocytes and a smaller set of cells called natural killer (NK) cells. All those cells circulate in the blood and are collectively referred to as white blood cells or leukocytes. Monocytes move out of the bloodstream into inflamed tissues, where they differentiate into macrophages or dendritic cells. Stem cells that are destined to become T lymphocytes migrate from the bone marrow to the thymus, where they acquire antigen-specific receptors. Antigen stimulation induces the T cells to differentiate into the several types involved in cell-mediated immunity. Progenitor or pre-B cells mature in the bone marrow into antigen-specific B cells. On encountering their cognate antigens, B cells differentiate into antibody-secreting plasma cells involved in humoral immunity; these result in multiple myeloma when they undergo malignant transformation.

images
FIGURE 8-1 Hematopoiesis of stem cell differentiation.
SOURCE: © Winslow, 2007, US government has certain rights.
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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LHCs originate in specific pluripotent or lineage-restricted cells at different stages in hematopoiesis and immune-cell development. The normal cells are transformed into a malignant tumor through multistep processes that involve genetic and epigenetic alterations. Traditionally, LHCs have been divided into leukemias, lymphomas, myelomas, and so on, according to their cell type and site of origin (see Figure 8-1). That information and morphologic, cytochemical, and immunophenotypic data are used to characterize LHCs further by their distinct subtypes.

Leukemias occur when a cell residing in the bone marrow becomes cancerous and its daughter cells crowd normal cells in the bone marrow or are released from the bone marrow and circulate in the blood. Leukemias have generally been classified as myeloid or lymphoid, depending on the lineage of the original mutated cell. If the original mutated cell of a cancer of the blood arises in a lymphocytic cell line, then the cancer is called lymphocytic leukemia; lymphocytic leukemias have been further partitioned into acute lymphocytic leukemia (ALL) forms, which are derived from precursor B or T lymphoid cells, and indolent lymphoproliferative disorders (ILDs), which are derived from more mature lymphoid cells, which tend to replicate less rapidly. Although “chronic lymphocytic leukemia” is commonly used to refer generally to this group of ILDs, chronic lymphocytic leukemia (CLL) is actually a specific form of ILD. Similarly, myeloid leukemias arise from a myeloid cell line and are classified into acute (AML) and chronic (CML) forms.

Lymphoma is a general term for cancers that arise from lymphocytes (B, T, or NK cells). Lymphomas generally present as solid tumors at lymphoid proliferative sites, such as lymph nodes and spleen. As stem cells mature into B or T cells, they pass through several developmental stages, each with unique functions. The developmental stage at which a cell becomes malignant defines the kind of lymphoma. About 85 percent of lymphomas are of B-cell origin, and 15 percent are of NK-cell or T-cell origin, referred to as NKTCL by WHO (Jaffe et al., 2001) and Liao et al. (2012). There are two major types of B-cell lymphomas: Hodgkin lymphoma (HL), previously referred to as Hodgkin disease, and non-Hodgkin lymphoma (NHL). B cells give rise to a number of types of neoplasms, which are given names based on the stage at which B-cell development was arrested when the cells became cancerous. Follicular, large-cell, and immunoblastic lymphomas result when a malignancy develops after a B cell has been exposed to antigens (such as bacteria and viruses). CLL is now believed to be a tumor of antigen-experienced (memory) B cells, not naive B cells (Chiorazzi et al., 2005); small lymphocytic lymphoma (SLL), which presents primarily in lymph nodes rather than in the bone marrow and blood, is now considered to be the same disease as CLL at a different stage (Jaffe et al., 2008).

Myeloma is another type of lymphohematopoietic malignancy derived from antibody-secreting plasma cells, which also have a B-cell lineage, that accumulate in the marrow of various bones. In most cases (90 percent), tumors are formed at multiple sites, and the disease is called multiple myeloma. The related

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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premalignant condition AL amyloidosis also arises from B cell–derived plasma cells. It occurs in 5 to 15 percent of patients who have multiple myeloma and causes an abnormal deposition of antibody fragments. Monoclonal gammopathy of undetermined significance (MGUS) is also recognized as a clonal condition that may progress to multiple myeloma.

ICD partitions these malignancies into leukemias and lymphomas primarily on the basis of whether the cancer cells circulated in the blood (disseminated) or appeared in the lymphatic system (solid tissue), respectively, before subdividing according to cell type. The emerging WHO classification of lymphohematopoietic malignancies (Campo et al., 2011; Jaffe, 2009) stratifies cancers of the blood and lymph nodes into disease categories according to their cell lineages—lymphoid or myeloid—as shown in Figure 8-1. It represents a substantial advance in understanding the biologic paths by which these cancers develop. The present committee decided, however, that it would not be productive to reformulate this entire section to correspond to the WHO categories. In practice, LHCs have routinely been reported in a variety of groupings, so it is a continuing challenge to parse out results, noting when results for broader groupings are presented in the results tables for several more specific diagnoses, while recognizing that the specific results will be muted by being “misclassified” with other entities. Most epidemiologic studies already in the evidentiary database that did specify diseases precisely used ICD-9 or earlier versions, but some recent studies have applied ICD-10. Furthermore, the existing records that will serve as the basis of many current and even future studies will use earlier and evolving classifications, so this is likely to remain the case even in new literature for a considerable period. The nomenclature has become more uniform in recent studies, but the possibility of ambiguity remains if earlier researchers did not use a unique code in accordance with some established system.

Because it has been the objective of VAO committees to address disease entities in as great specificity as possible with the available data, the overall results on the coarser grouping of LHCs are of little consequence for the conclusions of association that have been drawn for the more specific entities. The committee for Update 2010 noted, however, that the common biologic origin of LHCs that have been judged to have a substantial amount of evidence supporting association with the COIs (HL, NHL, CLL, hairy-cell leukemia [HCL], multiple myeloma, and AL amyloidosis) means that the WHO approach is supportive of and consistent with these decisions on the part of VAO committees. For this update, the committee decided to familiarize itself with the classification systems that have been used for lymphoid malignancies, taking particular care to investigate the recent efforts made by the International Lymphoma Epidemiology Consortium (InterLymph) to propose a classification of these cancers into subtypes that are particularly appropriate for epidemiologic research (Morton et al., 2007). The WHO classification system and its history were reviewed with presentations to the committee in a public forum. The committee was impressed by the implications of the now successful

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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efforts of the InterLymph to harmonize data, with standardized definitions of disease entities and rigorous quality control of these subtype assessments, and attempts to understand the implications of etiologic heterogeneity (Morton et al., 2014a,b). At the same time, as has been recognized by others (Saberi Hosnijeh et al., 2012c), given the type and quality of the historical data that constitute the vast majority of the material available to the committee for review and judgement, little of this impressive effort can be applied to our assessment of association.

VA asked previous VAO committees to address CLL, AML, and HCL individually. A scrutiny of the entire body of epidemiologic results on leukemias for findings on particular types (as had been the most common manner of grouping) revealed several studies that showed increased risks specifically of CLL (or ILDs more generally) but that did not provide support for an association of AML with exposure to the COIs. The committee for Update 2002 advised VA that CLL is recognized as a form of NHL, which is already recognized as a service-related condition, whereas the committee for Update 2006 did not recognize an association between the COIs and AML. Later, the committee responsible for Update 2008 advised VA that HCL should be grouped as an ILD. In light of the history and in accord with the current WHO classification, the present committee has incorporated data specifically on CLL and HCL into the section on NHL. After a brief synopsis of biologic plausibility of the LHCs overall, the more common cancers of the lymphatic system are described in the sections below on HL, NHL, and multiple myeloma (with a section on the related condition, AL amyloidosis), and then evidence on leukemias in general is discussed with a focus on information regarding those of myeloid origin.

Biologic Plausibility

Recent data indicate that the AHR pathway plays an integral role in B-cell maturation and that TCDD and dioxin-like chemical (DLC) exposure may alter the function of these cells and lead to critical changes in the immune response. Suppression of the immune response by TCDD and similar chemicals in rodents and primates has been known for more than 30 years, but the effect on human cells is less clear. Some recent reports indicate that TCDD and DLCs elicit similar effects in humans. The activation of nontransformed human B cells results in an increase in the expression of the AHR, and additional data indicate that this pathway has a role in normal B-cell function (Allan and Sherr, 2010; Sherr and Monti, 2013). Furthermore, treatment of these cells with benzo[a]pyrene suppresses B-cell differentiation. H Lu et al. (2010) demonstrated that, although human B cells appeared less responsive to TCDD in terms of increasing expression of AHR battery genes, the ability of TCDD to decrease immunoglobulin M production is similar in both mouse and human B cells. More recent work modeled the mode by which TCDD suppresses the terminal differentiation of B cells, offering distinct pathways whose action can be altered by exposure (Zhang

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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et al., 2013). Data on human hematopoietic stem cells (HSCs) and from the use of knockout AHR mouse models show that the AHR is critical in HSC maturation and differentiation (Ahrenhoerster et al., 2014; Fracchiolla et al., 2011; Singh et al., 2011, 2014; Smith et al., 2013). TCDD not only alters HSC maturation but alters proliferation and migration in vivo and in vitro (Casado et al., 2011). Finally, emblematic of the potential pleotropic effects of TCDD, Hughes et al. (2014) recently demonstrated that the AHR plays a critical role in promoting lymphocyte differentiation into mature NK cells. Several recent reviews have highlighted the complex and varied nature of the interaction of TCDD with the immune system (Gasiewicz et al., 2014; Lindsey and Papoutsakis, 2012).

Saberi Hosnijeh et al. (2012b, 2013a) recently assessed both the immune profile and levels of soluble immune signaling proteins in TCDD-exposed workers. Consistent with data published from the ACC, in 47 highly TCDD-exposed and 38 low TCDD-exposed workers, they found no effect of TCDD on major leukocyte subsets or on white blood cell counts. They did note a non-significant decrease in most lymphocyte subsets, which was most prominent for B cells. In these same workers, a study of soluble CD27 and soluble CD30 in sera found no clear dose–response relationship of TCDD with the level of these signaling proteins. However, there was a significant negative association of serum IL1RA (interleukin 1 receptor agonist) level with TCDD serum level among workers without chronic disease. Taken together, these data indicate that exposure to TCDD (and alteration of normal AHR function) may have multiple effects on immune cell differentiation and function.

On occasion, the observed number of cases is so small that researchers cannot perform useful analyses for each type of LHC and will provide summary statistics for the entire group of them. In updating mortality in the Hamburg cohort in 1952–2007, Manuwald et al. (2012) found non-significant increases in mortality from LHC in both men (SMR = 1.53, 95% CI 0.89–2.45) and women (SMR = 1.84, 95% CI 0.74–3.80), which combined to give a significant association between TCDD and all LHC deaths in the whole cohort (SMR = 1.61, 95% CI 1.03–2.40). In a Dutch cohort of workers in two phenoxy-herbicide plants, Boers et al. (2012) assessed plasma TCDD concentrations at the time of the assumed last exposure and reported a modest but nearly significant increase in the HR for LHC in the total cohort (HR = 1.12, 95% CI 0.94–1.35) but no increase in plant A, where workers were occupationally exposed to TCDD (HR = 0.96, 95% CI 0.71–1.30).

Hodgkin Lymphoma

HL (ICD-9 201), also known as Hodgkin disease, is distinguished from NHL primarily on the basis of its neoplastic cells, mononucleated Hodgkin cells, and multinucleated Reed–Sternberg cells originating in germinal-center B cells (Küppers et al., 2002). ACS estimated that 5,100 men and 3,950 women would

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

receive diagnoses of HL in the United States in 2015 and that 660 men and 490 women would die from it (Siegel et al., 2015). The average annual incidence is shown in Table 8-38.

The possibility that HL has an infectious etiology has been a topic of discussion since its earliest description. A higher incidence in people who have a history of infectious mononucleosis has been observed in some studies, and a link with Epstein–Barr virus has been proposed (Balfour et al., 2015; Murray and Bell, 2015). In addition to the occupational associations discussed below, higher rates of the disease have been observed in people who have suppressed or compromised immune systems.

Conclusions from VAO and Previous Updates

The committee responsible for VAO determined that there were sufficient epidemiologic data to support an association between exposure to the COIs and HL. Additional studies available to the committees responsible for later updates have not changed that conclusion.

Of the 32 studies reviewed by the committee responsible for VAO, two well-conducted Swedish studies with good exposure characterization provide the most comprehensive information on the association between exposure to phenoxy herbicides (2,4-D and 2,4,5-T), picloram, or chlorophenols and HL. Hardell et al. (1981) considered NHL and HL together, and Hardell and Bengtsson (1983) considered HL separately; they found statistically significant associations with exposure to phenoxy acids (after excluding people who were exposed to chlorophenols) and with exposure to chlorophenols. In a study of 54 HL cases, Persson et al. (1989) found a large but not statistically significant risk associated with exposure to phenoxy acids. Several of the other case-control and occupational-cohort studies reviewed in VAO showed an increased risk of HL, but only a few of the results were statistically significant. As with NHL, even the largest studies of production workers who were exposed to TCDD did not indicate an increased risk. The few studies of HL in Vietnam veterans tended to show increased risks, but only one (Holmes et al., 1986) was statistically significant.

TABLE 8-38 Average Annual Incidence (per 100,000) of Hodgkin Lymphoma in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Men 3.1 3.3 2.9 4.1 4.3 3.5 5.0 5.4 3.4
Women 2.5 2.5 3.9 2.6 2.9 2.7 3.5 3.8 2.5

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Update 1996 reviewed studies that showed no excess of HL in the IARC phenoxy-herbicide cohort (Kogevinas et al., 1993) or in US farmers in 23 states (Blair et al., 1993). A smaller study of Finnish herbicide appliers (Asp et al., 1994) showed a non-significant increase, whereas Persson et al. (1993) reported a significant increase in Swedish farmers who were exposed to phenoxy acid herbicides. Studies of the Seveso cohort (Bertazzi et al., 1993) and of Vietnam-era veterans in Michigan (Visintainer et al., 1995) did not provide data that strengthened the association.

In Update 1998, a proportionate mortality ratio analysis that compared the experience of 33,833 US Army and Marine Corps Vietnam veterans who died during 1965–1988 with that of 36,797 deceased non-Vietnam veterans found a significant increase in Marine Corps veterans, but not Army veterans, who had served in Vietnam (Watanabe and Kang, 1996). Two studies of manufacturing workers found no association between TCDD and HL (Becher et al., 1996) or between PCP and HL (Ramlow et al., 1996). An update of the large IARC phenoxy-herbicide cohort (Kogevinas et al., 1997) showed no association between phenoxy herbicides or chlorophenols and HL but did show a nonsignificant increase in HL in workers who were exposed to TCDD or higher chlorinated hydrocarbons. Waterhouse et al. (1996) demonstrated a significant increase in the combined incidence of lymphopoietic neoplasms in a prospective study of a Michigan farming community. A 15-year follow-up study of the Seveso cohort (Bertazzi et al., 1997) found no deaths from HL in Zone A and a non-significant increase in deaths from HL in men and women in Zone B.

The committee responsible for Update 2000 reviewed the 15-year update of the Ranch Hand study (AFHS, 2000), but the findings on HL were non-significant. In a retrospective cohort study of Dutch production and contract workers who were exposed to phenoxy herbicides, chlorophenols, and contaminants during 1950–1976, Hooiveld et al. (1998) reported a non-significant increase in HL. Rix et al. (1998) compared mortality in a cohort of Danish paper-mill workers with that in the general Danish population and found a statistically significant increase in men but not women. In an update and expansion of cohorts involved in the NIOSH study, Steenland et al. (1999) found that the three deaths attributed to HL were consistent with the number expected. The 20-year mortality update after the Seveso accident reported no additional HL deaths in Zone A or B (Bertazzi et al., 2001).

The only new study reviewed in Update 2002 followed mortality to 1994 in a cohort of Dow workers (Burns et al., 2001); the single death attributed to HL resulted in a slight but non-significant increase in mortality.

Update 2004 reviewed a study by Akhtar et al. (2004) that had found no excess of lymphopoietic cancers when comparing incidence and mortality between Ranch Hand veterans and veterans who had not served in Southeast Asia. Swaen et al. (2004) extended the follow-up of mortality by 13 years in a cohort of Dutch herbicide appliers; with no additional deaths observed, the earlier increase in HL remained non-significant (Swaen et al., 1992).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Update 2006 reviewed reports on the cancer experience of Australian Vietnam veterans. In comparison with the general population, the incidence of HL was significantly higher when veterans from the different armed forces were combined (ADVA, 2005a); there was a significant association between HL and service in the Army, but Navy and Air Force veterans showed non-significant increases. Mortality from HL was non-significantly increased in the Army veterans but not in all veterans combined or in the other branches (ADVA, 2005b). A comparison of deployed and non-deployed Vietnam-era Australian conscripted Army National Service veterans (ADVA, 2005c) found no association between deployment and the incidence of or mortality from HL. In a multinational IARC cohort of 60,468 pulp-and-paper-industry workers, McLean et al. (2006) found that death from HL was significantly higher in those who had ever been exposed to nonvolatile organochlorine compounds (which would include TCDD) but not in those who had never been exposed. Two reports from the US AHS (Alavanja et al., 2005; Blair et al., 2005a) found no excess risk of HL in pesticide applicators, commercial applicators, or their spouses. In the Cross Canada Study of Pesticides and Health, Pahwa et al. (2006) found no association of any exposure to phenoxy herbicides, 2,4-D, Mecoprop, or MCPA and HL.

The committee responsible for Update 2008 reviewed a study by Cypel and Kang (2008) that compared mortality from lymphopoietic cancers in female Vietnam veterans with that of female era-veterans and the US population; deaths from lymphopoietic cancers were not higher in those who served in Vietnam. Consonni et al. (2008) reported no statistically significant increase in deaths from HL in the Seveso cohort 25 years after the accident.

The committee for Update 2010 reviewed several occupational cohorts, a case-control study, and an update of cancer incidence in the Seveso cohort. No deaths from HL were identified in Dow PCP workers in Midland, Michigan (Collins et al., 2009c), but the TCP workers (Collins et al., 2009b) had an increased SMR of HL with a wide confidence interval. McBride et al. (2009a) examined mortality in TCP manufacturing workers in the Dow AgroSciences plant in New Plymouth, New Zealand, but a single observed HL death yielded inconclusive results. A French hospital-based case-control study of lymphoid neoplasms (Orsi et al., 2009) found a modest increase in the risk of HL after occupational exposure to herbicides in general and a greater increase after occupational exposure to phenoxy herbicides in particular, but neither was statistically significant; no association was observed with the domestic use of herbicides. In the 20-year follow-up of cancer incidence in the Seveso cohort (Pesatori et al., 2009), there were still no cases of HL in Zone A, whereas a modest non-significant increase in HL risk was found in Zone R and a less clear increase in Zone B.

The Update 2012 included no additional studies of Vietnam veterans, although there were several follow-up studies of occupational exposure to the COIs. Several of these noted very small numbers of additional cases of HL, which did not produce substantive changes in prior findings. Burns et al. (2011) reported

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

an additional case among Dow 2,4-D production workers. Ruder and Yin (2011) likewise reported one additional HL death in the NIOSH cohort of PCP workers. Updates of cancer incidence (Koutros et al., 2010a) and mortality (Waggoner et al., 2011) among participants in the AHS did not find increases in private applicators or their spouses, but the analyses were not herbicide specific. In case-control studies of Canadian pesticide and herbicide exposure, Karunanayake et al. (2012) and Pahwa et al. (2003) found no significant associations of exposure to COIs with HL, although many point estimates for association were greater than unity.

Table 8-39 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies After following up on a cohort of male Vietnam veterans from New Zealand, McBride et al. (2013) reported one death from HL compared with 0.4 expected (SMR = 2.30, 95% CI 0.03–12.8) and 3 incident cases of HL with 1.4 expected (SIR = 2.08, 95% CI 0.42–6.09).

Mortality (Yi et al., 2014b) and cancer incidence of (Yi and Ohrr, 2014) were assessed among Korean veterans who had served in Vietnam between 1964 and 1973. In analyses of cancer incidence, Yi and Ohrr (2014) reported a modestly increased risk of Hodgkin lymphoma (HR = 1.27, 95% CI 0.41–3.93) in the internal comparison of the high- and low-exposure groups based on the EOI scores. Yi et al. (2014b) did not provide mortality information for HL.

Occupational and Environmental Studies No occupational or environmental studies of exposure to the COIs and HL specifically have been published since the Update 2012.

Case-Control Studies The Cross Canada Study of Pesticides and Health was a population-based incident case-control study in six Canadian provinces conducted between 1991 and 1994. In a study using these data (Navaranjan et al., 2013), men 19 years and older who had a first diagnosis of soft tissue sarcoma, NHL, multiple myeloma, or HL during these years were included and followed in mailed and telephone interviews. Adjusting for age and province of residence, no risk of HL was observed for overall exposure to any one phenoxy herbicide (OR = 0.94, 95% CI 0.63–1.41), two phenoxy herbicides (OR = 1.01, 95% CI 0.57–1.78), or three or more phenoxy herbicides (OR = 1.01, 95% CI 0.48–2.11). Exposure specificity remains a major issue for this study.

Biologic Plausibility

HL arises from the malignant transformation of a germinal-center B cell and is characterized by malignant cells that have a distinctive structure and

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-39 Selected Epidemiologic Studies—Hodgkin Lymphoma (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)   All COIs  
Incidence
Through 1999—white subjects vs national rates     Akhtar et al., 2004
Ranch Hand veterans (n = 1,189) 10 0.9 (0.4–1.5)  
With tours between 1966–1970 7 0.7 (0.3–1.4)  
SEA comparison veterans (n = 1,776) 9 0.6 (0.3–1.0)  
With tours between 1966–1970 4 0.3 (0.1–0.8)  
Attended 1987 exam—Ranch Hand personnel (n = 995) vs SEA veterans (n = 1,299) 0 nr Wolfe et al., 1990
Mortality
Through 1987—Ranch Hand personnel (n = 1,261) vs SEA veterans (n = 19,102) 0 nr Michalek et al., 1990
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Mortality
1965–2000 2 0.9 (nr) Boehmer et al., 2004
Post-service–1983 0 nr Boyle et al., 1987
US CDC Selected Cancers Study—case-control study of incidence (Dec 1, 1984–Nov 30, 1989) among US males born 1929–1953 (CDC, 1990a)   All COIs CDC, 1990a
Vietnam veterans 28 1.2 (0.7–2.4)  
Army 12 1.0 (0.5–2.0)  
Marine Corps 4 1.7 (0.5–5.9)  
Air Force 5 1.7 (0.6–4.9)  
Navy 7 1.1 (0.4–2.6)  
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1988     Watanabe and Kang, 1996
Army, deployed (n = 27,596 ) vs non-deployed (n = 31,757 ) 125 1.0 (nr)
Marine Corps, deployed (n = 6,237) vs non-deployed (n = 5,040) 25 1.9 (1.2–2.7)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
1965–1984     Watanabe et al., 1991
Army, deployed (n = 24,145) vs non-deployed (n = 27,917 )    
Vs Army non-Vietnam veterans 116 1.0 (nr)  
Vs all non-Vietnam veterans 116 1.1 (nr)  
Marine Corps, deployed (n = 5,501 ) vs non-deployed (n = 4,505)      
Vs Marine non-Vietnam veterans 25 1.9 (nr)  
Vs all non-Vietnam veterans 25 1.0 (nr)  
1965–1982     Breslin et al., 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 92 1.2 (0.7–1.9)
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 22 1.3 (0.7–2.6)  
US VA Cohort of Female Vietnam Veterans   All COIs  
Mortality
Through 2004 (lymphopoietic cancersc) 18 0.7 (0.4–1.3) Cypel and Kang, 2008
Vietnam-veteran nurses 14 0.7 (0.3–1.3)
State Studies of US Vietnam Veterans      
Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs non-deployed 20 1.1 (0.7–1.8) Vistainer et al., 1995
New York—deployed vs non-deployed (lymphoma, HD) 10 99% CI
1.0 (0.4–2.2)
Lawrence et al., 1985
West Virginia—deployed vs non-deployed 5 8.3 (2.7–19.5) Holmes et al., 1986
923 White male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans 4 nr Anderson et al., 1986a,b
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 51 2.1 (1.5–2.6) ADVA, 2005b
Navy 7 1.3 (0.5–2.6)  
Army 40 2.3 (1.6–3.0)  
Air Force 4 2.1 (0.6–5.3)  
Mortality
All branches, return–2001 13 0.9 (0.5–1.5) ADVA, 2005a
Navy 2 0.6 (0.1–2.1)  
Army 11 1.1 (0.5–1.9)  
Air Force 0 0.0 (0.0–2.9)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence
1982–2000 12 0.9 (0.4–2.0) ADVA, 2005c
Mortality
1982–2000 12 0.9 (0.4–2.0) ADVA, 2005c
1966–2001 4 1.7 (0.3–11.8) ADVA, 2005c
1983–1985 0 nr Fett et al., 1987b
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008) 3 2.1 (0.4–6.1)  
Mortality (1988–2008) 1 2.3 (0.0–12.8)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—HL (C81) categorized high (n = 7) vs low (n = 6)   1.3 (0.4–3.9) Yi and Ohrr, 2014
OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Mortality 1939–1992 10 1.0 (0.5–1.8) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 8 1.3 (0.6–2.5)
7,553 not exposed to highly chlorinated PCDDs 1 0.3 (0.0–1.5)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort 2 0.4 (0.1–1.4) Saracci et al., 1991
Mortality, incidence of women in production (n = 699) and spraying (n = 2) compared to national death rates and cancer incidence rates   TCDD Kogevinas et al., 1993
1 nr
Mortality—IARC cohort (16,863 men and 1,527 women) 10–19 years since first exposure 3 0.6 (0.1–1.7) Kogevinas et al., 1992
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)   Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP  
Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)   Dioxins, 2,4,5-T, 2,4,5-TCP  
Mortality 1955–1991 1 3.2 (0.1–17.6) Hooiveld et al., 1998
German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 mo in 1951–1976) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4,5-TCP  
Mortality 1951–1992 0 nr Becher et al., 1996
German Production Workers at Bayer Plant in Dormagen (520 men working > 1 mo in 1965–1989) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4-DP; 2,4,5-T; MCPA; MCPP  
Mortality 1965–1989 0 nr Becher et al., 1996
German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 mo in 1957–1987) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4-DP; 2,4,5-T; MCPA; MCPP  
Mortality 1956–1989 0 nr Becher et al., 1996
BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)   Focus on TCDD  
Mortality
Through 1987 [Table 2] 0 nr Zober et al., 1990
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)   Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP  
Mortality 1952–1989 0 nr Becher et al., 1996
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; 2,4,5-TCP; MCPA; MCPB; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Ever-exposed workers 1 4.2 (0.1–23.3)
Never-exposed workers 0 0.0 (0.0–47.1)  
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)      
Mortality 1969–2000 1 5.6 (0.1–31.0) ’t Mannetje et al., 2005
Sprayers (697 men and 2 women on register of New Zealand applicators, 1973–1984)      
Mortality 1973–2000 0 0.0 (0.0–16.1) ’t Mannetje et al., 2005
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Through 1993 3 1.1 (0.2–3.2) Steenland et al., 1999
Chloracne subcohort (n = 608) (lymphatic, hematopoietic; ICD-9 200–208) 6 1.1 (0.4–2.5)
Through 1987 3 1.2 (0.3–3.5) Fingerhut et al., 1991
≥ 1-yr exposure, ≥ 20-yr latency 1 2.8 (0.1–15.3)
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (in IARC and NIOSH cohorts)   2,4,5-T;
2,4,5-TCP
 
1942–2003 (n = 1,615) 0 0.0 (0.0–6.4) Collins et al., 2009b
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
1940–2005 (n = 2,122) 1 0.6 (0.0–3.6)  
PCP and TCP (n = 720) 0 nr (0.0–6.9)  
PCP (no TCP) (n = 1,402) 1 1.0 (0.0–5.4)  
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3) 1 1.3 (0.0–7.2) Burns CJ et al., 2011
Through 1994 (n = 1,517) 1 1.5 (0.0–8.6) Burns et al., 2001
Through 1982 (n = 878) 1 2.7 (0.0–14.7) Bond et al., 1988
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) 2 1.8 (0.2–6.4) Collins et al., 2009c
Mortality 1940–1989 (n = 770)     Ramlow et al., 1996
0-yr latency 0 nr
15-yr latency 0 nr  
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Never 7 0.6 (0.2–1.2)  
Ever 17 1.8 (1.0–2.8)  
Danish paper workers     Rix et al., 1998
Men 18 2.0 (1.2–3.2)  
Women 2 1.1 (0.1–3.8)  
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
CANADA
Ontario Forestry Workers—1,222 men working ≥ 6 mo 1950–1982      
80 deaths through 1982; 18 cancers (lung greatest with 5) 0 nr Green, 1991
DENMARK
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Men
Self-employed 27 0.6 (p < 0.05)  
Employee 13 1.0 (nr)  
Women
Self-employed 1 1.1 (nr)  
Employee 1 1.2 (nr)  
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 2000 0 nr Swaen et al., 2004
Through 1987 1 3.3 (0.0–18.6) Swaen et al., 1992
FINNISH Phenoxy Herbicide Sprayers (1,909 men working 1955–1971 ≥ 2 wks) not IARC   Phenoxy herbicides  
Incidence 2 1.7 (0.2–6.0) Asp et al., 1994
Mortality 1972–1989 0 0.0 (0.0–5.0)  
Except for lung cancer, numbers too small for reporting mortality 1972–1980 0 nr Riihimaki et al., 1982
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401) 11 1.0 (0.5–1.7) Torchio et al., 1994
Italian rice growers with documented phenoxy use (n = 1,487)   Phenoxy herbicides Gambini et al., 1997
  1 0.7 (0.0–3.6)  
SWEDEN
Swedish Cancer-Environment Registry—National Cancer Registry linked to census   Herbicides  
Incidence data from Swedish Cancer Environment Register (1971–1984) linked to 1970 census     Eriksson et al., 1992a
Male sawmill workers 10 2.1 (1.0–4.0)  
Male farmers 97 1.2 (nr)  
Male forestry workers 35 1.2 (nr)  
Male horticulture workers 11 1.2 (nr)  
20,245 Swedish pesticide applicators with license issued between 1965 and 1976 15 1.5 (0.8–2.4) Wiklund et al., 1989a
354,620 Swedish agriculture, forestry workers     Wiklund et al., 1988a
Workers in land or in animal husbandry 242 1.0 (0.9–1.2)
Workers in silviculture 15 2.3 (1.3–3.7)  
Incident HD cases 1961–1973 with agriculture as economic activity in 1960 census 226 99% CI
1.0 (0.9–1.2)
Wiklund, 1983
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Men
Whites (n = 119,648) 56 1.0 (0.8–1.3)  
Nonwhites (n = 11,446) 2 0.7 (0.1–2.6)  
Women
Whites (n = 2,400) 0 0.0 (0.0–3.4)  
Nonwhites (n = 2,066) 0 0.0 (0.0–7.2)  
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Private applicators 18 1.0 (0.6–1.5)  
Commercial applicators 1 nr  
Spouses 7 0.9 (0.3–1.7)  
Enrollment through 2002     Alavanja et al., 2005
Private applicators 11 0.9 (0.4–1.6)
Spouses of private applicators (> 99% women) 4 0.7 (0.2–1.9)  
Commercial applicators 1 0.8 (0.1–4.2)  
Mortality
Enrollment through 2007, vs state rates     Waggoner et al., 2011
Applicators (n = 1,641)
Spouses (n = 676)
5 1.0 (0.3–2.4)
Enrollment through 2000, vs state rates 3 1.1 (0.2–3.3) Blair et al., 2005a
Private applicators (men and women) Spouses of private applicators (> 99% women) 3 0 1.7 (0.3–4.8) 0.0 (0.0–2.5)
US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 of HD   Herbicides  
Agricultural extension agents     Alavanja et al., 1988
PM analysis 6 2.7 (1.2–6.3)
Case-control analysis 6 1.1 (0.3–3.5)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
USDA forest, soil conservationists 4 2.2 (0.6–5.6) Alavanja et al., 1989
White Male Residents of Iowa—HD on death certificate, usual occupation: farmers vs not   Herbicides  
> 20 yrs old when died 1971–1978—PMR 47 1.2 (ns) Burmeister, 1981
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Incidence
20-yr follow-up to 1996—men and women      
Zone A 0 nr Pesatori et al., 2009
Zone B 3 1.2 (0.4–3.8)
Zone R 23 1.5 (0.9–2.3)  
10-yr follow-up to 1991—men     Bertazzi et al., 1993
Zone B 1 1.7 (0.2–12.8)
Zone R 4 1.1 (0.4–3.1)  
10-yr follow-up to 1991—women     Bertazzi et al., 1993
Zone B 1 2.1 (0.3–15.7)
Zone R 3 1.0 (0.3–3.2)  
Mortality
25-yr follow-up to 2001—men and women     Consonni et al., 2008
Zone A 0 nr
Zone B 3 2.2 (0.7–6.9)  
Zone R 9 0.9 (0.5–1.9)  
20-yr follow-up to 1996     Bertazzi et al., 2001
Zones A, B—men 2 2.6 (0.6–10.9)
Zones A, B—women 2 3.7 (0.9–16.0)  
15-yr follow-up to 1991—men     Bertazzi et al., 1997
Zone B 2 3.3 (0.4–11.9)
15-yr follow-up to 1991—women     Bertazzi et al., 1997
Zone B 2 6.5 (0.7–23.5)
Zone R 4 1.9 (0.5–4.9)  
Other International Environmental Studies
FRANCE      
Residents near French solid-waste incinerator—incidence   Dioxin Viel et al., 2000
1980–1995 9 1.5 (nr) (p = 0.89)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
NEW ZEALAND
Residents of New Plymouth Territorial Authority, New Zealand near plant manufacturing 2,4,5-T in 1962–1987   2,4,5-T Read et al., 2007
Incidence 49 1.1 (0.8–1.5)d  
1970–1974 9 1.2 (0.6–2.3)  
1975–1979 9 1.1 (0.5–2.2)  
1980–1984 8 1.1 (0.5–2.1)  
1985–1989 9 1.3 (0.6–2.5)  
1990–1994 7 1.3 (0.5–2.7)  
1995–1999 4 0.7 (0.2–1.7)  
2000–2001 3 1.0 (0.2–3.1)  
Mortality 22 1.3 (0.8–2.0)d  
1970–1974 7 1.6 (0.7–3.3)  
1975–1979 4 1.2 (0.3–3.0)  
1980–1984 6 2.1 (0.8–4.5)  
1985–1989 3 1.2 (0.2–3.5)  
1990–1994 1 0.6 (0.0–3.5)  
1995–1999 1 0.6 (0.0–3.6)  
2000–2001 0 nr  
CASE-CONTROL STUDIES
US Case-Control Studies
Kansas residents–duration and frequency of herbicide use—incidence   Phenoxy herbicides, 2.4-D Hoar et al., 1986
All farmers 71 0.8 (0.5–1.2)  
Farm-use of herbicides (phenoxy acids, others) 28 0.9 (0.5–1.5)  
Farmers using herbicides > 20 days/yr 3 1.0 (0.2–4.1)  
Farmers using herbicides > 15 days/yr 10 1.2 (0.5–2.6)  
Tecumseh, Michigan residents participating in longitudinal study (1959–1987) 13 Herbicides
2.0 (1.1–3.4)
Waterhouse et al., 1996
Hancock County, Ohio, residents—farmers 3 2.7 (nr) Dubrow et al., 1988
International Case-Control Studies
Cross Canada Study of Pesticides and Health—men in 1 of 6 Canadian provinces (≥ 19 yrs of age) diagnosed September 1991–December 1994 (n = 316) vs matched population-based controls (n = 1,506)   Phenoxy herbicides  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Effect of multiple pesticide exposure on HL risk   Phenoxy herbicides Navaranjan et al., 2013
Any 1 phenoxy herbicide 36 0.9 (0.6–1.4)  
Any 2 phenoxy herbicides 18 1.0 (0.6–1.8)  
3 or more phenoxy herbicides 10 1.0 (0.5–2.1)  
Association with specific herbicides and HL     Karunanayake et al., 2012;
Any phenoxy herbicides 65 0.9 (0.7–1.3)
2,4-D 57 0.9 (0.6–1.3) Pahwa et al., 2006
Mecoprop 20 1.4 (0.8–2.4)  
MCPA 11 1.0 (0.4–2.2)  
Diclofopmethyl 10 1.8 (0.7–4.5)  
France hospital-based case-control study   Herbicides Orsi et al., 2009
Occupational use of herbicides 7 1.5 (0.6–4.1)  
Phenoxy herbicides 6 2.5 (0.8–7.7)  
Domestic use of herbicides 19 0.8 (0.4–1.6)  
Italian incident cases of malignancies of hematolymphopoietic system (HD = 258) in men and women (20–74 yrs of age) from agricultural and mixed use areas   Herbicides Miligi et al., 2006
Men 5 0.4 (0.1–1.3)  
Women 1 0.5 (0.1–4.0)  
Italy—Residents of Milan area (men and women)—incidence   Herbicides LaVecchia et al., 1989
Agricultural occupations nr 2.1 (1.0–3.8)  
Chemical-industry occupations nr 4.3 (1.4–10.2)  
New Zealand National Cancer Registry (1977–1981) (≥ 20 yrs of age) with agricultural occupations—incidence (ICD-9 200, 202) 107 Herbicides
1.1 (0.6–2.0)
Pearce et al., 1985
Swedish Regional Cancer RegistryHD patients   Phenoxy herbicides Persson et al., 1993
Exposed to phenoxy herbicides   90% CI  
  5 7.4 (1.4–40.0)  
Örebro (Sweden) Hospital (men and women)—incidence   Phenoxy herbicides, chlorophenols Persson et al., 1989
    90% CI  
Farming 6 1.2 (0.4–3.5)  
Exposed to phenoxy acids 4 3.8 (0.7–21.0)  
Sweden—Umea Hospital patients (men and women, 25–85 yrs of age) (1974–1978)   Phenoxys, chlorophenols Hardell and Bengtsson, 1983
Exposed to phenoxy acids 14 5.0 (2.4–10.2)
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Exposed to high-grade chlorophenols 6 6.5 (2.2–19.0)  
Exposed to low-grade chlorophenols 5 2.4 (0.9–6.5)  
Swedish patients (1970–1977)   Phenoxy acids, chlorophenols Hardell, 1981
Exposed to phenoxy herbicides 41 4.8 (2.9–8.1)  
Exposed to chlorophenols 50 4.3 (2.7–6.9)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HD, Hodgkin disease; HL, Hodgkin lymphoma; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy) butanoic acid; MCPP, methylchlorophenoxypropionic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; PM, proportionate mortality; PMR, proportional mortality ratio; SEA, Southeast Asia; SIR, standardized incidence ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; USDA, US Department of Agriculture; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

cLymphopoietic cancers comprise all of forms of lymphoma (including Hodgkin disease and non-Hodgkin lymphoma) and leukemia (ALL, AML, CLL, CML).

dCommittee computed total SMR and SIR by dividing sum of observed values by sum of expected values over all years; 95% CIs on these total ratios were computed with exact methods.

phenotype; these binucleate cells are known as Reed–Sternberg cells (Jaffe et al., 2008). No animal studies have shown an increase in HL after exposure to the COIs. Reed–Sternberg cells have not been demonstrated in mice or rats, so there is no good animal model of HL. Thus, there are no specific animal data to support the biologic plausibility of an association between the COIs and HL.

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

The relative rarity of HL complicates the evaluation of epidemiologic studies because their statistical power is generally low. Earlier studies (Eriksson et al., 1992; Hardell et al., 1981; Holmes et al., 1986; LaVecchia et al., 1989;

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Persson et al., 1993; Rix et al., 1998; Waterhouse et al., 1996; Wiklund et al., 1988a) were generally well conducted and included excellent characterizations of exposure, and they formed the basis of previous VAO committees’ conclusions. Later findings have not contradicted those conclusions, especially given that most studies have had low statistical power. Although it has not been demonstrated as clearly as for NHL, a positive association between the COIs and the development of HL is biologically plausible because of the common lymphoreticular origin of HL and NHL and their common risk factors.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is sufficient evidence of an association between exposure to at least one of the COIs and HL.

Non-Hodgkin Lymphoma

NHL (ICD-9 200.0–200.8, 202.0–202.2, 202.8–202.9) is a general name for cancers of the lymphatic system other than HL or multiple myeloma. NHL consists of a large group of lymphomas that can be partitioned into acute and aggressive (fast-growing) or chronic and indolent (slow-growing) types of either B-cell or T-cell origin. B-cell NHL includes Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, large-cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle-cell lymphoma. T-cell NHL includes mycosis fungoides and anaplastic large-cell lymphoma. Precursor T-lymphoblastic lymphoma is not considered a type of NHL and is considered part of T-lymphoblastic lymphoma/leukemia, a precursor lymphoid neoplasm included with the broad group of “acute lymphoid leukemias,” which can be of either T-cell or B-cell origin.

As noted in earlier VAO updates, in response to requests from VA, CLL and HCL have been recognized as sharing many traits with NHL (including B-cell origin and immunohistochemical properties). The proposed WHO classification of NHL notes that CLL (ICD-9 204.1) and its lymphomatous form, SLL, are both derived from mature B cells (Chiorazzi et al., 2005; IARC, 2001). The committee for Update 2012 determined that it is more appropriate to consider those lymphatic malignancies with other forms of NHL. Therefore, the discussion of CLL and HCL has been moved into the NHL grouping.

ACS estimated that 39,850 men and 32,000 women would receive diagnoses of NHL in the United States in 2015 and that 11,480 men and 8,310 women would die from it (Siegel et al., 2015). The incidence of NHL is uniformly higher in men than in women and typically higher in whites than in blacks. In the groups that characterize most Vietnam veterans, incidence increases with age. In addition, ACS estimated that about 8,140 men and 6,480 women would receive diagnoses of CLL in the United States in 2015 and that 2,830 men and

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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1,820 women would die from it (Siegel et al., 2015). Nearly all cases occur after the age of 50 years. Average annual incidences of NHL are shown in Table 8-40 with the additional incidences of CLL.

The causes of NHL are poorly understood. People who have suppressed or compromised immune systems are known to be at higher risk, and some studies show an increased incidence in people who have HIV, human T-cell leukemia virus type I, Epstein–Barr virus, or gastric Helicobacter pylori infections. The human retrovirus HTLV-1 causes adult T-cell lymphoma, but early reports that HTLV-2 might play a role in the etiology of HCL have not been substantiated. A broad spectrum of behavioral, occupational, and environmental risk factors have been proposed as contributors to the occurrence of NHL, but given the diversity of malignancies included under this name and the evolving classification of the subtypes (to date, minimal exploration of etiologic heterogeneity has been done), it is not too surprising that—aside from infectious agents, immune problems, and particular chemotherapies—specific risk factors have not been definitively established (Morton et al., 2008, 2014a,b; Wang and Nieters, 2010).

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was sufficient evidence to support an association between exposure to at least one of the COIs and NHL. Additional information available to the committees responsible for later updates has not changed that conclusion.

As with HL, the epidemiologic data reviewed by previous VAO committees suggest that the phenoxy herbicides (including 2,4-D) rather than TCDD may be associated with NHL. The original VAO committee concluded that a positive association existed between exposure to herbicides and the development of NHL, and studies reviewed by later committees have continued to support that finding. A large, well-conducted case-control study in Sweden by Hardell (1981) examined NHL and HL together and found a significantly increased risk associated with exposure to phenoxy acids or chlorophenols on the basis of 105 cases. Those results were replicated in further investigations of the validity of the exposure

TABLE 8-40 Average Annual Incidence (per 100,000) of Non-Hodgkin Lymphoma in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Men 51.9 54.0 41.2 75.2 78.7 52.3 99.3 106.2 57.3
Women 37.2 39.1 28.8 54.4 57.9 40.8 69.2 74.4 42.3

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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assessment and potential biases (Hardell, 1981). Another Swedish case-control study by Hardell et al. (1994) found a statistically significant risk in a comparison of the occupational histories of 105 people who were exposed to phenoxy herbicides and chlorophenols and received diagnoses of NHL in 1974–1978 with 335 control subjects. Similar data by Persson et al. (1989) showed an increased risk of NHL in those exposed to phenoxy acids on the basis of a logistic regression analysis of 106 cases.

Studies of production workers have shown some association between TCDD exposure and NHL. A larger study of 21,863 workers in the IARC phenoxyherbicide cohort by Kogevinas et al. (1997) found a non-significant increase in NHL risk. Subjects in that expanded multinational study were followed from 1939 to 1992. Other studies of Danish and Dutch phenoxy-herbicide workers who were part of the IARC cohort have shown a non-significant increased risk of NHL (Boers et al., 2010; Bueno de Mesquita et al., 1993; Hooiveld et al., 1998; Lynge, 1993). A cohort of 2,479 workers in four plants in Germany with exposure to phenoxy herbicide and contaminants (dioxins and furans) had significantly increased risk of NHL on the basis of five cases (Becher et al., 1996). A variety of herbicides were produced in the plants, including those known to have been contaminated with TCDD. Increased but non-significant increases in risk have also been found in the NIOSH mortality study (Steenland et al., 1999). Risks were not significantly increased in the Dow Chemical Company Midland, Michigan, or Plymouth, New Zealand, chemical production workers, phenoxyherbicide sprayers, or 2,4-D production workers (Bloemen et al., 1993; Bodner et al., 2003; Burns et al., 2001; Collins et al., 2009b,c; McBride et al., 2009a,b; Ramlow et al., 1996; ’t Mannetje et al., 2005). A multinational IARC cohort study of paper-and-pulp workers found a statistically significant increase in workers who were exposed to chlorophenols (McLean et al., 2006).

Studies of farmers and agricultural workers have been generally positive for an association between herbicides or TCDD and NHL; however, only a few were statistically significant. A meta-analysis of several studies of the association between employment as a farmer in the central United States and NHL showed a statistically significant risk (Keller-Bryne et al., 1997). All the studies of US agricultural workers reviewed showed increased RRs, and two NCI studies of farmers in Kansas and Nebraska (Hoar et al., 1986; Zahm et al., 1990) showed patterns of increased risk linked to use of 2,4-D. A study of a subcohort of Hispanic workers in a larger cohort of 139,000 California members of the United Farm Workers of America (Mills et al., 2005) and a population-based case-control study in Italy of NHL and CLL cases (combined) identified during 1991–1993 (Miligi et al., 2006) both showed statistically significant associations with 2,4-D.

A large, well-conducted, population-based, cross-Canada case-control study reported on pesticide use and NHL incidence in men identified from cancer registries of six Canadian provinces from 1991 through 1994. Statistically significant associations were found between exposure to phenoxy herbicides, 2,4-D,

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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or Mecocrop and NHL. A reanalysis of the data from that study confirmed the findings on phenoxy herbicides but found that the association with 2,4-D, although still increased, was no longer significantly so (McDuffie et al., 2001). A population-based case-control study in 2000–2001 in men and women 20–74 years old living in New South Wales, Australia, found an increased risk of NHL associated with “substantial” exposure to phenoxy herbicides (Fritschi et al., 2005). Spinelli et al. (2007) reported on a population-based case-control study in Vancouver and Victoria, British Columbia, which found strong monotonic increases in serum concentrations of two dioxin-like PCBs (PCB 118 and 156). Chiu et al. (2004) and Lee et al. (2004a) conducted a pooled (combined) analysis of two case-control studies that were carried out in three midwestern US states—Iowa and Minnesota (Cantor et al., 1992) and Nebraska (Zahm et al., 1990)—and found that risks were increased in farmers by use of herbicides, including 2,4-D and 2,4,5-T. In a study of NHL incidence in people who lived in the vicinity of 13 French municipal waste incinerators, Viel et al. (2008b) found a small but statistically significant increase in the risk of NHL and evidence of a dose–response relationship with increased exposure to dioxin. A case-control study of NHL rates in people who lived near a municipal solid-waste incinerator in Bensaçon, France, found that the incidence of NHL was significantly increased in the area determined to have the highest dioxin contamination, but no increases were found in the low and intermediate categories (Floret et al., 2003). A French hospital-based case-control study of lymphoid neoplasms (Orsi et al., 2009) did not find the occurrence of NHL to be associated with occupational or domestic use of pesticides or phenoxy herbicides in particular.

Evidence of an association between the COIs and NHL in Vietnam veterans, the primary population of interest in the VAO updates, has been lacking. The CDC Selected Cancers Study (CDC, 1990e) showed a significantly increased risk of NHL in all Vietnam veterans; however, in an analysis that took into account the branch of service, Army and Air Force personnel were found not to be at increased risk. Marine Corps veterans had higher mortality in the CDC Selected Cancers Study and significantly increased risks in several other studies (Breslin et al., 1988; Burt et al., 1987; Watanabe and Kang, 1996; Watanabe et al., 1991), but the implications of these findings are unclear. No increased risk has been seen in Ranch Hand veterans (AFHS, 2000; Akhtar et al., 2004; Michalek et al., 1990; Wolfe et al., 1990) or in members of the ACC (Boehmer et al., 2004).

With 25 years of follow-up of the Seveso population and a relatively small number of observed cases, evidence of an increased incidence of NHL is emerging in the subgroup who lived in the most highly exposed zones (Bertazzi et al., 1989b, 1993, 1997, 2001; Consonni et al., 2008; Pesatori et al., 1992, 2009).

The findings of several PCB-focused studies (Bertrand et al., 2010; Engel et al., 2007; Laden et al., 2010) are consistent with the associations with NHL repeatedly observed in connection with the COIs in the VAO series, but the extent

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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of intercorrelation of these persistent organic pollutants greatly curtails the degree to which any effect can be specifically attributed to dioxin-like activity.

Table 8-41 summarizes the results of the relevant studies of all forms of NHL.

Update 2002 was the first to discuss CLL separately from other leukemias. The epidemiologic studies indicated that farming, especially with exposure to 2,4-D and 2,4,5-T, is associated with significant mortality from CLL. Many more studies support the hypothesis that herbicide exposure can contribute to NHL risk. Most cases of CLL and NHL reflect the malignant transformation of germinal-center B cells, so these diseases could have a common etiology.

Studies concerning CLL reviewed in Update 2002, Update 2004, Update 2006, Update 2008, Update 2010, and Update 2012 are summarized in Table 8-42.

Update of the Epidemiologic Literature

Vietnam-Veteran and Environmental Studies Based on deaths rates from the general male population of New Zealand, McBride et al. (2013) calculated that seven were expected (SMR = 0.43, 95% CI 0.09–1.25). In assessing incidence, based upon 14 cases, the incidence of NHL was not elevated (SIR = 0.85, 95% CI 0.46–1.42). The researchers also reported on lymphoid leukemia, showing an SMR of 0.57 (95% CI 0.01–3.16) based upon one observed death. Similarly, there were 14 observed cases of lymphoid leukemia (which would include any cases of CLL, a specific NHL), which did constitute a significant increase (SIR = 1.91, 95% CI 1.04–3.20).

Mortality (Yi et al., 2014b) and cancer incidence (Yi and Ohrr, 2014) were assessed among Korean Veterans who had served in Vietnam from 1964 through 1973. In analyses of cancer incidence, Yi and Ohrr (2014) reported a small excess risk of NHL (HR = 1.09, 95% CI 0.81–1.47) in the internal comparison of the high- and-low exposure groups based on the EOI scores. Similarly for NHL mortality, Yi et al. (2014b) reported a modestly increased risk for the high- versus low-exposure groups (HR = 1.18, 95% CI 0.79–1.77) and a small increased risk with the individual log-transformed EOI scores (HR = 1.04, 95% CI 0.95–1.15). Lymphoid leukemia had an aHR of 0.45 (95% CI 0.15–1.37) based upon nine low-exposure and five high-exposure deaths.

Occupational Studies Since Update 2012, two new NHL occupational studies have been published (Cocco et al., 2012; Pronk et al., 2013). Using the EPILYMPH multicenter study (conducted in the Czech Republic, France, German, Ireland, Italy, and Spain from 1998 to 2004), Cocco et al. (2012) assessed occupational exposure in 2,348 lymphoma cases and 2,462 controls, seeking to understand the relationship of pesticide use with lymphomas. In assessing exposure, a “crop-exposure” matrix was assembled and the exposure was estimated by a group of trained occupational experts. There were numerous analyses of multiple

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-41 Selected Epidemiologic Studies—Non-Hodgkin Lymphoma (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)   All COIs  
Incidence
Through 1999—White subjects vs national rates (lymphopoietic cancerc)     Akhtar et al., 2004
Ranch Hand veterans (n = 1,189) 10 0.9 (0.4–1.5)  
With tours between 1966–1970 7 0.7 (0.3–1.4)  
SEA comparison veterans (n = 1,776) 9 0.6 (0.3–1.0)  
With tours between 1966–1970 4 0.3 (0.1–0.8)  
Attended 1987 exam—Ranch Hand personnel (n = 995) vs SEA veterans (n = 1,299) 1 nr Wolfe et al., 1990
Mortality
Through 1987—Ranch Hand personnel (n = 1,261) vs SEA veterans (n = 19,102) 0 nr Michalek et al., 1990
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Army enlisted Vietnam veterans (all lymphomas) (1965–1983) 7 1.8 (nr) O’Brien et al., 1991
Mortality
1965–2000 6 0.9 (0.3–2.9) Boehmer et al., 2004
US CDC Selected Cancers Study—case-control study of incidence (Dec 1, 1984–Nov 30, 1989) among US males born 1929–1953 (CDC, 1990a)   All COIs CDC, 1990b
  99 1.5 (1.1–2.0)  
Army Vietnam veterans 45 1.2 (0.8–1.8)  
Marine Vietnam veterans 10 1.8 (0.8–4.3)  
Air Force Vietnam veterans 12 1.0 (0.5–2.2)  
Navy Vietnam veterans 32 1.9 (1.1–3.2)  
Blue Water Navy Vietnam veterans 28 2.2 (1.2–3.9)  
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1988     Watanabe and Kang, 1996
Army, deployed (n = 27,596) vs non-deployed (n = 31,757) 171  
Marine Corps, deployed (n = 6,237) vs non-deployed (n = 5,040) 46 1.7 (1.2–2.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
1965–1984—Army, deployed (n = 24,145) vs non-deployed (n = 27,917) (ICD-8 200, 202)s 140 1.7 (1.2–2.2) Watanabe et al., 1991
Army Vietnam veterans vs combined Army and Marine Vietnam-era veterans 140 0.9 (nr)  
Marine Vietnam veterans vs non-Vietnam veterans 42 1.8 (1.3–2.4)  
Marine Vietnam veterans vs combined Army and Marine Vietnam-era veterans 42 1.2 (nr)  
1965–1982 (ICDA-8 200, 202)     Breslin et al.,1986, 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 108 0.8 (0.6–1.0)  
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 35 2.1 (1.2–3.8)  
Nested case-control study of NHL 39 1.1 (0.7–1.5) Burt et al., 1987
Army combat Vietnam veterans 17 3.2 (1.4–7.4)  
Marine combat Vietnam veterans 64 0.9 (0.7–1.3)  
Army Vietnam veterans (service 1967–1969) 17 2.5 (1.1–5.8)  
Marine Vietnam veterans (service 1967–1969) 4 1.8 (0.4–8.0)  
US VA Cohort of Female Vietnam Veterans   All COIs  
Mortality
Through 2004 (lymphopoietic cancersc) 18 0.7 (0.4–1.3) Cypel and Kang, 2008
Vietnam–veteran nurses 14 0.7 (0.3–1.3)  
Through 1987 (ICD-8 200, 200–203, 208) 3 1.3 (0.3–1.8) Thomas et al., 1991
US Navy Enlisted Personnel (1974–1983)
Active duty 68 0.7 (0.5–0.9) Garland et al., 1988
VA Case-Control Studies
US Vietnam veterans—incidence 100 1.0 (0.7–1.5) Dalager et al., 1991b
State Studies of US Vietnam Veterans
Massachusetts Vietnam-era veterans who served 1958–1973—cases diagnosed 1982–1988 (served in Vietnam) 1.2 (0.6–2.4) Clapp et al., 1991
Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs non-deployed 32 1.5 (1.0–2.1) Vistainer et al., 1995
New York—deployed vs non-deployed 10 1.0 (0.4–2.2) Lawrence et al., 1985
West Virginia—deployed vs non-deployed 2 1.1 (nr) Holmes et al., 1986
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
923 White male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans (includes lymphosarcoma, reticulosarcoma) 4 nr Anderson et al., 1986a,b
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 126 0.7 (0.6–0.8) ADVA, 2005b
Navy 31 0.8 (0.5–1.0)  
Army 86 0.7 (0.5–0.8)  
Air Force 9 0.5 (0.2–0.9)  
Validation Study   Expected number of exposed cases AIHW, 1999
  62 48 (34–62)  
Men 137 48 (34–62) CDVA, 1998a
Women 2 0 (0–4) CDVA, 1998b
Mortality
All branches, return–2001 70 0.8 (0.6–1.0) ADVA, 2005a
Navy 10 0.5 (0.3–0.9)
Army 52 0.9 (0.6–1.1)  
Air Force 8 0.9 (0.4–1.6)  
1980–1994 33 0.9 (0.6–1.2) CDVA, 1997a
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence
1982–2000 35 1.1 (0.7–1.9) ADVA, 2005c
Mortality
1966–2001 21 1.4 (0.7–2.8) ADVA, 2005c
1983–1985 (ICD-8 200, 202) 4 1.8 (0.4–8.0) Fett et al., 1987b
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008) 14 0.9 (0.5–1.4)  
Mortality (1988–2008) 3 0.4 (0.1–1.3)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—NHL (C82–C85) categorized high (n = 96) vs low (n = 89)   1.1 (0.8–1.5) Yi and Ohrr, 2014
Mortality (1992–2005)—categorized high (n = 56) vs low (n = 47)   1.2 (0.8–1.8) Yi et al., 2014b
HR per unit of log EOI scores (n = 180,639) 103 1.0 (1.0–1.2)  
OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Mortality 1939–1992 34 1.3 (0.9–1.8) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 24 1.4 (0.9–2.1)  
7,553 not exposed to highly chlorinated PCDDs 9 1.0 (0.5–1.9)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort     Saracci et al., 1991
Nested case-control study      
IARC cohort (men and women)—incidence     Kogevinas et al., 1995
Exposed to 2,4,5-T 10 1.9 (0.7–4.8)  
Exposed to TCDD 11 1.9 (0.7–5.1)  
Mortality—IARC cohort (16,863 men and 1,527 women) 10–19 yrs since first exposure 11 1.0 (0.5–1.7) Kogevinas et al., 1992
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)   Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP  
Mortality 1955–2006 7 1.4 (1.1–1.7) Boers et al., 2012
TCDD plasma level (HRs, by tertile)      
Background (≤ 0.4) 1 nr  
Low (0.4–4.1) 3 3.8 (0.4–34.3)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Medium (4.1–20.1) 2 7.8 (0.7–89.3)  
High (≥ 20.1) 1 8.1 (0.4–149.1)  
Incidence 1943–1987 (men only) 10 1.7 (0.5–4.5) Lynge, 1993
Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)   Dioxins, 2,4,5-T, 2,4,5-TCP  
Mortality 1955–2006 (HRs for lagged TCDD plasma levels) 6 1.3 (1.0–1.7) Boers et al., 2012
Mortality 1955–2006 4 vs 3 0.9 (0.2–4.5) Boers et al. 2010
Mortality 1955–1991 3 3.8 (0.8–11.0) Hooiveld et al., 1998
Mortality 1955–1985 1 2.0 (0.1–11.4) Bueno de Mesquita et al., 1993
Dutch production workers in Plant B (414 men exposed during production 1965–1986; 723 unexposed) (in IARC cohort)   2,4-D; MCPA; MCPP; highly chlorinated dioxins unlikely  
Mortality 1965–2006 1 vs 0 nr Boers et al., 2010
Mortality 1965–1986 1 5.6 (0.1–31.0) Bueno de Mesquita et al., 1993
German Production Workers—2,479 workers at 4 plants (in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
All 4 plants 6 3.3 (1.2–7.1) Becher et al., 1996
German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 mo in 1951–1976) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4,5-TCP  
Mortality 1951–1992 2 12.0 (1.5–43.5) Becher et al., 1996
German Production Workers at Bayer Plant in Dormagen (520 men working > 1 mo in 1965–1989) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4-DP; 2,4,5-T; MCPA; MCPP  
Mortality 1965–1989 0 Becher et al., 1996
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 mo in 1957–1987) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4-DP; 2,4,5-T; MCPA; MCPP  
Mortality 1956–1989 0 Becher et al., 1996
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)   Dioxins; 2,5-DCP; 2,4,5-T; 2,4,5-TCP  
Mortality 1952–2007 7 1.6 (0.6–3.3) Manuwald et al., 2012
Men 5 1.6 (0.5–3.7)  
Women 2 1.7 (0.2–6.0)  
Mortalilty 1952–1989 4 3.8 (1.0–9.6) Becher et al., 1996
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Ever-exposed workers 3 1.6 (0.3–4.7)  
Never-exposed workers 1 1.6 (0.0–8.7)  
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)      
Mortality 1969–2000 1 0.9 (0.0–4.9) ’t Mannetje et al., 2005
Sprayers (697 men and 2 women registered any time 1973–1984)      
Mortality 1973–2000 1 0.7 (0.0–3.8) ’t Mannetje et al., 2005
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Through 1993 12 1.1 (0.6–1.9) Steenland et al., 1999
Chloracne subcohort (n = 608) (Lymphatic and hematopoietic, ICD-9 200–208) 6 1.1 (0.4–2.5)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (in IARC and NIOSH cohorts)   2,4,5-T; 2,4,5-TCP  
1942–2003 (n = 1,615) 9 1.3 (0.6–2.5) Collins et al., 2009b
1940–1994 (n = 2,187 men) nr 1.4 (0.6–2.7) Bodner et al., 2003
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
1940–2005 (n = 2,122) (ICD-9 200, 202, 273.3) 17 1.8 (1.0–2.8)  
PCP and TCP (n = 720) 8 2.5 (1.1–4.9)  
PCP (no TCP) (n = 1,402) 9 1.4 (0.6–2.7)  
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3) 14 1.7 (0.9–2.9) Burns CJ et al., 2011
Through 1994 (n = 1,517) 3 1.0 (0.2–2.9) Burns et al., 2001
Through 1986 (n = 878) vs national vs 36,804 “unexposed” workers at same location 2 2.0 (0.2–7.1) Bloemen et al., 1993
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) 8 2.4 (1.0–4.7) Collins et al., 2009c
Mortality 1940–1989 (n = 770)     Ramlow et al., 1996
All lymphopoietic cancer (ICDA-8 200–209)      
0-yr latency 7 1.4 (0.6–2.9)  
15-yr latency 5 1.3 (0.4–3.1)  
Other, unspecified lymphopoietic cancer (ICDA-8 200, 202–203, 209)      
0-yr latency 5 2.0 (0.7–4.7)  
15-yr latency 4 2.0 (0.5–5.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Never 35 0.9 (0.7–1.3)  
Ever 25 0.9 (0.6–1.3)  
Exposure to chlorophenols 50 4.3 (2.7–6.9)  
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
CANADA
Canadian Farm Operator Study—156,242 men farming in Manitoba, Saskatchewan, and Alberta in 1971; mortality from NHL June 1971–December 1987      
Farm operators ≥ 35 yrs of age (June 1971–December 1987)     Morrison et al., 1994
All farm operators nr 0.8 (0.7–0.9)  
Highest quartile of herbicides sprayed 19 2.1 (1.1–3.9)  
Highest quartile of herbicide sprayed relative to no spraying 6 3.0 (1.1–8.1)  
Farm operators ≥ 35 yrs of age during study period (June 1971–December 1985)     Wigle et al., 1990
All farmers 103 0.9 (0.8–1.1)  
Spraying herbicides on 250+ acres 10 2.2 (1.0–4.6)  
DENMARK
Danish gardeners—incidence from 3,156 male and 859 female gardeners     Hansen et al., 2007
25-yr follow-up (1975–2001)   Herbicides  
Born before 1915 (high exposure) 16 1.4 (0.9–2.3)  
Born 1915–1934 (medium exposure) 25 1.2 (0.8–1.8)  
Born after 1934 (low exposure) 1 0.2 (0.0–1.0)  
10-yr follow-up (1975–1984) of male gardeners (ICD-7) 15 1.4 (0.8–2.4) Hansen et al., 1992
(lymphohematopoietic, 200–2005)      
NHL (200, 202, 205) 6 1.7 (0.6–3.8)  
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 1987 0 nr Swaen et al., 1992
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
FINNISH Phenoxy Herbicide Sprayers (1,909 men working 1955–1971 ≥ 2 wks) not IARC   Phenoxy herbicides  
Incidence     Asp et al., 1994
No latency 1 0.4 (0.0–2.0)  
10-yr latency 1 0.4 (0.0–2.4)  
Except for lung cancer, numbers too small for reporting mortality 1972–1980 0 nr Riihimaki et al., 1982, 1983
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401) (ICD-8 202.0–202.9) 15 0.9 (0.5–1.5) Torchio et al., 1994
Incidence 1976–1983 (n = 25,945)     Corrao et al., 1989
Licensed pesticide users and nonusers 45 1.4 (1.0–1.9)  
Farmers in arable land areas 31 1.8 (1.2–2.5)  
Italian rice growers with documented phenoxy use (n = 1,487)   Phenoxy herbicides Gambini et al., 1997
  4 1.3 (0.3–3.3)  
SWEDEN
20,245 Swedish pesticide applicators with license issued from 1965 through 1976 27 1.1 (0.7–1.6) Wiklund et al., 1989b
354,620 Swedish agriculture, forestry workers     Wiklund et al., 1988a
Workers in land, animal husbandry 670 1.0 (0.9–1.1)  
Timber cutters 111 0.9 (0.7–1.1)  
Incident NHL cases 1961–1973 with agriculture as economic activity in 1960 census 476 99% CI
1.1 (0.9–1.2)
Wiklund, 1983
Swedish lumberjacks—Used phenoxys 1954–1967, Incidence 1958–1992     Thörn et al., 2000
Exposed (n = 154)
Foremen (n = 15) 0  
Lumberjacks (n = 139) 1 1.9 (0.0–10.7)  
Unexposed lumberjacks (n = 241) 1 0.8 (0.0–4.5)  
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Men
Whites (n = 119,648) 843 1.2 (1.1–1.3)  
Nonwhites (n = 11,446) 24 0.7 (0.5–1.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Women
Whites (n = 2,400) 18 1.1 (0.6–1.7)  
Nonwhites (n = 2,066) 6 1.1 (0.4–2.3)  
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
NHL
Private applicators 195 1.0 (0.9–1.1)  
Commercial applicators 9 0.8 (0.4–1.6)  
Spouses 86 1.0 (0.8–1.2)  
B-cell
Private applicators 167 1.0 (0.9–1.2)  
Commercial applicators 8 0.9 (0.4–1.7)  
Spouses 78 1.1 (0.8–1.3)  
Enrollment through 2002     Samanic et al., 2006
Dicamba—lifetime days exposure      
None 39 1.0  
1– < 20 18 1.8 (1.0–3.2)  
20– < 56 14 1.3 (0.7–2.5)  
56– < 116 7 0.9 (0.4–2.2)  
≥ 116 7 1.2 (0.5–2.9) p-trend = 0.92  
Enrollment through 2002     Alavanja et al., 2005
Private applicators 114 1.0 (0.8–1.2)  
Spouses of private applicators (> 99% women) 42 0.9 (0.6–1.2)  
Commercial applicators 6 1.0 (0.4–2.1)  
Mortality
Enrollment through 2007, vs state rates     Waggoner et al., 2011
Applicators (n = 1,641) 90 0.8 (0.7–1.0)  
Spouses (n = 676) 42 1.1 (0.8–1.5)  
Enrollment through 2000, vs state rates     Blair et al., 2005a
Private applicators (men and women) 33 0.9 (0.6–1.2)  
Spouses of private applicators (> 99% women) 16 1.2 (0.7–2.0)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
California United Farm Workers of America
Nested case-control analysis of Hispanic workers in cohort of 139,000 CA United     Mills et al., 2005
Farm Workers    
Ever used 2,4-D nr 3.8 (1.9–7.8)  
US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 of NHL   Herbicides  
Agricultural extension agents (from Table 3) nr 1.2 (0.7–2.3) Alavanja et al., 1988
White Male Residents of Iowa—NHL cancer on death certificate, usual occupation: farmers vs not   Herbicides  
> 30 yrs old when died     Burmeister et al., 1983
1964–1978—case-control 1,101 1.3 (nr)  
H0: only for “modern methods” → born after 1900      
Born before 1880 154 2.9 (nr)  
Born 1980–1900 336 1.6 (nr)  
Born after 1900 611 0.9 (nr)  
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Incidence
20-yr follow-up to 1996—men and women     Pesatori et al., 2009
Zone A 1 0.8 (0.1–5.7)  
Zone B 12 1.5 (0.9–2.7)  
Zone R 49 0.9 (0.7–1.2)  
10-yr follow-up to 1991—men     Bertazzi et al., 1993
Zone A 0 nr  
Zone B 3 2.3 (0.7–7.4)  
Zone R 12 1.3 (0.7–2.5)  
10-yr follow-up to 1991—women     Bertazzi et al., 1993
Zone A 0 nr  
Zone B 1 0.9 (0.1–6.4)  
Zone R 10 1.2 (0.6–2.3)  
Mortality
25-yr follow-up to 2001—men and women     Consonni et al., 2008
Zone A 3 3.4 (1.1–10.5)  
Zone B 7 1.2 (0.6–2.6)  
Zone R 40 1.0 (0.7–1.4)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
20-yr follow-up to 1996     Bertazzi et al., 2001
Zone A—men and women 2 3.3 (0.8–13.1)  
Zone B—men and women 5 1.2 (0.5–3.0)  
Zones A and B—men 3 1.2 (0.4–3.9)  
Zones A and B—women 4 1.8 (0.7–4.9)  
15-yr follow-up to 1991—men     Bertazzi et al., 1997, 1998
Zone A 0 0.0 (0.0–18.1)  
Zone B 2 1.5 (0.2–5.3)  
Zone R 10 1.1 (0.5–2.0)  
15-yr follow-up to 1991—women     Bertazzi et al., 1997, 1998
Zone A 0 0.0 (0.0–19.6)  
Zone B 0 0.0 (0.0–3.0)  
Zone R 8 0.9 (0.4–1.7)  
10-yr follow-up to 1986—men     Bertazzi et al., 1989a,b
Zone B nr nr  
Zone R 3 1.0 (0.3–3.4)  
10-yr follow-up to 1986—women      
Zone B 2 1.0 (0.3–4.2)  
Zone R 4 1.6 (0.5–4.7)  
Other International Environmental Studies
FINLAND
Finnish community exposed to chlorophenol contamination (men and women)—incidence 16 Chlorophenol 2.8 (1.4–5.6) Lampi et al., 1992
FRANCE
Residents near French solid-waste incinerator in Besancon. NHL cases diagnosed 2003–2005—incidence   Dioxin, furans, PCBs Viel et al., 2011
pg WHO1998 TEQ/g lipid:
Σ PCDD 13.4 1.1 (1.0–1.3) (p-trend < 0.01)  
Σ PCDF 9.4 1.2 (1.0–1.4) (p-trend = 0.01)  
Σ dl PCBs 33.1 1.0 (1.0–1.1) (p-trend = 0.01)  
Residents near French solid-waste incinerator—incidence   Dioxin Viel et al., 2008a
Highly exposed census group vs slightly exposed nr 1.1 (1.0–1.3)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Residents near municipal solid-waste incinerator—incidence   Dioxin Floret et al., 2003
High exposure category 31 2.3 (1.4–3.8)  
Residents near municipal solid-waste incinerator—incidence   Dioxin Viel et al., 2000
Spatial cluster 286 1.3 (p = 0.00003)  
1994–1995 109 1.8 (p = 0.00003)  
NEW ZEALAND
Residents of New Plymouth Territorial Authority, New Zealand near plant manufacturing 2,4,5-T in 1962–1987   2,4,5-T Read et al., 2007
Incidence 223 1.0 (0.9–1.1)d  
1970–1974 33 1.8 (1.2–2.5)  
1975–1979 29 1.3 (0.9–1.9)  
1980–1984 22 0.8 (0.5–1.3)  
1985–1989 24 0.7 (0.5–1.1)  
1990–1994 35 0.8 (0.6–1.1)  
1995–1999 61 1.1 (0.8–1.4)  
2000–2001 19 0.8 (0.5–1.3)  
Mortality 138 1.1 (0.9–1.3)d  
1970–1974 19 1.6 (0.9–2.4)  
1975–1979 24 1.6 (1.0–2.4)  
1980–1984 14 1.0 (0.5–1.6)  
1985–1989 25 1.3 (0.9–2.0)  
1990–1994 23 0.9 (0.6–1.4)  
1995–1999 21 0.7 (0.4–1.1)  
2000–2001 12 1.0 (0.5–1.8)  
CASE-CONTROL STUDIES
US Case-Control Studies
Central US—meta-analysis of NHL and farmers nr Pesticides 1.3 (1.2–1.6) Keller-Byrne et al., 1997
Pooled incidence data on herbicide use from 3 case-control studies in Iowa/Minnesota,   Herbicides Chiu et al., 2004
Kansas, and Nebraska (n = 973)      
Farmers (no herbicide use) 294 1.2 (1.0–1.5)  
Farmers (herbicide use) 273 1.0 (0.8–1.2)  
Pooled data from case-control studies in Iowa, Minnesota, and Nebraska—effect of asthma on NHL and pesticide use (n = 872)   Pesticides Lee et al., 2004a
Asthmatics—incidence
Herbicide exposure—phenoxy acid 17 1.3 (0.7–2.4)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Exposure among farmers
2,4-D 17 1.3 (0.7–2.5)  
2,4,5-T 7 2.2 (0.8–6.1)  
Non-asthmatics—incidence
Herbicide exposure—phenoxy acid Exposure among farmers 176 1.0 (0.8–1.3)  
2,4-D 172 1.0 (0.8–1.3)  
2,4,5-T 36 1.1 (0.7–1.8)  
Kansas residents–duration and frequency of herbicide use—incidence   Phenoxy herbicides, 2.4-D Hoar et al., 1986
All farmers 133 1.4 (0.9–2.1)  
Farm-use of herbicides 7 6.0 (1.9–19.5)  
NCI SEER study (Iowa, Los Angeles County, Detroit, Seattle), 1998–2000; 1,321 NHL patients and 1,057 controls—residential exposures   2,4-D Hartge et al., 2005
2,4-D exposure in carpet dust (ng/g)
Under detection limit 147 1.0  
< 500 257 1.1 (0.8–1.6)  
500–999 86 0.9 (0.6–1.5)  
1,000–9,999 165 0.7 (0.5–1.0)  
> 10,000 24 0.8 (0.4–1.7)  
Nebraska residents (men and women), NHL reclassified according to specific chromosomal translocation (t[14;18][q32;q21])—incidence   Herbicides Chiu et al., 2006
Translocation present in cases
Herbicides 25 2.9 (1.1–7.9)  
Translocation present in cases
Herbicides 22 0.7 (0.3–1.2)  
Females on Eastern Nebraska farms 119 Herbicides 1.0 (0.7–1.4) Zahm et al., 1993
Eastern Nebraska residents—incidence   2,4-D Zahm et al., 1990
Ever done farm work 147 0.9 (0.6–1.4)  
Ever mixed or applied 2,4-D 43 1.5 (0.9–2.5)  
Upstate New York—population-based study, women (20–79 yrs old), 1995–1998 (376 cases vs 463 controls)   Herbicides, pesticides Kato et al., 2004
Home use only of herbicides, pesticides (times)      
0 231 1.0  
1–4 33 0.9 (0.5–1.5)  
5–17 30 0.7 (0.4–1.3)  
18–39 27 1.0 (0.6–1.7)  
≥ 40 40 0.9 (0.5–1.5)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Hancock County, Ohio, residents—farmers 15 1.6 (0.8–3.4) Dubrow et al., 1988
Washington state residents—incidence (1983–1985)   Phenoxy herbicides, chlorinated phenols Woods et al., 1987
Phenoxy herbicide use nr 1.1 (0.8–1.4)  
Chlorophenol use nr 1.0 (0.8–1.2)  
Farming occupations nr 1.3 (1.0–1.7)  
Forestry herbicide appliers nr 4.8 (1.2–19.4)  
Self-reported chloracne nr 2.1 (0.6–7.0)  
Wisconsin residents—farmers (ICD-8 200.0, 200.1, 202.2) 175 Herbicides 1.2 (1.0–1.5) Cantor, 1982
International Case-Control Studies
Asian patients (≥ 20 yrs old) from China, Korea, and Japan diagnosed with NKTCL between March 2000 and March 2005–occupational exposures   Herbicides, pesticides Xu et al., 2006
Pesticide use 23 4.0 (2.0–8.1)  
Herbicide 13 3.2 (1.4–7.4)  
Insecticide 20 3.5 (1.7–7.1)  
Fungicide 10 6.1 (2.0–18.5)  
Australian population-based study in New Wales (2000–2001)   Phenoxy compounds Fritschi et al., 2005
Phenoxy herbicides
Nonsubstantial exposures 10 0.7 0.3–1.7)  
Australian residents in Victorian Cancer Registry (1982–1987)   Phenoxy compounds Smith and Christophers, 1992
Exposure > 1 day 15 1.5 (0.6–3.7)
Exposure > 30 days 7 2.7 (0.7–9.6)  
Canadian population-based study (March 2000–February 2004), men and women subjects and matched controls (20–79 yrs of age)—organochlorines and NHL   dl PCBs Spinelli et al., 2007
Total dl PCBs
Lowest quartile 82 1.0  
Second quartile 96 1.4 (0.9–2.2)  
Third quartile 82 1.6 (1.0–2.5)  
Highest quartile 143 2.4 (1.5–3.7) p-trend < 0.001  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Cross Canada Study of Pesticides and Health—men in 1 of 6 Canadian provinces (≥ 19 yrs of age) diagnosed (09/1991–12/1994) (n = 517) vs matched population-based controls (n = 1,506)   Phenoxy herbicides, 2,4-D  
Pesticide use, immunologic conditions, and NHL risk     Pahwa et al., 2012b
Phenoxy herbicides 44 1.5 (1.0–2.3)  
MCPA 7 2.7 (0.9–7.9)  
Mecoprop 16 1.7 (0.9–3.4)  
2,4-D 39 1.4 (0.9–2.2)  
Exposure to multiple pesticides     Hohenadel et al., 2011
0 369 1.0 (nr)  
1 45 1.2 (0.9–1.8)  
2–4 73 1.6 (1.2–2.2)  
5+ 26 1.6 (1.0–2.6)  
Exposure to phenoxy herbicides
0 384 1.0 (nr)  
1 66 1.3 (1.0–1.8)  
2+ 63 1.8 (1.3–2.5)  
Exposure to Mecoprop 23 2.1 (1.2–5.4)  
Exposure to 2,4-D 49 0.9 (0.7–1.3)  
Pesticide exposure of ≥ 10 h/yr 131 1.4 (1.1–1.8) McDuffie et al., 2001
2,4-D 111 1.3 (1.0–1.7)  
Mecoprop 53 2.3 (1.6–3.4)  
Danish residents (Copenhagen and Aarhus) in the Diet, Cancer and Health prospective study diagnosed with NHL from enrollment (1994–5/1977) through 2008   Organochlorines Bräuner et al., 2012
Organochlorines in adipose tissue (ug/kg lipids)      
dl PCB 118
10–25 53 1.0 (nr)  
25–34 63 0.9 (0.5–1.6)  
34–48 58 1.0 (0.6–1.7)  
48–62 34 0.7 (0.3–1.3)  
62–150 25 0.7 (0.4–1.4)  
dl PCB 156
13–28 62 1.0 (nr)  
28–34 51 0.6 (0.3–1.0)  
34–41 54 0.7 (0.4–1.2)  
41–50 45 0.9 (0.5–1.8)  
50–88 23 0.7 (0.3–1.4)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Denmark—Danish farm workers—incidence   Phenoxy herbicides Ronco et al., 1992
  147 1.0 (nr)  
Italian farm workers—mortality 14 1.3 (nr)  
France hospital-based case-control study   Herbicides Orsi et al., 2009
Occupational use of herbicides 25 1.3 (0.7–2.2)  
Phenoxy herbicides 11 0.9 (0.4–1.9)  
Domestic use of herbicides 86 1.0 (0.7–1.5)  
German population-based study (1986–1998), men and women, 15–75 yrs of age—occupational factors associated with NHL   TCDD, Herbicides Richardson et al., 2008
Chlorophenols
NHL—high-grade malignancy 61 2.0 (1.3–2.9)  
NHL—low-grade malignancy 77 1.3 (1.0–1.8)  
CLL 44 0.9 (0.6–1.3)  
Herbicides
NHL—high-grade malignancy 56 2.2 (1.4–3.3)  
NHL—low-grade malignancy 79 1.4 (1.0–1.9)  
CLL 43 1.2 (0.8–1.7)  
Irish farmers and farm workers   Herbicides Dean, 1994
Other malignant neoplasms of lymphoid and histiocytic tissue (including some types of NHL) (ICD-9 202) 164 1.8 (1.2–2.6)  
Italian incident cases of malignancies of the hematolymphopoietic system in men and women (20–74 yrs of age) from agricultural and mixed use areas (HD cases = 258)   Herbicides Miligi et al., 2006
Men, women 73 1.0 (0.7–1.4)  
Men 49 0.8 (0.5–1.3)  
Women 24 1.3 (0.7–2.5)  
NHL (men, women)      
Phenoxy herbicides—ever 32 1.1 (0.6–1.8)  
Probability of use more than “low,” lack of protective equipment 13 2.4 (0.9–7.6)  
2,4-D—ever 17 0.9 (0.5–1.8)  
Probability of use more than “low,” lack of protective equipment 9 4.4 (1.1–29.1)  
MCPA—ever 18 0.9 (0.4–1.8)  
Probability of use more than “low,” lack of protective equipment 7 3.4 (0.8–23.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Italian residents of 11 areas (NHL other than lymphosarcoma and reticulosarcoma)—incidence   Herbicides Miligi et al., 2003
Phenoxy acid herbicides exposure
Men 18 1.0 (0.5–2.0)  
Women 11 1.3 (0.5–3.7)  
2,4-D exposure
Men 6 0.7 (0.3–1.9)  
Women 7 1.5 (0.4–5.7)  
Italian farming and animal-breeding workers (men and women) (NHL other than lymphosarcoma and reticulosarcoma)—incidence   Herbicides Nanni et al., 1996
Exposure to herbicides 3 1.4 (0.4–5.7)  
Italian farming, animal-breeding workers (men and women)—incidence   Herbicides Amadori et al., 1995
NHL, CLL combined 164 1.8 (1.2–2.6)  
Residents of selected Italian provinces   Herbicides Vineis et al., 1991
Male residents of contaminated areas nr 2.2 (1.4–3.5)  
Residents of Milan, Italy, area (men and women)—incidence   Herbicides LaVecchia et al., 1989
Agricultural occupations nr 2.1 (1.3–3.4)  
New Zealand National Cancer Registry (1980–1984)—case-control study of 652 incident NHL cases vs remainder of 19,904 men with any incident cancer   Herbicides Reif et al., 1989
Forestry workers (n = 134)
Aged 20–59 4 2.0 (0.7–5.6)  
Aged ≥ 60 3 1.7 (0.5–5.4)  
Sawmill workers (n = 139)   Herbicides,  
    Chlorophenols  
  4 1.2 (0.4–3.2)  
New Zealand National Cancer Registry (1977–1981) (< 70 yrs of age)—incidence (1977–1981) (ICD-9 200, 202)   Herbicides Pearce et al., 1987
Farming occupations 33 1.0 (0.7–1.5)  
Fencing work 68 1.4 (1.0–2.0)  
New Zealand National Cancer Registry (1977–1981) (< 70 yrs of age)—incidence (1977–1981) (ICD-9 202 only)   Phenoxy herbicides Pearce et al., 1986b
Agricultural sprayers 19 1.5 (0.7–3.3)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
New Zealand National Cancer Registry (1977–1981) (≥ 20 yrs of age) with agricultural occupations—incidence (ICD-9 200 and 202) nr Herbicides

1.4 (0.9–2.0)
Pearce et al., 1985
Sweden—male, female subjects (18–74 yrs of age) with NHL living in Sweden between Dec 1, 1999, and April 30, 2002 vs controls from national population registry   Pesticides, herbicides Eriksson et al., 2008
Herbicides, total 74 1.7 (1.2–2.5)  
≤ 20 days 36 1.6 (1.0–2.7)  
> 20 days 38 1.9 (1.1–3.2)  
Phenoxyacetic acids 47 2.0 (1.2–3.4)  
≤ 45 days 32 2.8 (1.5–5.5)  
> 45 days 15 1.3 (0.6–2.7)  
MCPA 21 2.8 (1.3–6.2)  
≤ 32 days 15 3.8 (1.4–10.5)  
> 32 days 6 1.7 (0.5–6.0)  
2,4,5-T, 2,4-D 33 1.6 (0.9–3.0)  
≤ 29 days 21 2.1 (1.0–4.4)  
> 29 days 12 1.3 (0.6–3.1)  
Sweden—male and female patients (18–74 yrs of age) diagnosed Dec 1999–April 2002   Pesticides, herbicides Hardell et al., 2002
Chlorophenols      
NHL—high grade malignancy 61 2.0 (1.3–2.9)  
Sweden—pooled analysis of case-control NHL, hairy-cell leukemia studies   Herbicides Hardell et al., 2002
Herbicide exposure 77 1.8 (1.3–2.4)  
Phenoxyacetic acids 64 1.7 (1.2–2.3)  
MCPA 21 2.6 (1.4–4.9)  
2,4-D, 2,4,5-T 48 1.5 (1.0–2.2)  
Other 15 2.9 (1.3–6.4)  
Substantial exposure 5 1.8 (0.4–7.4)  
Sweden—adipose tissue from 33 NHL patients and 39 surgical controls from Örebro-Uppsala medical region (1994–1997)   Dioxin, dibenzofurans Hardell et al., 2001
TEQ > 27.8, EA > 80 8 2.8 (0.5–18.0)  
Umea (Sweden) Hospital patients—incidence   Phenoxy herbicides, chlorophenols Hardell et al., 1994
Exposed to phenoxy herbicides 25 5.5 (2.7–11.0)  
Exposed to chlorophenols 35 4.8 (2.7–8.8)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Swedish Regional Cancer Registry—NHL patients   Phenoxy herbicides Persson et al., 1993
Exposed to phenoxy herbicides 10 2.3 (0.7–7.2)  
Exposed to chlorophenols 9 6.0 (1.1–31.0)  
Örebro (Sweden) Hospital (men and women)—incidence   Phenoxy herbicides, chlorophenols Persson et al., 1989
Exposed to phenoxy acids 6 4.9 (1.0–27.0)  
Lund (Sweden) Hospital patients—incidence   Herbicides Olsson and Brandt, 1988
Exposed to herbicides nr 1.3 (0.8–2.1)
Exposed to chlorophenols nr 1.2 (0.7–2.0)  
Swedish patients (1970–1977)   Phenoxy acids, chlorophenols Hardell, 1981
Exposed to phenoxy herbicides 41 4.8 (2.9–8.1)  
Exposed to chlorophenols 50 4.3 (2.7–6.9)  
CASE-CONTROL STUDIES
Participants in the EPILYMPH study in six European countries (1998–2003)   Pesticides Cocco et al., 2012
Exposure to phenoxy herbicides and CLL 2 0.9 (0.2–4.1)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; ACC, Army Chemical Corps; CA, California; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; CLL, chronic lymphocytic leukemia; COI, chemical of interest; dl, dioxin-like; EA, early antigen; EOI, Exposure Opportunity Index; HD, Hodgkin disease; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; ICDA, International Classification of Diseases, Adapted for Use in the United States; JEM, job–exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; MOS, military occupation specialty; NCI, National Cancer Institute; NHL, non-Hodgkin lymphoma; NIOSH, National Institute for Occupational Safety and Health; NKTCL, NK/T-cell lymphoma; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCDF, polychlorinated dibenzofuran; PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; PM, proportionate mortality; SEA, Southeast Asia; SEER, Surveillance, Epidemiology, and End Results; SIR, standardized incidence ratio; SMR, standardized mortality rate; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; TEQ, toxicity equivalent; USDA, United States Department of Agriculture; VA, US Department of Veterans Affairs; WHO, World Health Organization.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

cLymphopoietic cancers comprise all of forms of lymphoma (including Hodgkin disease and non-Hodgkin lymphoma) and leukemia (ALL, AML, CLL, CML).

dCommittee computed total SMR and SIR by dividing sum of observed values by sum of expected values over all years; 95% CIs on these total ratios were computed with exact methods.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-42 Selected Epidemiologic Studies—Chronic Lymphocytic Leukemia (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
International Vietnam-Veteran Study
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 58 1.2 (0.7–1.7) ADVA, 2005b
Navy 12 1.5 (0.8–2.6)  
Army 42 1.7 (1.2–2.2)  
Air Force 4 0.9 (0.2–2.2)  
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
CANADA
Sawmill Workers in British Columbia—23,829 workers for ≥ 1 yr at 11 mills using chlorophenates 1940–1985   Chlorophenates, not TCDD  
Incidence—all leukemias (1969–1989) 47 1.2 (0.9–1.5) Hertzman et al., 1997
ALL 2 1.0 (0.2–3.1)  
CLL 24 1.7 (1.2–2.4)  
AML 5 0.8 (0.3–1.7)  
CML 7 1.1 (0.5–2.0)  
Other, unspecified 5 0.5 (0.2–1.0)  
DENMARK
Danish gardeners—incidence from 3,156 male and 859 female gardeners   Herbicides Hansen et al., 1992, 2007
10-year follow-up (1975–1984) of Danish gardeners      
All gardeners 6 2.5 (0.9–5.5)  
Male gardeners 6 2.8 (1.0–6.0)  
UNITED STATES
White Male Residents of Iowa—chronic lymphocytic leukemia on death certificate, usual occupation: farmers vs not   Herbicides  
> 30 yrs old when died 1964–1978—case-control (1,675 leukemia deaths, 1968–1978)     Burmeister et al., 1982
Farmer usual occupation on death certificate   1.2 (p < 0.05))  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
CLL 132 1.7 (1.2–2.4)  
Lived in counties with highest nr 1.9 (1.2–3.1)  
herbicide use      
White Male Residents of Iowa and Minnesota— > 30 yrs old diagnosed 1981–1983 in Iowa or 1980–1982 in Minnesota—case-control   Herbicides  
> 30 yrs old diagnosed 1981–1983 in Iowa or 1980–1982 in Minnesota—case-control (ever farmer)     Brown et al., 1990
Ever farmed 156 1.4 (1.1–1.9)  
Any herbicide used 74 1.4 (1.0–2.0)  
Ever used 2,4,5-T 10 1.6 (0.7–3.4)  
Use at least 20 yrs before interview 7 3.3 (1.2–8.7)  
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Incidence
20-yr follow-up to 1996—men and women (lymphatic leukemia, ICD-9 204)      
Zone A 1 2.8 (0.4–19.9) Pesatori et al., 2009
Zone B 0 nr
Zone R 13 0.8 (0.5–1.5)  
Mortality      
25-yr follow-up to 2001—men and women (lymphatic leukemia, ICD-9 204)     Consonni et al., 2008
Zone A 0 nr  
Zone B 3 1.3 (0.4–4.1)  
Zone R 23 1.4 (0.9–2.2)  
20-yr follow-up to 1996 (lymphatic leukemia)     Bertazzi et al., 2001
Zones A, B—men 2 1.6 (0.4–6.8)
Zones A, B—women 0 nr  
Other International Environmental Studies
NEW ZEALAND
Residents of New Plymouth Territorial Authority, New Zealand near plant manufacturing 2,4,5-T in 1962–1987   2,4,5-T Read et al., 2007
Incidence 104 1.3 (1.1–1.6)c  
1970–1974 16 2.5 (1.4–4.1)  
1975–1979 7 0.9 (0.4–1.8)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
1980–1984 21 2.6 (1.6–3.9)  
1985–1989 16 1.4 (0.8–2.3)  
1990–1994 13 0.9 (0.5–1.6)  
1995–1999 19 0.9 (0.5–1.4)  
2000–2001 12 1.1 (0.6–1.9)  
Mortality 40 1.3 (0.9–1.8)c  
1970–1974 7 1.7 (0.7–3.5)  
1975–1979 7 1.8 (0.7–3.6)  
1980–1984 6 1.4 (0.5–3.0)  
1985–1989 4 0.8 (0.2–2.2)  
1990–1994 6 1.1 (0.4–2.5)  
1995–1999 8 1.3 (0.6–2.6)  
2000–2001 2 0.8 (0.1–2.8)  
CASE-CONTROL STUDIES
US Case-Control Studies
Tecumseh, Michigan residents participating in longitudinal study (1959–1987) 10 Herbicides 1.8 (0.8–3.2) Waterhouse et al., 1996
Nebraska—1,084 leukemia deaths in 1957–1974; farmers–usual occupation on death certificate nr Herbicides, pesticides 1.3 (p < 0.05) Blair and White, 1985
248 CLL cases nr 1.7 (p < 0.05)  
International Case-Control Studies
Europe—Participants in the EPILYMPH study in six European countries (1998–2003)   Pesticides Cocco et al., 2012
Exposure to phenoxy herbicides and CLL 2 0.9 (0.2–4.1)  
France hospital-based case-control study   Herbicides Orsi et al., 2009
Occupational use of herbicides 5 0.5 (0.2–1.3)
Phenoxy herbicides 3 0.4 (0.1–1.7)  
German population-based study (1986–1998), men and women, 15–75 yrs of age—occupational factors associated with CLL   TCDD, Herbicides Richardson et al., 2008
Chlorophenols 44 0.9 (0.6–1.3)  
Lowest tertile cumulative exposure 12 0.9 (0.4–1.8)  
Middle tertile 15 0.9 (0.5–1.8)  
Highest tertile 17 0.9 (0.5–1.6)  
    p-trend = 0.770  
Herbicides 43 1.2 (0.8–1.7)  
Lowest tertile cumulative exposure 13 1.3 (0.7–2.7)  
Middle tertile 15 1.3 (0.7–2.5)  
Highest tertile 15 1.0 (0.5–1.9)  
    p-trend = 0.755  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Italian farming, animal-breeding workers (men and women)—incidence 15 Herbicides 2.3 (0.9–5.8) Amadori et al., 1995
Farming workers only 5 1.6 (0.5–5.2)  
Breeding workers only 10 3.1 (1.1–8.3)  

NOTE: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; CI, confidence interval; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; COI, chemical of interest; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; nr, not reported; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

cThe total SMR/SIR were computed by dividing sum of observed values by sum of expected values over all years; 95% CIs on these total ratios were computed with exact methods.

pesticide exposures, and no significant association was observed between any kind of pesticide or herbicide use and lymphomas or its subtypes, including between exposure to phenoxy acid and CLL (OR = 0.9, 95% CI 0.2–4.1).

Pronk et al. (2013) conducted a population-based case-control study of NHL in four NCI SEER Centers (Detroit, Iowa, Los Angeles, and Seattle) from 1998 to 2000. They used residential history from 15 years prior to diagnoses to link residence to EPA databases of dioxin-emitting facilites, studying 969 cases and 749 controls. Proximity to any dioxin-emitting facility was not associted with NHL (3km OR = 1.0, 95% CI 0.8–1.3). However despite the fact that these are relatively well-conducted studies, the lack of exposure specificity makes both of limited utility for the committee.

Environmental and Case-Control Studies The Cross Canada Study of Pesticides and Health is a population-based incident case-control study in six Canadian provinces conducted between 1991 to 1994. Men 19 years and older who had a first diagnosis of STS, NHL, multiple myeloma, or HL during these years were included and followed in mailed and telephone interviews. Pahwa et al. (2012b) used these data to examine the joint effects of asthma, allergies, or asthma and allergies and hay fever combined with pesticide exposure in the genesis of NHL. Incident NHL cases (n = 513) diagnosed between 1991 and 1994 were compared with the experience of 1,506 controls, and a stratified analysis was employed to calculate adjusted ORs in estimating effect modification. Subjects with asthma, allergies, or hay fever had non-significantly elevated risks associated with the use of phenoxy herbicides (OR = 1.49, 95% CI 0.95–2.33), MCPA

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

(4-chloro-2-methylphenoxy) acetic (OR = 2.67, 95% CI 0.90–7.93), or 2,4-D (OR = 1.36, 95% CI 0.86–2.16). The results overall were not supportive of any major effect modification by these immune conditions.

Boccolini et al. (2013) sought to examine the possible correlation between sales of pesticides and NHL mortality rates in Brazil. This ecological study included a lagged design (exposure from sales in 1985 with deaths from NHL in 1996–2005) with examinations of sales in microregions (proxies for exposure levels) of the country. The authors reported a moderate correlation of per capita pesticide sales and the SMR for NHL (r = 0.597). There was a suggestion of an increase in the correlation of sales and NHL occurrence by quartile of pesticide consumption, as well. However, the exposure is essentially unknowable, making this work of minimal use to the committee.

Finally, Salem et al. (2014) conducted a relatively small case-control study in Egypt, assessing self-reported pesticide exposure and lymphoproliferative disorders in a hospital-based retrospective study of 130 cases and 130 controls conducted in 2011–2012. In this study, exposure to pesticides was a significant risk factor (OR = 2.24, 95% CI 1.22–4.11). While this is supportive of much of the large body of evidence reviewed here, again there is no exposure specificity and the study is quite underpowered, again offering the committee little new information.

Biologic Plausibility

The diagnosis of NHL encompasses a wide variety of lymphoma subtypes. In humans, about 85 percent are of B-cell origin and 15 percent of T-cell origin. In commonly used laboratory mice, the lifetime incidence of spontaneous B-cell lymphomas is about 30 percent in females and about 10 percent in males. Although researchers seldom note the subtypes of B-cell lymphomas observed, lymphoblastic, lymphocytic, follicular, and plasma-cell lymphomas are seen in mice and are similar to the types of NHL seen in humans. Laboratory rats, however, are less prone to develop lymphomas, although Fisher 344 rats do have an increased incidence of spontaneous mononuclear-cell leukemia of non-specific origin. The lifetime incidence of leukemia is about 50 percent in male rats and about 20 percent in female rats. Neither mice nor rats develop T-cell lymphomas spontaneously at a predictable incidence, but T cell–derived tumors can be induced by exposure to some carcinogens.

Several long-term feeding studies of various strains of mice and rats have been conducted over the past 30 years to determine the effects of TCDD on cancer incidence. Few of them have shown effects of TCDD on lymphoma or leukemia incidence. The NTP (1982a) reported no increase in the overall incidence of lymphoma in female B6C3F1 mice exposed to TCDD at 0.04, 0.2, or 2.0 µg/kg per week for 104 weeks but found that histiocytic lymphomas (now considered to be equivalent to large B-cell lymphomas) were more common in

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

the high-dose group. No effects on lymphoma incidence were seen in Osborne–Mendel rats treated with TCDD at 0.01, 0.05, or 0.5 µg/kg per week. Sprague Dawley rats treated with TCDD at 0.003, 0.010, 0.022, 0.046, or 0.100 µg/kg per day showed no change in incidence of malignant lymphomas. Long-term exposure to phenoxy herbicides or cacodylic acid also has not resulted in an increased incidence of lymphomas in laboratory animals. Thus, few laboratory animal data support the biologic plausibility of promotion of NHL by TCDD or the other COIs, but it should be noted that the standard rodent models are not particularly sensitive for the detection of chemicals that cause lymphohematopoietic cancers.

In contrast, more recent studies at the cellular level indicate that activation of the AHR by TCDD inhibits apoptosis, a mechanism of cell death that controls the growth of cancer cells. Vogel et al. (2007) studied human cancer cells in tissue culture and showed that the addition of TCDD inhibited apoptosis in histiocytic-lymphoma cells, Burkitt-lymphoma cells, and NHL cell lines. The reduction in apoptosis was associated with an increase in the expression of Cox-2, C/EBP β, and Bcl-xL mRNA in the cells. Those genes code for proteins that protect cells from apoptosis. The effects of TCDD on apoptosis were blocked when an AHR antagonist or a Cox-2 inhibitor was added to the culture; this demonstrated the underlying AHR-dependent mechanism of the effects. More important, when C57Bl/10J mice were given multiple doses of TCDD over a period of 140 days, premalignant lymphoproliferation of B cells was induced before the appearance of any spontaneous lymphomas in the control mice. When the B cells were examined, they were found to manifest changes in gene expression similar to those induced by TCDD in the human cell lines, which provided support for this mechanism of lymphoma promotion by TCDD.

It is well established that AHR activation by TCDD in human breast and endocervical cell lines induces sustained high concentrations of the interleukin-6 (IL-6) cytokine, which has tumor-promoting effects in numerous tissues (Hollingshead et al., 2008). IL-6 plays a roll in B-cell maturation and induces a transcriptional inflammatory response. It is known to be increased in B-cell neoplasms, including multiple myeloma and various lymphomas, especially diffuse large B-cell lymphomas (Hussein et al., 2002; Kato et al., 1998; Kovacs, 2006).

An alternative link that could help to explain the association between TCDD and NHL has been explored in human studies. Chromosomal rearrangements, with the consequent dysregulation of expression of various genes, are prevalent in B-cell lymphomas, and the t(14;18) reciprocal translocation, which juxtaposes the BCL2 with the locus of the immunoglobin heavy chain, is found in tumor cells in most cases of follicular lymphoma. Roulland et al. (2004) investigated the prevalence of the t(14;18) translocation that is characteristic of most cases of follicular lymphoma in 53 never-smoking and pesticide-using men in a cohort of French farmers whose pesticide exposures and confounding information had previously been well characterized; blood samples had been gathered from 21 of them during periods of high pesticide use and samples from the other 32 during

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

a period of low pesticide use. The authors found a higher prevalence of cells carrying the translocation in the farmers whose blood had been drawn during a period of high pesticide use than in those whose blood had been drawn during a low-use period. Baccarelli et al. (2006) reported an increase in t(14;18) chromosomal translocation in lymphocytes from humans who were exposed to TCDD in the Seveso accident. In most cases of follicular lymphoma, tumor cells carry the t(14;18) chromosomal translocation, and there is evidence that an increased frequency of lymphocytes from the peripheral blood carrying this tumor marker may be a necessary but not sufficient step toward development of follicular lymphoma (Roulland et al., 2006).

More recently, Saberi Hosnijeh et al. (2011, 2012a,b, 2013a,b) have published a series of papers examining factors associated with immune regulations and possibly related to B-cell neoplasms and serum TCDD levels in Dutch production workers from a subcohort of the IARC study sample. The mortality status of the entire subcohort was updated and blood samples were gathered in 2007–2008 from a small number of survivors (Boers et al., 2010)—45 who had TCDD exposure in factory A, 39 whose jobs in factory A did not expose them to TCDD, and 69 in factory B that produced phenoxy herbicides not subject to TCDD contamination. Boers et al. (2012) modeled the resulting contemporary TCDD serum levels to back extrapolated TCDD concentrations at the end of employment for each worker. When examining immunoglobulin (IgG, IgA, IgM, IgD, and IgE) and complement (C3 and C4) concentrations measures of humoral immunity, Saberi Hosnijeh et al. (2011) found a consistent pattern only for C4, which was negatively associated with both measured current and estimated maximum TCDD serum concentrations. Limiting the analyses to workers from Factory A and examining serum concentrations of 16 cytokines, 10 chemokines, and 6 growth factors, Saberi Hosnijeh et al. (2012a) found most analytes were negatively associated with current and estimated past maximum TCDD levels. Saberi Hosnijeh et al. (2012b) found that for both cell counts and lymphocytes, results were similar between high- and low-exposed workers from Factory A, except for a non-dose-dependent increase in the CD4/CD8 ratio among the high-exposed workers. Most lymphocyte subsets, in particular the B-cell compartment, showed decreases with higher levels of both current and estimated maximum levels of TCDD. Saberi Hosnijeh et al. (2013a) addressed plasma levels of CD27, CD30, and IL1RA, which are proteins that regulate immune function and thought to be involved in lymphopoeitic neoplasms, and found a tendency toward decreased levels with increasing TCDD concentrations, which would be consistent with immune suppression. Similarly, Saberi Hosnijeh et al. (2013b) investigated the possibility of a relationship between TCDD levels and serum metabolites, but found no notable patterns. Overall, this set of findings in a group of workers with an elevated incidence of NHL at its most recent mortality update provides some insight into the biological processes, particularly immunological ones, that TCDD might stimulate on the path to this malignancy.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Synthesis

The first VAO committee found the evidence to be sufficient to support an association between exposure to at least one of the COIs and NHL. The evidence was drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. As has generally been the case in previous updates, the new studies of NHL incidence and mortality that were reviewed in this update (McBride et al., 2013; Pahwa et al., 2012; Yi and Ohrr, 2014; Yi et al., 2014b) were largely concordant with the conclusion that there is an association with the COIs, as were the new analyses of various biomarkers of immune function and TCDD serum levels in workers from the Dutch IARC subcohort (Saberi Hosnijeh et al., 2012b, 2013a,b).

Individual findings on CLL are fairly few compared with the considerable number of studies supporting an association between exposure to the COIs and NHL. Results of some high-quality studies show that exposure to 2,4-D and 2,4,5-T appears to be associated with CLL, including the incidence study of Australian veterans (ADVA, 2005a), the case-control study by Hertzman et al. (1997) of British Columbia sawmill workers who were exposed to chlorophenates, the Danish-gardener study (Hansen et al., 1992), and the population-based case-control study in two US states by Brown et al. (1990) that showed increased risks associated with any herbicide use and specifically the use of 2,4,5-T for at least 20 years before the interview. Other studies that showed positive associations but do not contribute greatly to the overall conclusion include the population-based case-control study by Amadori et al. (1995) that used occupational titles but did not include specific assessments of exposure to the chemicals; the cancer-incidence study in Tecumseh County, Michigan, in which no exposure assessments were available (Waterhouse et al., 1996); and proportionate-mortality studies by Blair and White (1985) and Burmeister et al. (1982).

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is sufficient evidence of an association between exposure to at least one of the COIs and NHL.

Multiple Myeloma

Multiple myeloma (ICD-9 203.0) is characterized by a proliferation of bone-marrow stem cells that results in an excess of neoplastic plasma cells and in the production of excess abnormal proteins, usually fragments of immunoglobulins. Multiple myeloma is sometimes grouped with other immunoproliferative neoplasms (ICD-9 203.8). ACS estimated that 14,090 men and 12,760 women would receive diagnoses of multiple myeloma in the United States in 2015 and that

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

6,240 men and 5,000 women would die from it (Siegel et al., 2015). The average annual incidence of multiple myeloma is shown in Table 8-43.

The incidence of multiple myeloma is highly age-dependent and is relatively low in people under 40 years old. The incidence is slightly higher in men than in women, and the difference becomes more pronounced with age.

An increased incidence of multiple myeloma has been observed in several occupational groups, including farmers and other agricultural workers and those with workplace exposure to paint strippers, petroleum, and certain metals, minerals, and chemical substances (Sergentanis et al., 2015). People who have high exposure to ionizing radiation and those who suffer from other plasma-cell diseases, such as monoclonal gammopathy of unknown significance or solitary plasmacytoma, are also at greater risk (Sergentanis et al., 2015).

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to the COIs and multiple myeloma. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, Update 2010, and Update 2012 did not change that conclusion.

Table 8-44 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran and Environmental Studies McBride and colleagues (2013) followed 2,783 male veterans from New Zealand, who served in Vietnam between 1964 and 1972, for cancer incidence and mortality. Standardized incidence and mortality ratios were generated by comparing the observed incident cases and deaths in this cohort with the corresponding expected numbers of new cases and deaths rates from the general male population of New Zealand. The researchers reported a non-significant excess of deaths from multiple myeloma (SMR = 1.58, 95% CI 0.51–3.69), based upon five deaths. Consistent with this, they also report

TABLE 8-43 Average Annual Incidence (per 100,000) of Multiple Myeloma in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Men 19.5 18.1 39.4 29.2 26.9 60.9 41.7 39.1 79.8
Women 13.1 10.9 32.7 19.6 17.6 41.7 24.9 22.1 53.1

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-44 Selected Epidemiologic Studies—Multiple Myeloma (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)   All COIs  
Incidence
Through 1999—White subjects vs national rates     Akhtar et al., 2004
Ranch Hand veterans (n = 1,189) 10 0.9 (0.4–1.5)
With tours between 1966–1970 7 0.7 (0.3–1.4)  
SEA comparison veterans (n = 1,776) 9 0.6 (0.3–1.0)  
With tours between 1966–1970 4 0.3 (0.1–0.8)  
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Mortality     Boehmer et al., 2004
1965–2000 1 0.4 (nr)
US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973   All COIs  
1965–1988     Watanabe and Kang, 1996
Army, deployed (n = 27,596) vs non-deployed (n = 31,757) 36 0.9 (nr)
Marine Corps, deployed (n = 6,237) vs non-deployed (n = 5,040) 4 0.6 (nr)  
1965–1982     Breslin et al., 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 18 0.8 (0.2–2.5)
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 2 0.5 (0.0–17.1)  
US VA Cohort of Female Vietnam Veterans   All COIs  
Mortality, through 2004 18 0.7 (0.4–1.3) Cypel and Kang, 2008
Vietnam-veteran nurses only 14 0.7 (0.3–1.3)
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 31 0.7 (0.4–0.9) ADVA, 2005b
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Navy 4 0.4 (0.1–1.0)  
Army 21 0.7 (0.4–1.0)  
Air Force 6 1.1 (0.4–2.4)  
Mortality
All branches, return–2001 24 0.9 (0.5–1.2) ADVA, 2005a
Navy 3 0.5 (0.1–1.5)  
Army 15 0.8 (0.4–1.3)  
Air Force 6 1.7 (0.6–3.6)  
1980–1994 6 0.6 (0.2–1.3) CDVA, 1997a
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence
1982–2000 8 2.1 (0.7–6.0) ADVA, 2005c
Mortality
1966–2001 5 0.9 (0.2–3.4) ADVA, 2005c
1982–1994 0 nr CDVA, 1997b
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008) 9 1.5 (0.7–2.9)  
Mortality (1988–2008) 5 1.6 (0.5–3.7)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—MM (90) categorized high (n = 28) vs low (n = 23) 28 1.1 (0.7–2.0) Yi and Ohrr, 2014
Mortality (1992–2005)—MM (90) categorized high (n = 19) vs low (n = 20)   0.8 (0.4–1.5) Yi et al., 2014b
HR per unit of log EOI scores (n = 180,639) 39 1.0 (0.9–1.1)  
OCCUPATIONAL—Industrial IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality 1939–1992 17 1.3 (0.8–2.1) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 9 1.2 (0.6–2.3)
7,553 not exposed to highly chlorinated PCDDs 8 1.6 (0.7–3.1)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort 4 0.7 (0.2–1.8) Saracci et al., 1991
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)   Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP  
Incidence 1943–1987 (men only) 0 nr Lynge, 1993
Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)   Dioxins, 2,4,5-T, 2,4,5-TCP  
Mortality 1955–1991 0 0.0 (nr) Hooiveld et al., 1998
German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 mo in 1951–1976) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4,5-TCP  
Mortality 1951–1992 0 nr Becher et al., 1996
German Production Workers at Bayer Plant in Dormagen (520 men working > 1 mo in 1965–1989) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4-DP; 2,4,5-T; MCPA; MCPP  
Mortality 1965–1989 0 nr Becher et al., 1996
German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 mo in 1957–1987) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4-DP; 2,4,5-T; MCPA; MCPP  
Mortality 1956–1989 0 nr Becher et al., 1996
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)   Dioxins; 2,5-DCP; 2,4,5-T; 2,4,5-TCP  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality 1952–1989 3 5.4 (1.1–15.9) Becher et al., 1996
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004     McBride et al., 2009a
Ever-exposed workers 2 2.2 (0.2–8.1)
Never-exposed workers 0 0.0 (0.0–12.2)  
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)     ’t Mannetje et al., 2005
Mortality 1969–2000 3 5.5 (1.1–16.1)  
Sprayers (697 men and 2 women on register of New Zealand applicators, 1973–1984)      
Mortality 1973–2000 0 0.0 (0.0–5.3)  
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Through 1993 10 2.1 (1.0–3.8) Steenland et al., 1999
Through 1987 5 1.6 (0.5–3.9) Fingerhut et al., 1991
≥ 1-yr exposure, ≥ 20-yr latency 3 2.6 (0.5–7.7)
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
1940–2005 (n = 2,122) 7 1.5 (0.6–3.1)  
PCP and TCP (n = 720) 1 0.7 (0.0–4.0)  
PCP (no TCP) (n = 1,402) 6 1.8 (0.7–4.0)  
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (subset of all TCP-exposed workers)   2,4-D, lower chlorinated dioxins  
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3) 2 0.8 (0.1–2.9) Burns CJ et al., 2011
Through 1994 (n = 1,517) 1 0.8 (0.0–4.5) Burns et al., 2001
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
OCCUPATIONAL—Paper And Pulp Workers   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Never 21 0.8 (0.5–1.3)  
Ever 20 1.1 (0.7–1.7)  
OCCUPATIONAL—Herbicide-Using Workers (not related to IARC sprayer cohorts)      
CANADA
Canadian Farm Operator Study—156,242 men farming in Manitoba, Saskatchewan, and Alberta in 1971; mortality from MM June 1971–Dec 1987      
Farmers from Canadian prairie provinces 160 0.8 (0.7–1.0) Semenciw et al., 1994
DENMARK
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 2000 3 2.1 (0.4–6.1) Swaen et al., 2004
Through 1987 3 8.2 (1.6–23.8) Swaen et al., 1992
FINNISH Phenoxy Herbicide Sprayers (1,909 men working 1955–1971 ≥ 2 wks) not IARC   Phenoxy herbicides  
Incidence 2 1.5 (0.2–5.2) Asp et al., 1994
Mortality 1972–1989 3 2.6 (0.5–7.7)  
Except for lung cancer, #s too small for reporting mortality 1972–1980   Expected number of exposed cases Riihimaki et al., 1982
  1 0.2 (nr)  
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401) 5 0.4 (0.1–1.0) Torchio et al., 1994
Italian rice growers with documented phenoxy use (n = 1,487)   Phenoxy herbicides Gambini et al., 1997
  0 nr  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of incident multiple myeloma cancer cases vs remainder of 19,904 men with any incident cancer   Herbicides Reif et al., 1989
Forestry workers (n = 134) 1 0.5 (0.1–3.7)  
SWEDISH lumberjacks—Used phenoxys 1954–1967, incidence (1958–1992)     Thörn et al., 2000
Exposed (n = 154)
Foremen (n = 15) 0    
Lumberjacks (n = 139) 0    
Unexposed lumberjacks (n = 241) 1 1.5 (0.0–8.6)  
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Men
Whites (n = 119,648) 413 1.2 (1.0–1.3)  
Nonwhites (n = 11,446) 51 0.9 (0.7–1.2)  
Women
Whites (n = 2,400) 14 1.8 (0.97–3.0)  
Nonwhites (n = 2,066) 11 1.1 (0.6–2.0)  
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Private applicators 71 1.2 (0.9–1.5)  
Commercial applicators 1 nr  
Spouses 21 0.9 (0.6–1.4)  
Nested case-control study of MGUS among male private and commercial applicators     Landgren et al., 2009
2,4-D 33 1.8 (0.7–4.8)  
Dicamba 17 0.9 (0.5–1.8)  
Enrollment through 2002     Alavanja et al., 2005
Private applicators 43 1.3 (1.0–1.8)
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Spouses of private applicators (> 99% women) 13 1.1 (0.6–1.9)  
Commercial applicators 0 0.0 (0.0–2.7)  
Mortality
Enrollment through 2007, vs state rates     Waggoner et al., 2011
Applicators (n = 1,641) 52 1.0 (0.8–1.3)
Spouses (n = 676) 10 0.6 (0.3–1.0)  
Enrollment through 2000, vs state rates     Blair et al., 2005a
Private applicators (men and women) 11 0.6 (0.3–1.2)
Spouses of private applicators (> 99% women) 5 0.9 (0.3–2.1)  
US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 of MM   Herbicides  
Forest conservationists 1.3 nr (p-trend = 0.35) Alavanja et al., 1989
Soil conservationists 1.3 nr (p-trend = 0.32)  
White Male Residents of Iowa—MM on death certificate, usual occupation: farmers vs not   Herbicides  
> 30 yrs old diagnosed 1981–1984—case-control (ever farmer) 111 1.2 (0.8–1.7) Brown et al., 1993
> 30 yrs old when died 1964–1978—case-control     Burmeister et al., 1983
H0: only for “modern methods” → born after 1900      
Born 1980–1900 nr 2.7 (p < 0.05)  
Born after 1900 nr 2.4 (p < 0.05)  
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Incidence
20-yr follow-up to 1996—men and women
Zone A 1 2.9 (0.4–20.7) Pesatori et al., 2009
Zone B 6 2.8 (1.2–6.3)
Zone R 18 1.2 (0.7–1.9)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
10-yr follow-up to 1991—men     Bertazzi et al., 1993
Zone B 2 3.2 (0.8–13.3)
Zone R 1 0.2 (0.0–1.6)  
10-yr follow-up to 1991—women     Bertazzi et al., 1993
Zone B 2 5.3 (1.2–22.6)
Zone R 2 0.6 (0.2–2.8)  
Mortality
25-yr follow-up to 2001—men and women     Consonni et al., 2008
Zone A 2 4.3 (1.1–17.5)  
Zone B 5 1.7 (0.7–4.1)  
Zone R 24 1.1 (0.7–1.7)  
20-yr follow-up to 1996     Bertazzi et al., 2001
Zones A, B—men 1 0.6 (0.1–4.3)
Zones A, B—women 4 3.2 (1.2–8.8)  
15-yr follow-up to 1991—men     Bertazzi et al., 1997
Zone B 1 1.1 (0.0–6.2)
Zone R 5 0.8 (0.3–1.9)  
15-yr follow-up to 1991—women     Bertazzi et al., 1997
Zone B 4 6.6 (1.8–16.8)
Zone R 5 1.0 (0.3–2.3)  
CASE-CONTROL STUDIES      
US Case-Control Studies      
ACS Prevention Study II subjects, MM on   Herbicides, Boffetta et al., 1989
death certificate (128 MM cases vs 154 controls)   pesticides
  12 2.1 (1.0–4.2)  
Farmers using herbicides, pesticides 8 4.3 (1.7–10.9)  
Residents of four SEER program areas, 698 cases (< 80 yrs of age) vs 1,683 controls (July 1977–June 1981) nr Pesticides 2.9 (1.5–5.5) Morris et al., 1986
Nebraska herbicide and pesticide use by Nebraska residents   Herbicides Zahm et al., 1992
Eastern Nebraska users of herbicides
Men 8 0.6 (0.2–1.7)  
Women 10 2.3 (0.8–7.0)  
Eastern Nebraska users of insecticides
Men 11 0.6 (0.2–1.4)  
Women 21 2.8 (1.1–7.3)  
Wisconsin mortality listings (1968–1976)—farmers (30–39 yrs of age) in counties with highest herbicide use nr Herbicides 1.4 (0.8–2.3) Cantor and Blair, 1984
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
International Case-Control Studies
Cross Canada Study of Pesticides and Health—men in 1 of 6 Canadian provinces (> 19 yrs of age) diagnosed 09/1991–12/1994 (n = 342) vs population-based matched controls (n = 1,506)   Phenoxy herbicides Kachuri et al., 2013; Pahwa et al., 2006, 2012a,b
Expose to any phenoxy herbicide 87 1.3 (1.0–1.8)  
2,4-D 80 1.3 (1.0–1.8)  
Mecoprop 27 1.9 (1.2–3.2)  
MCPA 8 0.7 (0.3–1.5)  
Days/year of mixing or applying phenoxy herbicides      
> 0 and ≤ 2 35 1.5 (1.0–2.3)  
> 2 and ≤ 5 23 1.3 (0.8–2.8)  
> 5 26 1.1 (0.7–1.9)  
France hospital-based case-control study   Herbicides Orsi et al., 2009
Occupational use of herbicides 12 2.9 (1.3–6.5)  
Phenoxy herbicides 7 2.6 (0.9–7.0)  
Domestic use of herbicides 22 1.0 (0.6–2.0)  
Irish farmers and farm workers   Herbicides Dean, 1994
Other malignant neoplasms of lymphoid and histiocytic tissue (including some types of NHL) (ICD-9 202) 171 1.0 (nr)  
Italian residents of 11 areas (NHL other than lymphosarcoma and reticulosarcoma)—incidence   Herbicides Miligi et al., 2003
Herbicide exposure 11 1.6 (0.8–3.5)  
Men 8 1.4 (0.6–3.5)  
Women 3 3.2 (0.7–14.7)  
Residents of Milan, Italy, area (men and women)—incidence   Herbicides LaVecchia et al., 1989
Agricultural occupations nr 2.0 (1.1–3.5)  
New Zealand National Cancer Registry   Phenoxy Pearce et al., 1986a
(1977–1981)—agricultural workers (< 70 yrs of age) (76 MM cases vs 315 controls)—incidence   herbicides, chlorophenols  
Use of agricultural spray 16 1.3 (0.7–2.5)  
Likely sprayed 2,4,5-T 14 1.6 (0.8–3.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Swedish residents from 4 counties diagnosed with MM (n = 275) vs 275 controls from population registry (July 1982–June 1986)   Phenoxy herbicides 90% CI Eriksson and Karlsson, 1992
Exposed to phenoxy herbicides 20 2.2 (1.2–4.7)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; ACS, American Cancer Society; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; SEA, Southeast Asia; SEER, Surveillance, Epidemiology, and End Results; SIR, standardized incidence ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

a non-significant excess incidence (SIR = 1.51, 95% CI 0.69–2.86) based upon nine cases.

Mortality (Yi et al., 2014b) and cancer incidence (Yi and Ohrr, 2014) were assessed among Korean veterans who had served in Vietnam between 1964 and 1973. In analyses of cancer incidence, Yi and Ohrr (2014) reported a non-significant increased risk of multiple myeloma (HR = 1.14, 95% CI 0.65–2.01) in the internal comparison of the high- and low-exposure groups based on the EOI scores. Similarly for multiple myeloma mortality, Yi et al. (2014b) reported a decreased risk for the high- versus low-exposure groups (HR = 0.81, 95% CI 0.43–1.54) and with the individual log-transformed EOI scores (HR = 1.0, 95% CI 0.85–1.14).

Occupational and Environmental Studies Since Update 2012 there have been no new publications on occupational or environmental studies of association between multiple myeloma and exposure to the COIs.

Case-Control Studies The Cross Canada Study of Pesticides and Health is a population-based incident case-control study in six Canadian provinces conducted between 1991 and1994. Men 19 years and older who had a first diagnosis

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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of STS, NHL, multiple myeloma, or HL during these years were included and followed in mailed and telephone interviews. Kachuri et al. (2013) assessed the association of pesticide exposures in these agricultural workers, asking if lifetime use of multiple pesticides was associated with multiple myeloma risk. Studying 342 cases (58 percent of those contacted) and 1,357 controls (48 percent of those contacted), they grouped pesticides by type, chemical class, and their carcinogenic potential and estimated risk, adjusted for age, residence, medical history and smoking. An increased risk of multiple myeloma was seen with exposure to Mecoprop (OR = 1.94, 95% CI 1.19–3.19) but not with exposure to 2,4-D (OR = 1.3, 95% CI 0.95–1.78). An evaluation of days per year of mixing or applying phenoxy herbicides were non-significantly elevated for less than or equal to 2 days per year (OR = 1.47, 95% CI 0.95–2.28), between 2 and 5 days (OR = 1.33, 95% CI 0.80–2.23), and more than 5 days (OR = 1.23, 95% CI 0.75–2.02). Although more precise in its exposure characterization than many similar studies, this work was limited in its usefulness by the lack of exposure specificity.

Biologic Plausibility

No animal studies have reported an association between exposure to the COIs and multiple myeloma. Thus, there are no specific animal data to support the biologic plausibility of such an association between the COIs and multiple myeloma.

The AHR activation by TCDD in human breast and endocervical cell lines induces sustained high concentrations of the IL-6 cytokine, which has tumor-promoting effects in numerous tissues (Hollingshead et al., 2008). IL-6 plays a role in B-cell maturation and induces a transcriptional inflammatory response. It is known to be increased in B-cell neoplasms, including multiple myeloma and various lymphomas (Hussein et al., 2002; Kovacs, 2006).

In comparing the frequency of specific variants of several metabolic genes between multiple myeloma cases and controls, Gold et al. (2009) found some indication of differences, particularly in CYP1B1 and AHR alleles, that might reflect increased susceptibility to multiple myeloma after exposure to particular chemicals. A biochemical link to the COIs, however, is far from being established.

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

Previous VAO reports found limited or suggestive evidence of an association between exposure to at least one of the COIs and multiple myeloma. Multiple myeloma is a type of lymphohematopoietic malignancy that is derived from antibody-secreting plasma cells from the B-cell lineage. The evidence of an association between the COIs and lymphomas (NHL, HL, and CLL/HCL) has

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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been classified as sufficient. Most of these cancers also arise from B cells, so the committee hypothesized that it would be etiologically plausible for the association with multiple myeloma to belong with the lymphomas in the sufficient category. Although many studies of exposure to pesticides in general and multiple myeloma found strong or at least positive associations, a review of studies that addressed an association between the specific COIs and multiple myeloma found that the results were considerably weaker than those for the other B-cell neoplasms and did not justify advancing multiple myeloma out of the limited or suggestive category.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to at least one of the COIs and multiple myeloma.

AL Amyloidosis

The committee responsible for Update 2006 moved the discussion of AL amyloidosis from the chapter on miscellaneous non-neoplastic health conditions to the cancer chapter to put it closer to related neoplastic conditions, such as multiple myeloma and some types of B-cell lymphomas. The conditions share several biologic features, notably the clonal hyperproliferation of B cell–derived plasma cells and the production of abnormal amounts of immunoglobulins.

The primary feature of amyloidosis (ICD-9 277.3; ICD-10 E85) is the accumulation and deposition in various tissues of insoluble proteins that were historically denoted by the generic term amyloid. Amyloid protein accumulates in the extracellular spaces of various tissues. The pattern of organ involvement depends on the nature of the protein; some amyloid proteins are more fibrillogenic than others. Amyloidosis is classified according to the biochemical properties of the fibril-forming protein. Excessive amyloid protein can have modest clinical consequences or can produce severe, rapidly progressive multiple-organ-system dysfunction. The annual incidence is estimated at 1/100,000; there are about 2,000 new cases each year in the United States.3 Amyloidosis occurs mainly in people 50 to 70 years old and occurs more often in males than in females.

AL amyloidosis is the most common form of systemic amyloidosis; the A stands for amyloid, and the L indicates that the amyloid protein is derived from immunoglobin light chains. That links AL amyloidosis with other B-cell disorders that involve the overproduction of immunoglobin, such as multiple myeloma and some types of B-cell lymphomas. AL amyloidosis results from the overproduction of immunoglobulin light-chain protein from a monoclonal

________________

3See http://www.cancer.net/cancer-types/amyloidosis/statistics, accessed June 13, 2013.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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population of plasma cells. Clinical findings can include excessive AL protein or immunoglobulin fragments in the urine or serum, renal failure with nephrotic syndrome, liver failure with hepatomegaly, heart failure with cardiomegaly, marcroglossia, carpal tunnel syndrome, and peripheral neuropathy. Bone marrow biopsies commonly show an increased density of plasma cells, which suggests a premalignant state. Historically, that test emphasized routine histochemical analysis, but modern immunocytochemistry and flow cytometry now commonly identify monoclonal populations of plasma cells with molecular techniques. AL amyloidosis can progress rapidly and is often far advanced by the time it is diagnosed (Buxbaum, 2004).

Conclusions from VAO and Previous Updates

VA identified AL amyloidoisis as of concern after the publication of Update 1998. The committees responsible for Update 2000, Update 2002, and Update 2004 concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and AL amyloidosis. Although there are few epidemiologic data specifically on AL amyloidosis, the committee responsible for Update 2006 changed the categorization to limited or suggestive evidence of an association on the basis of commonalities in its cellular lineage with multiple myeloma and B-cell lymphomas. Later committees have not changed that categorization.

Update of the Epidemiologic Literature

Epidemiologic results for amyloidosis (E85) were reported for the first time in Vietnam veterans in the publication from the Korean Veterans Health Study (Yi et al., 2014a) on the prevalence of diseases as confirmed by insurance records, but no information on mortality from this condition was presented in Yi et al. (2014b). From the internal comparison of veterans in the category with high EOI scores (nine cases) to those in the low-potential-exposure group (six cases) with adjustment for age, rank, smoking, drinking, physical activity, domestic herbicide use, education, income, and body mass index, Yi et al. (2014a) reported a significantly elevated risk of amyloidosis (OR = 3.02, 95% CI 1.02–8.93). When regression with the same adjustments was performed on the logarithms of the individual EOI scores for the entire set of veterans, a significant relationship was again found (OR = 1.32, 95% CI 1.02–1.71).

Biologic Plausibility

A 1979 study reported the dose-dependent development of a “generalized lethal amyloidosis” in Swiss mice that were treated with TCDD for 1 year (Toth et al., 1979). That finding has not been validated in 2-year carcinogenicity studies

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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of TCDD in mice or rats, but the use of differing strains may explain the discrepancies. Thus, few animal data support an association between TCDD exposure and AL amyloidosis in humans, and no animal data support an association between the other COIs and AL amyloidosis.

It is known, however, that AL amyloidosis is associated with B-cell diseases, and 15 to 20 percent of cases of AL amyloidosis occur with multiple myeloma. Other diagnoses associated with AL amyloidosis include B-cell lymphomas (Cohen et al., 2004), monoclonal gammopathy, and agammaglobulinemia (Rajkumar et al., 2006).

Synthesis

AL amyloidosis is very rare, and previous VAO committees have noted that it was unlikely that population-based epidemiology will ever provide substantial direct evidence regarding its causation. Assignment of this condition to the “limited or suggestive” category of association has been based on the biologic and pathophysiologic features linking AL amyloidosis, multiple myeloma, and some types of B-cell lymphomas—especially the clonal hyperproliferation of plasma cells and abnormal immunoglobulin production—thus indicating that AL amyloidosis is pathophysiologically related to these conditions. Although the positive findings in the cohort of Korean Vietnam veterans was based on a small number of cases and validation of the EOI scores has not been possible, the committee was very interested to see the confirmatory information of an elevation in this condition among Korean veterans who served in Vietnam.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to the COIs and AL amyloidosis.

Leukemias

Leukemias (ICD-9 202.4, 203.1, 204.0–204.9, 205.0–205.9, 206.0–206.9, 207.0–207.2, 207.8, 208.0–208.9) have traditionally been divided into four primary types: acute and chronic lymphocytic leukemias and acute and chronic myeloid leukemias. There are numerous subtypes of AML (ICD-9 205), which is also called acute myelogenous leukemia, granulocytic leukemia, or acute nonlymphocytic leukemia.

ACS estimated that 30,900 men and 23,370 women would receive diagnoses of some form of leukemia in the United States in 2015 and that 14,210 men and 10,240 women would die from it (Siegel et al., 2015). Collectively, leukemias were expected to account for 3 percent of all new diagnoses of cancer and 4

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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percent of deaths from cancer in 2015. Different forms of leukemias have different patterns of incidence and in some cases different risk factors. The incidences of the various forms of leukemias are presented in Table 8-45.

Myeloid Leukemias

In adults, acute leukemia is nearly always in the form of AML (ICD-9 205.0, 207.0, 207.2). ACS estimated that about 12,730 men and 8,100 women would receive new diagnoses of AML in the United States in 2015 and that 6,110 men and 4,350 women would die from it (Siegel et al., 2015). Overall, AML is slightly more common in men than in women. Risk factors associated with AML include high doses of ionizing radiation, occupational exposure to benzene, and exposure to some medications used in cancer chemotherapy (such as melphalan). Fanconi anemia and Down syndrome are associated with an increased risk of AML, and tobacco use is thought to account for about 20 percent of AML cases.

Vietnam veterans have expressed concern about whether myelodysplastic syndromes, most often precursors to AML, are associated with Agent Orange exposure. However, no results on those conditions in conjunction with the COIs have been found in VAO literature searches. Epidemiologic research on those hematologic disorders has been undertaken fairly recently; for instance, the LATIN case-control study (Maluf et al., 2009) has undertaken investigation of aplastic anemia in South America, but the reported exposures have been only as specific as “herbicides” and “agricultural pesticides.”

TABLE 8-45 Average Annual Incidence (per 100,000) of Leukemias in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
All Leukemias:
Men 32.0 33.9 22.4 49.7 52.4 40.2 67.0 70.4 53.6
Women 18.5 19.2 17.7 27.2 28.6 24.0 36.9 38.8 32.2
Acute Lymphocytic Leukemia:
Men 1.3 1.4 1.1 1.7 1.9 0.9 1.6 1.6 0.6
Women 1.3 1.3 1.1 1.3 1.2 1.6 1.3 1.4 0.8
Acute Myeloid Leukemia:
Men 8.8 9.1 7.4 13.9 15.0 10.2 20.2 21.4 15.1
Women 6.3 6.4 6.1 9.0 9.5 7.4 12.5 12.5 14.0
Chronic Lymphocytic Leukemia:
Men 14.2 15.3 8.2 23.5 24.8 18.6 31.1 32.9 23.6
Women 7.4 7.8 5.8 11.4 12.2 8.5 15.6 16.8 11.4
Chronic Myeloid Leukemia:
Men 4.0 4.1 3.4 5.9 6.0 5.6 7.8 8.1 7.0
Women 2.3 2.3 3.1 3.4 3.5 4.1 4.3 4.6 3.2
All Other Leukemiab
Men 1.1 1.2 1.1 1.5 1.4 2.4 2.4 2.4 3.8
Women 0.5 0.5 0.6 1.0 1.0 1.1 1.4 1.5 1.7

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

bIncludes leukemic reticuloendotheliosis (hairy cell leukemia), plasma-cell leukemia, monocytic leukemia, and acute and chronic erythremia and erythroleukemia.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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exposure. However, no results on those conditions in conjunction with the COIs have been found in VAO literature searches. Epidemiologic research on those hematologic disorders has been undertaken fairly recently; for instance, the LATIN case-control study (Maluf et al., 2009) has undertaken investigation of aplastic anemia in South America, but the reported exposures have been only as specific as “herbicides” and “agricultural pesticides.”

The incidence of CML increases steadily with age in people older than 30 years. Its lifetime incidence is roughly equal in whites and blacks and is slightly higher in men than in women. CML accounts for about one-fifth of cases of leukemias in people in the age groups that include most Vietnam veterans. It is associated with an acquired chromosomal abnormality known as the Philadelphia chromosome, for which exposure to high doses of ionizing radiation is a known risk factor.

Lymphoid Leukemias

ALL is a disease of young children (peak incidence at the age of 2–5 years) and of people over 70 years old. It is relatively uncommon in the age groups that include most Vietnam veterans. The lifetime incidence of ALL is slightly higher in whites than in blacks and higher in men than in women. Exposure to high doses of ionizing radiation is a known risk factor for ALL, but there is little consistent evidence on other factors.

CLL shares many traits with lymphomas (such as immunohistochemistry, B-cell origin, and progression to an acute, aggressive form of NHL), so the committee now considers it in the section above on NHL, as classified in the WHO system.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and all types of leukemias. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, and Update 2010 did not change that conclusion.

The committee responsible for Update 2002, however, considered CLL separately and judged that there was sufficient evidence of an association with the herbicides used in Vietnam and CLL alone, and Update 2008 noted that HCL is closely related to CLL.

The committee responsible for Update 2006 considered AML individually but did not find evidence to suggest that its occurrence is associated with exposure to the COIs, and there is still not sufficient evidence to support such

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

an association, so AML has been retained with other non-CLL leukemias in the category of inadequate and insufficient evidence.

Table 8-46 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies After following up on cancer for incidence and mortality in 2,783 male Vietnam veterans from New Zealand, McBride et al. (2013) reported four leukemia deaths, for an SMR overall of 0.71 (95% CI 0.19–1.83). This included three non-lymphoid and one lymphoid leukemia (SMR = 0.78, 95% CI 0.16–2.28 and 0.57, 95% CI 0.01–3.16, respectively). They also reported the incidence of 21 leukemias overall, for a significantly elevated SIR of 1.64 (95% CI 1.02–2.51). There were 7 incident non-lymphoid and 14 incident lymphoid leukemias (SIR = 1.29, 95% CI 0.52–2.66 and 1.91, 95% CI 1.04–3.20, respectively), as noted above in the NHL section.

From the Korean Health Study, Yi et al. (2014b) reported 107 leukemia deaths, with 49 low-exposure deaths (HR = 1.04, 95% CI 0.95–1.14) and a high-exposure HR of 1.18 (95% CI 0.80–1.76). This included 5 ALL (low-exposure HR 0.86, 95% CI 0.57–1.28; high-exposure HR 0.66, 95% CI 0.11–4.10), 46 AML (low-exposure HR 1.02, 95% CI 0.89–1.18; high-exposure HR 1.17, 95% CI 0.64–2.15), and 15 CML deaths (low-exposure HR 1.55, 95% CI 1.06–2.27; high-exposure HR 7.91, 95% CI 1.67–37.52). There were 2 low-exposure deaths from CML and 13 high-exposure deaths, making these risk estimates quite unstable. When examined including the Stellman exposure modeling (Stellman et al., 2003; Yi and Ohrr, 2014) the adjusted HR for myeloid leukemia in the high-exposure group was 1.13 (95% CI 0.73–1.77), including 25 and 20 AML cases in the low- and high-exposure groups, respectively (HR for AML = 0.84, 95% CI 0.46–1.56). There were 6 low- and 17 high-exposure CML cases for an HR = 2.37 (95% CI 0.91–6.18).

Occupational, Environmental, and Case-Control Studies No occupational, environmental, or case-control studies of exposure to the COIs and leukemias have been published since Update 2012.

Biologic Plausibility

Leukemias are a relatively rare spontaneous neoplasm in mice, but it is less rare in some strains of rats. A small study reported that 5 of 10 male rats fed TCDD at 1 ng/kg per week for 78 weeks showed an increased incidence of various cancers, one of which was lymphocytic leukemia (Van Miller et al., 1977). Later studies of TCDD’s carcinogenicity have not shown an increased incidence of lymphocytic leukemia in mice or rats.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-46 Selected Epidemiologic Studies—Leukemias (Shaded entries are new information for this update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans
US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)   All COIs  
Incidence
Through 1999—White subjects vs national rates (lymphopoietic cancerc)     Akhtar et al., 2004
Ranch Hand veterans (n = 1,189) 10 0.9 (0.4–1.5)  
With tours between 1966–1970 7 0.7 (0.3–1.4)  
SEA comparison veterans (n = 1,776) 9 0.6 (0.3–1.0)  
With tours between 1966–1970 4 0.3 (0.1–0.8)  
Mortality
Through 1999—White subjects vs national rates (lymphopoietic cancerc)     Akhtar et al., 2004
Ranch Hand veterans (n = 1,189) 6 1.0 (0.4–2.0)  
SEA comparison veterans (n = 1,776) 5 0.6 (0.2–1.2)  
US VA Cohort of Army Chemical Corps—Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 non-deployed) serving during Vietnam era (7/1/1965–3/28/1973)   All COIs  
Mortality—Through 2005     Cypel and Kang, 2010
All lymphopoietic    
Deployed vs non-deployed 6 vs 6 1.1 (0.4–2.5)  
ACC veterans vs US men      
Vietnam cohort 6 0.5 (0.2–1.0)  
Non-Vietnam cohort 6 0.6 (0.2–1.4)  
Leukemia
Deployed vs non-deployed 2 vs 4 0.6 (0.1–3.2)  
ACC veterans vs US men
Vietnam cohort 2 0.4 (0.1–1.5)  
Non-Vietnam cohort 4 1.2 (0.3–3.0)  
Mortality—Through 2001   1.0 (0.1–3.8) Dalager and Kang, 1997
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   All COIs  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality
1965–2000 8 1.0 (0.4–2.5) Boehmer et al., 2004
US VA Cohort of Female Vietnam Veterans   All COIs  
Mortality
Through 2004 (lymphopoietic cancersc) 18 0.7 (0.4–1.3) Cypel and Kang, 2008
Vietnam–veteran nurses 14 0.7 (0.3–1.3)
State Studies of US Vietnam Veterans
Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs non-deployed 30 1.0 (0.7–1.5) Vistainer et al., 1995
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 130 1.1 (1.0–1.4) ADVA, 2005b
Lymphocytic leukemia 72 1.4 (1.1–1.7)  
Myeloid leukemia 54 1.0 (0.8–1.3)  
Navy 35 1.5 (1.0–2.0)  
Lymphocytic leukemia 14 1.3 (0.7–2.1)  
Myeloid leukemia 19 1.7 (1.0–2.6)  
Army 80 1.1 (0.8–1.3)  
Lymphocytic leukemia 50 1.4 (1.0–1.8)  
Myeloid leukemia 28 0.8 (0.5–1.1)  
Air Force 15 1.2 (0.7–2.0)  
Lymphocytic leukemia 8 1.4 (0.6–2.7)  
Myeloid leukemia 7 1.3 (0.5–2.6)  
Validation Study   Expected number of exposed cases AIHW, 1999
  27 26 (16–36)  
Men 64 26 (16–36 CDVA, 1998a
Women 1 0 (0–4) CDVA, 1998b
Mortality
All branches, return–2001 84 1.0 (0.8–1.3) ADVA, 2005c
Lymphocytic leukemia 24 1.2 (0.7–1.7)  
Myeloid leukemia 55 1.1 (0.8–1.3)  
Army 48 0.1 (0.7–1.2)  
Lymphocytic leukemia 17 1.3 (0.7–2.0)  
Myeloid leukemia 30 0.8 (0.5–1.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Air Force 14 1.6 (0.8–2.6)  
Lymphocytic leukemia 6 2.7 (1.0–5.8)  
Myeloid leukemia 8 1.3 (0.5–2.5)  
1980–1994 33 1.3 (0.8–1.7) CDVA, 1997a
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence—1982–2000 16 0.6 (0.3–1.1) ADVA, 2005c
Lymphocytic leukemia 9 0.8 (0.3–2.0)  
Myeloid leukemia 7 0.5 (0.2–1.3)  
Mortality—1966–2001 11 0.6 (0.3–1.3) ADVA, 2005c
Lymphocytic leukemia 2 0.4 (0.0–2.4)  
Myeloid leukemia 8 0.7 (0.3–1.7)  
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008)
All leukemia 21 1.6 (1.0–2.5)  
Non-lymphoid leukemia 7 1.3 (0.5–2.7)  
Lymphoid leukemia 14 1.9 (1.0–3.2)  
Mortality (1988–2008)
All leukemia 4 0.7 (0.2–1.8)  
Non-lymphoid leukemia 3 0.8 (0.2–2.3)  
Lymphoid leukemia 1 0.6 (0.0–3.2)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)     Yi and Ohrr, 2014
Lymphoid leukemia (C91) 5 vs 9 0.5 (0.2–1.4)
ALL (C91) 3 vs 5 0.5 (0.1–2.2)  
Myeloid leukemia (C92–C94) 45 vs 38 1.1 (0.7–1.8)  
AML (C92) 20 vs 25 0.8 (0.5–1.6)  
CML (C92.1) 17 vs 6 2.4 (0.9–6.2)  
Mortality (1992–2005)     Yi et al., 2014b
HR per unit of log EOI (n = 180,639)    
Leukemia (C91–C95) 107 1.0 (1.0–1.1)  
ALL (C91) 5 0.9 (0.6–1.3)  
AML (C92) 46 1.0 (0.9–1.2)  
CML (C92.1) 15 1.6 (1.1–2.3)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
High exposure vs low exposure      
Leukemia (C91–C95) 58 vs 49 1.2 (0.8–1.8)  
ALL (C91) 2 vs 3 0.7 (0.1–4.1)  
AML (C92) 24 vs 22 1.2 (0.6–2.2)  
CML (C92.1) 13 vs 2 7.9 (1.7–37.5)  
OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Mortality 1939–1992 34 1.0 (0.7–1.4) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 16 0.7 (0.4–1.2)
7,553 not exposed to highly chlorinated PCDDs 17 1.4 (0.8–2.3)  
Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort 18 1.2 (0.7–1.9) Saracci et al., 1991
Mortality, incidence of women in production (n = 699) and spraying (n = 2) compared to national death rates and cancer incidence rates (myeloid leukemia) 1 TCDD 2.0 (0.2–7.1) Kogevinas et al., 1993
Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)   Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP  
Mortality 1955–2006 9 0.9 (0.6–1.4) Boers et al., 2012
Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)   Dioxins, 2,4,5-T, 2,4,5-TCP  
Mortality 1955–2006 (HRs for lagged TCDD plasma levels) 5 0.7 (0.4–1.4) Boers et al., 2012
Mortality 1955–2006     Boers et al., 2010
LHC 11 vs 7 0.9 (0.3–2.6)
Leukemia 2 vs 3 0.3 (0.0–2.6)  
Mortality 1955–1991 1 1.0 (0.0–5.7) Hooiveld et al., 1998
Mortality 1955–1985     Bueno de Mesquita et al., 1993
Leukemia, aleukemia (ICD-8 204–207) 1 1.5 (0.0–8.2)
Myeloid leukemia (205) 1 2.9 (0.0–15.9)
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Dutch production workers in Plant B (414 men exposed during production 1965–1986; 723 unexposed) (in IARC cohort)   2,4-D; MCPA; MCPP; highly chlorinated dioxins unlikely  
Mortality 1965–2006     Boers et al., 2010
LHC 3 vs 3 1.5 (0.3–7.5)
Leukemia 2 vs 2 1.5 (0.2–10.8)  
Mortality 1965–1986     Bueno de Mesquita et al., 1993
Leukemia, aleukemia (ICD-9 204–207) 1 4.4 (0.1–24.2)
Myeloid leukemia (ICD-8 205) 1 7.7 (0.2–42.9)
German Production Workers—2,479 workers at 4 plants (in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)   Focus on TCDD  
Mortality
Through 1987   90% CI Zober et al., 1990
All cohorts (n = 247) 1 1.7 (nr)  
Cohort 3 1 5.2 (0.4–63.1)  
German Production Workers at Bayer Plant in Uerdingen (135 men working >1 mo in 1951–1976) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4,5-TCP  
Mortality 1951–1992 0 Becher et al., 1996
German Production Workers at Bayer Plant in Dormagen (520 men working > 1 mo in 1965–1989) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Mortality 1965–1989 0 Becher et al., 1996
German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 mo in 1957–1987) (in IARC cohort as of 1997) and women—no results   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP  
Mortality 1956–1989 0 Becher et al., 1996
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)   Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP  
Mortalilty 1952–1989 4 1.8 (0.5–4.7) Becher et al., 1996
New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)   Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram  
Mortality 1969–2004 (leukemia, aleukemia)     McBride et al., 2009a
Ever-exposed workers 1 0.6 (0.0–3.1)
Never-exposed workers 0 0.0 (0.0–6.0)  
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984)      
Mortality 1969–2000 0 0.0 (0.0–5.3) ’t Mannetje et al., 2005
Sprayers (697 men and 2 women registered any time 1973–1984)      
Mortality 1973–2000 1 1.2 (0.0–6.4) ’t Mannetje et al., 2005
NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
Through 1993 10 0.8 (0.4–1.5) Steenland et al., 1999
Through 1987 6 0.7 (0.2–1.5) Fingerhut et al., 1991
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (in IARC and NIOSH cohorts)   2,4,5-T; 2,4,5-TCP  
1942–2003 (n = 1,615) (leukemia, aleukemia) 13 1.9 (1.0–3.2) Collins et al., 2009b
Excluding subset with PCP exposure 2 1.9 (1.0–3.4)
1942–2003 (n = 1,615) (other lymphopoietic) 2 0.6 (0.1–2.3)  
Excluding subset with PCP exposure 2 0.7 (0.1–2.6)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
1940–2005 (n = 2,122) 9 0.9 (0.4–1.7)  
PCP and TCP (n = 720) 2 0.6 (0.1–2.2)  
PCP (no TCP) (n = 1,402) 7 1.0 (0.4–2.1)  
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP)     Collins et al., 2009c
1942–2003 (n = 773) (leukemia, aleukemia) 2 0.6 (0.1–2.0)  
Excluding subset with TCP exposure 1 0.4 (0.0–2.0)  
1942–2003 (n = 773) (other lymphopoietic) 2 1.3 (0.2–4.6)  
Excluding subset with TCP exposure 2 1.7 (0.2–6.0)  
Mortality 1940–1989 (n = 770)     Ramlow et al., 1996
0-yr latency 2 1.0 (0.1–3.6)
15-yr latency 1 nr  
Dow 2,4-D Production Workers (1945–1982 in Midland, Michigan)   2,4-D, lower chlorinated dioxins  
Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3) 5 0.9 (0.3–2.0) Burns CJ et al., 2011
Through 1994 (n = 1,517)—lymphopoietic mortality in workers with high 2,4-D exposure 4 1.3 (0.4–3.3) Burns et al., 2001
Through 1982 (n = 878) 2 3.6 (0.4–13.2) Bond et al., 1988
OCCUPATIONAL—PAPER AND PULP WORKERS   TCDD  
IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Never 49 1.0 (0.7–1.3)  
Ever 35 0.9 (0.6–1.2)  
Danish paper workers     Rix et al., 1998
Men 20 0.8 (0.5–1.2)  
Women 7 1.3 (0.5–2.7)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
OCCUPATIONAL—Herbicide-Using Workers (not related to IARC sprayer cohorts)      
CANADA
Canadian Farm Operator Study—156,242 men farming in Manitoba, Saskatchewan, and Alberta in 1971; mortality from leukemia June 1971–Dec 1987   Herbicides  
Farm operators ≥ 35 yrs of age (June 1971–Dec 1987) 357 0.9 (0.8–1.0) Semenciw et al., 1994
Lymphatic 132 0.9 (0.8–1.1)  
Myeloid 127 0.8 (0.7–0.9)  
Farm operators ≥ 35 yrs of age during study period (June 1971–Dec 1985) 138 0.9 (0.7–1.0) Wigle et al., 1990
Sawmill workers in British Columbia—23,829 workers for ≥ 1 yr at 11 mills using chlorophenates 1940–1985   Chlorophenates, not TCDD Hertzman et al., 1997
All leukemias—incidence 47 1.2 (0.9–1.5)  
ALL 2 1.0 (0.2–3.1)  
CLL 24 1.7 (1.2–2.4)  
AML 5 0.8 (0.3–1.7)  
CML 7 1.1 (0.5–2.0)  
Other, unspecified 5 0.5 (0.2–1.0)  
DENMARK
Danish gardeners—incidence from 3,156 male and 859 female gardeners (ICD-7)   Herbicides Hansen et al., 2007
25-yr follow-up (1975–2001) 42 1.1 (0.8–1.4)  
Leukemia (204) 22 1.4 (0.9–2.1)  
Born before 1915 (high exposure) 16 1.4 (0.9–2.3)  
Leukemia (204) 12 2.3 (1.3–4.1)  
Born 1915–1934 (medium exposure) 25 1.2 (0.8–1.8)  
Leukemia (204) 9 1.0 (0.5–2.0)  
Born after 1934 (low exposure) 1 0.2 (0.0–1.0)  
Leukemia (204) 1 0.5 (0.0–3.4)  
10-yr follow-up (1975–1984) reported in Hansen et al. (1992) (ICD-7) 15 1.4 (0.8–2.4)  
NHL (200, 202, 205) 6 1.7 (0.6–3.8)  
HD (201) 0 nr  
Multiple myeloma (203) 0 nr  
CLL (204.0) 6 2.8 (1.0–6.0)  
Other leukemia (204.1–204.4) 3 1.4 (0.3–4.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
10-yr follow-up (1975–1984) of male gardeners     Hansen et al., 1992
All gardeners—CLL 6 2.5 (0.9–5.5)  
Men 6 2.8 (1.0–6.0)  
All gardeners—all other types of leukemia 3 1.2 (0.3–3.6)  
Men 3 1.4 (0.3–4.2)  
Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)   Herbicides Ronco et al., 1992
Men
Self-employed 145 0.9 (nr)  
Employee 33 1.0 (nr)  
Women      
Self-employed 8 2.2 (p < 0.05)  
Employee 3 1.3 (nr)  
Family worker 27 0.9 (nr)  
Dutch Licensed Herbicide Sprayers—1,341
certified before 1980      
Through 2000 3 1.3 (0.3–3.7) Swaen et al., 2004
FINNISH Phenoxy Herbicide Sprayers (1,909 men working 1955–1971 ≥ 2 wks) not IARC   Phenoxy herbicides  
Incidence     Asp et al., 1994
Lymphatic 3 1.0 (0.2–3.0)  
Mortality 2 nr  
Lymphatic 1 0.9 (0.0–5.1)  
Myeloid 1 0.7 (0.0–3.7)  
ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974      
Mortality 1970–1986 (n = 23,401) (ICD-8 202.0–202.9) 27 0.8 (0.5–1.1) Torchio et al., 1994
Italian rice growers with documented phenoxy use (n = 1,487)   Phenoxy herbicides Gambini et al., 1997
  4 0.6 (0.2–1.6)  
NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of 571 incident pancreatic cancer cases vs remainder of 19,904 men with any incident cancer   Herbicides Reif et al., 1989
Forestry workers (n = 134) (leukemia) 4 1.0 (0.4–2.6)  
Aged 20–59 (AML) 2 2.8 (0.7–11.0)  
Aged ≥ 60 (AML) 1 1.6 (0.2–11.5)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Sawmill workers (n = 139)   Herbicides, chlorophenols  
Leukemia (ICD-7 204–248) 2 0.5 (0.1–2.1)  
AML (ICD-7 205.0) 1 0.9 (0.1–6.4)  
SWEDEN
Swedish lumberjacks—Used phenoxys 1954–1967, Incidence 1958–1992 0 nr Thörn et al., 2000
UNITED STATES
US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states   Herbicides PCMRs Blair et al., 1993
Men
Whites (n = 119,648) 1,072 1.3 (1.2–1.4)  
Nonwhites (n = 11,446) 55 0.9 (0.7–1.3)  
Women
Whites (n = 2,400) 24 1.5 (0.9–2.2)  
Nonwhites (n = 2,066) 8 0.9 (0.4–1.9)  
US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Incidence
Enrollment through 2006—SIRs for participants     Koutros et al., 2010a
Private applicators 133 1.0 (0.8–1.1)
Commercial applicators 7 0.9 (0.4–1.9)  
Spouses 37 0.8 (0.6–1.1)  
Enrollment through 2002     Alavanja et al., 2005
Private applicators 70 0.9 (0.7–1.2)
Spouses of private applicators (> 99% women) 17 0.7 (0.4–1.2)  
Commercial applicators 4 0.9 (0.3–2.4)  
Mortality
Enrollment through 2007, vs state rates     Waggoner et al., 2011
Applicators (n = 1,641) 91 0.9 (0.7–1.0)
Spouses (n = 676) 33 1.1 (0.8–1.5)  
Enrollment through 2000, vs state rates     Blair et al., 2005a
Private applicators (men and women) 27 0.8 (0.5–1.1)
Spouses of private applicators (> 99% women) 14 1.4 (0.8–2.4)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
California United Farm Workers of America
Nested case-control analysis of Hispanic workers in cohort of 139,000 CA United Farm Workers     Mills et al., 2005
Ever used 2,4-D—total leukemia nr 1.0 (0.4–2.6)  
Lymphocytic leukemia nr 1.5 (0.3–6.6)  
Granulocytic (myeloid) leukemia nr 1.3 (0.3–5.4)  
US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 of NHL   Herbicides  
Agricultural extension agents 23 1.9 (1.0–3.5) Alavanja et al., 1988
Lymphatic nr 2.1 (0.7–6.4)
Trend over years worked   (p < 0.01)  
Myeloid nr 2.8 (1.1–7.2)  
Trend over years worked   (p < 0.01)  
White Male Residents of Iowa—leukemia cancer on death certificate, usual occupation: farmers vs not   Herbicides  
> 30 yrs old when died   1.2 (p < 0.05) Burmeister et al., 1983
1964–1978—case-control    
ALL 28 0.7 (0.4–1.2)  
CLL 132 1.7 (1.2–2.4)  
Lived in one of 33 counties with highest herbicide use nr 1.9 (1.2–3.1)  
Unspecified lymphatic 64 1.7 (1.0–2.7)  
AML 86 1.0 (0.8–1.5)  
CML 46 1.0 (0.7–1.7)  
Unspecified myeloid 36 0.8 (0.5–1.4)  
Acute monocytic 10 1.1 (0.4–2.6)  
Unspecified leukemia 31 1.1 (0.6–2.0)  
White Male Residents of Iowa and Minnesota— > 30 yrs old diagnosed 1981–1983 in Iowa or 1980–1982 in Minnesota (ever farmer, used herbicides) 578 Herbicides Brown et al., 1990
Ever farmed 335 1.2 (1.0–1.5)  
AML 81 1.2 (0.8–1.8)  
CML 27 1.1 (0.6–2.0)  
CLL 156 1.4 (1.1–1.9)  
ALL 7 0.9 (0.3–2.5)  
Myelodysplasias 32 0.8 (0.5–1.4)  
Any herbicide use 157 1.2 (0.9–1.6)  
AML 39 1.3 (0.8–2.0)  
CML 16 1.3 (0.7–2.6)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
CLL 74 1.4 (1.0–2.0)  
ALL 2 0.5 (0.1–2.2)  
Myelodysplasias 10 0.7 (0.3–1.5)  
Phenoxy acid use 120 1.2 (0.9–1.6)  
2,4-D use 98 1.2 (0.9–1.6)  
2,4,5-T use 22 1.3 (0.7–2.2)  
First use > 20 yrs before 11 1.8 (0.8–4.0)  
MCPA 11 1.9 (0.8–4.3)  
First use > 20 yrs before 5 2.4 (0.7–8.2)  
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9)   TCDD  
Incidence—20-yr follow-up to 1996—men and women      
Leukemia (204–208)     Pesatori et al., 2009
Zone A 2 2.2 (0.5–8.8)
Zone B 8 1.4 (0.7–2.7)  
Zone R 31 0.8 (0.5–2.1)  
Lymphatic leukemia (204)
Zone A 1 2.8 (0.4–19.9)  
Zone B 0 nr  
Zone R 13 0.8 (0.5–1.5)  
Myeloid leukemia (205)
Zone A 1 2.2 (0.3–16.0)  
Zone B 7 2.4 (1.1–5.2)  
Zone R 15 0.8 (0.4–1.3)  
Leukemia, unspecified (208)
Zone A 0 nr  
Zone B 1 2.2 (0.3–16.1)  
Zone R 2 0.6 (0.1–2.6)  
10-yr follow-up to 1991—men     Bertazzi et al., 1993
Zone B 2 1.6 (0.4–6.5)
Myeloid leukemia (205) 1 2.0 (0.3–14.6)  
Zone R 8 0.9 (0.4–1.9)  
Myeloid leukemia (205) 5 1.4 (0.5–3.8)  
10-yr follow-up to 1991—women     Bertazzi et al., 1993
Zone B 2 1.8 (0.4–7.3)
Myeloid leukemia (205) 2 3.7 (0.9–15.7)  
Zone R 3 0.4 (0.1–1.2)  
Myeloid leukemia (205) 2 0.5 (0.1–2.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality—25-yr follow-up to 2001 (men and women)      
Leukemia (204–208)     Consonni et al., 2008
Zone A 1 0.9 (0.1–6.3)
Zone B 13 1.7 (1.0–3.0)  
Zone R 51 1.0 (0.7–1.3)  
Lymphatic leukemia (204)
Zone A 0 nr  
Zone B 3 1.3 (0.4–4.1)  
Zone R 23 1.4 (0.9–2.2)  
Myeloid leukemia (205)
Zone A 1 2.1 (0.3–15.2)  
Zone B 6 2.0 (0.9–4.5)  
Zone R 16 0.7 (0.4–1.2)  
Monocytic leukemia (206) 0 nr  
Leukemia, unspecified (208)
Zone A 0 nr  
Zone B 4 2.4 (0.9–6.5)  
Zone R 10 0.8 (0.4–1.6)  
20-yr follow-up to 1996     Bertazzi et al., 2001
Zones A, B—men 9 2.1 (1.1–4.1)
Zones A, B—women 3 1.0 (0.3–3.0)  
15-yr follow-up to 1991—men     Bertazzi et al., 1998
Zone B 7 3.1 (1.4–6.7)
Zone R 12 0.8 (0.4–1.5)  
15-yr follow-up to 1991—women     Bertazzi et al., 1998
Zone B 1 0.6 (0.1–4.0)
Zone R 12 0.9 (0.5–1.6)  
Chapaevsk, Russia Residential Cohort   Dioxin Revich et al., 2001
Incidence—Crude incidence rate in 1998 vs    
Men
Regional (Samara) nr 14.6 (nr)  
National (Russia) nr 15.2 (nr)  
Women
Regional (Samara) nr 13.9 (nr)  
National (Russia) nr 10.7 (nr)  
Mortality—1995–1998 (SMR vs regional rates)
Men 11 1.5 (0.8–2.7)  
Women 15 1.5 (0.8–2.4)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Other International Environmental Studies
SWEDEN
Swedish fishermen (high consumption of fish with persistent organochlorines)   Organochlorine compounds Svensson et al., 1995a
Incidence
Lymphocytic
East coast (higher serum TEQs) 4 1.2 (0.3–3.3)  
West coast (lower serum TEQs) 16 1.3 (0.8–2.2)  
Myeloid
East coast (higher serum TEQs) 2 0.9 (0.1–3.1)  
West coast (lower serum TEQs) 6 0.5 (0.2–1.1)  
Mortality—all leukemias
East coast (higher serum TEQs) 5 1.4 (0.5–3.2)  
West coast (lower serum TEQs) 24 1.0 (0.6–1.5)  
CASE-CONTROL STUDIES
US Case-Control Studies
1,084 leukemia deaths in Nebraska in 1957–1974; farmers–usual occupation on death certificate   Herbicides, pesticides Blair and White, 1985
    1.3 (p < 0.05)  
99 ALL cases nr 1.3 (nr)  
248 CLL cases nr 1.7 (p < 0.05)  
105 unspecified lymphatic cases nr 0.9 (nr)  
235 AML cases nr 1.2 (nr)  
96 CML cases nr 1.1 (nr)  
39 unspecified myeloid cases nr 1.0 (nr)  
39 acute monocytic cases nr 1.9 (nr)  
52 acute unspecified leukemia cases nr 2.4 (nr)  
65 unspecified leukemia cases nr 1.2 (nr)  
Tecumseh, Michigan residents participating in longitudinal study (1959–1987)   Herbicides Waterhouse et al., 1996
All leukemias
Men 42 1.4 (1.0–1.9)  
Women 32 1.2 (0.9–1.8)  
CLL 10 1.4 (1.0–1.9)  
International Case-Control Studies
Italian residents of 11 areas (incidence of leukemia excluding CLL)   Herbicides Miligi et al., 2003
Exposure to phenoxy herbicides 6 2.1 (0.7–6.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Italian farming, animal-breeding workers (men and women)—incidence (CLL) 15 Herbicides 2.3 (0.9–5.8) Amadori et al., 1995
Farmers 5 1.6 (0.5–5.2)  
Breeders 10 3.1 (1.1–8.3)  

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; ACC, Army Chemical Corps; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; COI, chemical of interest; EOI, Exposure Opportunity Index; HD, Hodgkin disease; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job–exposure matrix; LHC, lymphohematopoietic cancers; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; MOS, military occupation specialty; NHL, non-Hodgkin lymphoma; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; PM, proportionate mortality; SEA, Southeast Asia; SIR, standardized incidence ratio; SMR, standardized mortality rate; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; TEQ, toxicity equivalent; VA, US Department of Veterans Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

cLymphopoietic cancers comprise all forms of lymphoma (including HL and NHL) and leukemia (ALL, AML, CLL, CML).

Two studies that used cells in tissue culture suggested that TCDD exposure does not promote leukemia. The proliferation of cultured human bone marrow stem cells (the source of leukemic cells) was not influenced by the addition of TCDD to the culture medium (van Grevenynghe et al., 2005). Likewise, Mulero-Navarro et al. (2006) reported that the AHR promoter is silenced in ALL—an effect that could lead to a reduced expression of the receptor, which binds TCDD and mediates its toxicity. No reports of animal studies have noted an increased incidence of leukemia after exposure to the phenoxy herbicides or other COIs. The AHR plays a role in hematopoetic stem cell expansion as well as in erythroid and megakaryocytic differentiation (Smith et al., 2013). In this context, information in a letter to the editor of the American Journal of Hematology from Nguyen-Khac et al. (2014) is interesting. The researchers described a chromosomal translocation found in a human acute leukemia that recombines the TEL gene with the ARNT (AhR-Aryl Receptor Nuclear Translocator) gene producing a fusion gene product. This recent functional work strongly suggests that

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

the translocation impairs the normal functions of ARNT, potentially contributing to leukemogenesis.

The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

The new epidemiologic data, which is largely null, is not coherent, and the committee continues to have concerns about the misclassification of leukemia types and finds the correspondence between the intensity of exposure and the magnitude of risk for leukemias (other than CLL) to be erratic.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and leukemias in general. An exception is the specific leukemia subtypes of chronic B-cell hematoproliferative diseases, including CLL and HCL, which are more appropriately grouped with lymphomas.

Non-Malignant Myeloid Diseases

The myelodysplastic syndromes (MDSs) are a collection of proliferative diseases (ICD-9 238.7, ICD-10 D46) that involve myeloid dysplasia. Patients often develop anemia and cytopenia caused by progressive bone marrow failure. MDSs are neither malignancies, nor necessarily fatal, but aggressive cases of MDS frequently progress to AML. On the basis of SEER program data collected from 2001 to 2003, the age-adjusted incidence of MDS in the United States was estimated to be 3.4 per 100,000 people per year, which means about 10,000 new cases per year (Sekeres, 2011). Various factors determine prognosis, and several scoring systems are used. Most involve the number of cytopenias, dependence on transfusion, cytogenetic abnormalities, and the number of blasts in the marrow. For low-risk disease, the median survival is about 7 years; for high risk, it is less than 1 year. MDS does not always progress to AML, and the incidence of progression varies with the risk category. Of cases with high-risk MDS, around 25 to 35 percent progress to AML. More people die from complications of infection or bleeding than through transformation to AML. Myeloproliferative neoplasms (ICD-9 205.1, 238.4, 289.89, 289.9; ICD-10 D47.1) are generally less serious clonal diseases of the myeloid lineage, but they may progress into MDS or AML.

Aplastic anemia (AA) (ICD-9 284, ICD-10 D60-D61) is another disease of the bone marrow in which stem cells are damaged in such a way that there are simultaneous decreases in red blood cells (anemia), white blood cells (leukopenia),

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

and platelets (thrombocytopenia)—pancytopenia. Exposures to radiation, a number of drugs, and some industrial chemicals (such as benzene) are recognized as risk factors for this condition, but it may also arise from an autoimmune disease.

Update of the Epidemiologic Literature

Vietnam Veteran Studies Cancer incidence (Yi and Ohrr, 2014) was assessed among Korean veterans who had served in Vietnam between 1964 and 1973. Researchers reported a non-significant increased risk of MDS (HR = 1.46, 95% CI 0.24–8.86) in the internal comparison of the high- and low-exposure groups, based on the EOI scores.

Occupational, Environmental, and Case-Control Studies There were no case-control, environmental, or occupational studies with adequate exposure specificity to contribute to the committee’s work since Update 2012.

Biologic Plausibility

Singh et al. (2014) have explored the relationship of the absence of the AHR locus and changes in hematopoetic stem cells (HSCs) associated with aging. They followed AHR-null mice, showing that they have diminished survival, splenomegaly, leukocytosis, and anemia. The HSCs showed diminished self-renewal capacity with somatic changes in the HSCs compatible with a profile of accelerated aging and HSC exhaustion.

Synthesis

There are minimal data with which to assess the role that specific COIs may play in the occurrence of the various nonmalignant bone marrow–derived diseases.

Conclusion

On the basis of the available tangential information, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and nonmalignant myeloid diseases.

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From 1962 to 1971, the US military sprayed herbicides over Vietnam to strip the thick jungle canopy that could conceal opposition forces, to destroy crops that those forces might depend on, and to clear tall grasses and bushes from the perimeters of US base camps and outlying fire-support bases. Mixtures of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid made up the bulk of the herbicides sprayed. The main chemical mixture sprayed was Agent Orange, a 50:50 mixture of 2,4-D and 2,4,5-T. At the time of the spraying, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic form of dioxin, was an unintended contaminant generated during the production of 2,4,5-T and so was present in Agent Orange and some other formulations sprayed in Vietnam.

Because of complaints from returning Vietnam veterans about their own health and that of their children combined with emerging toxicologic evidence of adverse effects of phenoxy herbicides and TCDD, the National Academy of Sciences was asked to perform a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and the various components of those herbicides, including TCDD. Updated evaluations were conducted every two years to review newly available literature and draw conclusions from the overall evidence. Veterans and Agent Orange: Update 2014 is a cumulative report of the series thus far.

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