Veterans and Agent Orange Update 11 (2018) (2018) / Chapter Skim
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7 Cancer
7 Cancer
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, and MGUS. • There is limited or suggestive evidence of an association between the COIs and bladder cancer; laryngeal cancer; cancers of the lung, b ronchus, or trachea; prostate cancer; multiple myeloma; and AL amyloidosis.
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. The objective of this chapter is to provide an assessment of whether the occurrence of cancers in Vietnam veterans may be associated with exposures to herbicides that they may have experienced during their military service.
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population is included in the background material to provide a context for consideration of the cancer risk in Vietnam veterans; the numbers presented are estimates of incidence in the entire U.S. population, not predictions for the Vietnam veteran cohort.
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The significant challenges in deriving useful quantitative estimates of the risks of various health outcomes in Vietnam veterans are explained in Chapter 2 of this report. ORGANIZATION OF CANCER GROUPS Consistent with the previous report in this series, 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; Robinson et al., 2006)
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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 (C.
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, liver cancer (Beebe et al., 1995) , and skin cancers (Wyde et al., 2004)
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For example, studies reviewed by this committee (and further described in specific cancer outcome sections below) include investigations of TCDD and other AHR ligands that found anti-proliferative and anti-metastatic activity in cell lines of different cancers, including breast, ovarian, and prostate (Hanieh, 2015; Hanieh et al., 2016; Ide et al., 2017; Y
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between the veterans and the control group in the mean frequency of sister-chromatid exchanges, which is thought to be an indicator of genetic damage. The distribution was skewed left, and the Vietnam veterans also had a much higher proportion of cells with sister-chromatid exchanges frequencies above the 95th percentile (≥17 sister chromatid exchanges per cell)
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has classified TCDD in group 1 as carcinogenic to humans. The strongest evidence for carcinogenicity was observed when all cancers sites were aggregated, but a positive association between TCDD exposure and soft-tissue sarcomas, non-Hodgkin lymphomas, and lung cancer has also been found (IARC, 2012b)
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While experiments using animal models can be carefully designed to control for confounding risk factors, this is often not possible in human studies. Therefore, conclusions about the potential carcinogenicity of a chemical in humans rely heavily on the results of epidemiologic studies that examine evidence of an excess cancer risk for individual or multiple organ sites.
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It views the result of all cancers combined as a conglomeration of information on individual malignancies. However, it also recognizes that melanoma and prostate cancer are two malignancies for which increased risk has been published (Akhtar et al., 2004; Pavuk et al., 2006)
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Data were derived from individual employment and health care system records as well as from cancer registries and death records to detect additional cases. SMRs were reported, and the effect estimates were reported for all workers, workers exposed to herbicide levels above background, and workers exposed for more than 1 year at levels above background.
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or among workers potentially exposed to phenoxy herbicide levels above background (SMR = 1.02, 95% CI 0.99–1.06 and SMR = 1.02, 95% CI
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For each outcome, the relevant studies are presented for populations of Vietnam veterans and then for other exposed, nonveteran subjects (occupational cohort studies, environmental studies, and casecontrol studies)
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The larynx refers to only the laryngeal structures and is covered separately. Although the above cancers are classified together in the same category, the epidemiological risk factors for cancers that occur in the oral cavity and oropharynx are different from the risk factors for cancer of the nasopharynx.
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. Nasopharyngeal cancer is a very specific malignancy, and although alcohol, tobacco, and other environmental pollutants are risk factors, infection with the Epstein–Barr virus in combination with certain genetic predispositions and the consumption of poorly preserved food (Chang and Adami, 2006)
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The Korean Veterans Health Study followed 185,265 male Vietnam veterans who were alive in 1992 for cancer incidence through 2003 (Yi, 2013; Yi and Ohrr, 2014) and for mortality through 2005 (Yi et al., 2014b)
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. Update of the Epidemiologic Literature No new studies of Vietnam veterans or published environmental or casecontrol studies of exposure to the COIs and oral, nasal, or pharyngeal cancers were identified for the current update.
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, workers exposed to herbicide levels above background (n = 4; SMR = 0.66, 95% CI 0.18–1.68) , and workers exposed for more than 1 year at levels above background (n = 0; SMR = 0.00, 95% CI 0.00–1.34)
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Synthesis Tonsil cancers, or more generally squamous-cell carcinomas of the oropharynx, remain of interest to Vietnam veterans and the committee, but no new information on them with respect to possible herbicide exposure was available for this update. Previous studies on Vietnam veterans from the Korean Veterans Health Study did not find an association between herbicide exposure and the risk of tonsillar cancers.
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. Risk factors for the cancers vary but always include a family history of the same form of cancer, some diseases of the affected organ, and diet.
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. Adjusted estimates did not show any statistically significant excess in mortality from all cancers of the digestive tract in ACC Vietnam veterans compared with non-Vietnam veterans.
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, and one examined 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.
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Update of the Epidemiologic Literature No studies of Vietnam veterans or published environmental or case-control studies of exposure to the COIs and esophageal cancer were identified for the current update. Reviews of the relevant studies are presented in the earlier reports.
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Synthesis In this update, two studies were reviewed that increased the follow-up period of workers exposed to dioxins (Collins et al., 2016) and phenoxy herbicides (Coggon et al., 2015)
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. Among men over age 65 years (the age group of Vietnam veterans)
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Update of the Epidemiologic Literature No studies of Vietnam veterans or published environmental or case-control studies of exposure to the COIs and stomach cancer were identified for the current update. Reviews of the relevant studies are presented in the earlier reports.
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Synthesis Studies that examined the association between the COIs and stomach cancer that were reviewed in previous VAO Updates reported mixed findings. Among the studies of Vietnam veterans, analyses from the AFHS did not report a statistically significant association of increasing serum levels of TCDD and stomach cancer (Pavuk et al., 2005)
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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 Based on 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.
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Update of the Epidemiologic Literature No studies of Vietnam veterans or published environmental or case-control studies of exposure to the COIs and colorectal cancer were identified for the current update. Reviews of the relevant studies are presented in the earlier reports.
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One lacked sufficient exposure specificity to be included as contributing to the evidence base of the potential effect of the COIs (Ruder et al., 2014)
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Conclusion Based on 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; ICD-10 C22)
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. Known risk factors for liver cancer include chronic infection with the hepatitis B or hepatitis C virus and exposure to the carcinogens aflatoxin and vinyl chloride.
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The risk for liver cancer mortality was not different for any of the groups of workers: all workers (n = 20; SMR = 1.24, 95% CI 0.76–1.91) , workers exposed to herbicide levels above background (n = 14; SMR = 1.14, 95% CI 0.62–1.91)
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(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.
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. For example, TCDD exposure has been reported to increase liver fibrosis in mice via an Ahr-dependent pathway (Andreola et al., 2004)
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and AHR expression as mRNA and protein levels. Expression of both HDAC8 and AHR was significantly upregulated in hepatocellular carcinoma cell lines and tumor tissues compared with normal hepatocytes; inhibition of HDAC8 inhibited hepatoma cell proliferation and transformation.
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Overall, the available evidence does not support an association between the COIs and hepatobiliary 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 hepatobiliary cancers.
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, but committees for subsequent updates have concurred with the decision of the committee for Update 2006, which concluded that there is inadequate or insufficient evidence of an association of exposure to any of the COIs and pancreatic cancer. Four studies of Vietnam veterans were reviewed in Update 2014: a follow-up study of U.S.
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However, none of the veteran studies controlled for smoking status, a known risk factor of pancreatic cancer. Update of the Epidemiologic Literature No studies of Vietnam veterans or environmental studies of the COIs and pancreatic cancer have been identified since Update 2014.
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The first lacked sufficient exposure specificity to be included as contributing to the evidence base of the potential effect of the COIs (Ruder et al., 2014)
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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. Other Digestive Cancers Findings on cancers of the small intestine (ICD-9 152; ICD-10 C17)
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The incidence of laryngeal cancer increases with age; the age-adjusted modeled incidence rate of laryngeal cancer for men 65 years and older (the age of Vietnam veterans) for all races combined was 25.1 per 100,000 for 2000–2014.6 It is more common in men than in women and in blacks than in whites.
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The AFHS did not have sufficient power to detect whether an association existed. The New Zealand cohort of 2,783 Vietnam veterans reported a total of five incident cases and two deaths from larynx cancers, but the study was insufficiently powered to provide reliable estimates (McBride et al., 2013)
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Other Identified Studies One other study of laryngeal cancer was identified. However, it lacked sufficient exposure specificity to be included as contributing to the evidence base of the potential effect of the COIs (Ruder et al., 2014)
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Studies of Vietnam veterans have provided modest, generally not statistically significant, associations. Conclusion Based on one additional study reviewed for the current update, the committee concurs with prior VAO committees and concludes that there is limited or suggestive evidence of an association between exposure to at least one COI and laryngeal cancer.
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, and an increased risk of lung cancer was associated with increased serum TCDD concentrations in AFHS Ranch Hand veterans (Pavuk et al., 2005)
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Similar results were observed also among male Vietnam veterans in New Zealand. Despite their limitations, these studies of Vietnam veterans are largely suggestive of modest associations between herbicide exposure and lung cancer incidence and mortality.
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, through December 31, 2009, or date of death. Compared with the general population, workers exposed for more than 1 year were at increased risk of mortality from malignant tumors of the larynx, trachea, bronchi, and lungs (reported as a group)
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. 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 e xposed to TCDD at high concentrations (Kociba et al., 1978; Van Miller et al., 1977)
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PCP workers had slight but not statistically significant increased risks of all respiratory system cancers combined as well as for lung, bronchus, and trachea cancers (Collins et al., 2016)
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(2014) lacked sufficient exposure specificity to be included as contributing to the evidence base of the potential effect of the COIs.
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Table 10, which can be found at www.nap.edu/catalog/25137, summarizes the results of studies related to bone and joint cancers. Biologic Plausibility No animal studies have reported an increased incidence of bone and joint cancers after exposure to the COIs.
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The VAO committee concluded that although those studies have been criticized, there is insufficient justification to discount the consistent pattern of increased risks in these well-designed and conducted studies. Furthermore, a reanalysis of the data by Hardell (1981)
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Case-control studies conducted among international populations have, for the most part, reported null associations. Studies of Vietnam veterans have not found significant increases in STS.
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The authors concluded that any increased risk of STS with TCDD should be interpreted with caution, given the small numbers of cases of STS and the uncertainty of the diagnosis. In an extension of the follow-up of UK phenoxy herbicide manufacturers and sprayers to examine the carcinogenicity of phenoxy herbicides and their association primarily with HL, STS, and chronic lymphocytic leukemia, Coggon et al.
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Dioxin is poorly absorbed and, in order to accumulate a high level, an individual is also likely to have accumulated a high level of the primary chemical, which perhaps is more likely to be the real carcinogen. The authors concluded that the number of cases of STS was so low that it is unlikely that chlorophenols or phenoxy herbicides were major risk factors for STS.
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The two most common non-melanoma skin cancers are squamous-cell carcinomas, which are derived from the squamous epithelium, and basal-cell carcinomas, which are derived from stem cells. Melanomas are derived from melanocytes.
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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 expo ure to the COIs and skin cancers. The Update 1998 committee considered s the literature on melanoma separately from that of non-melanoma skin cancers and found that there was inadequate or insufficient information to determine 9 Modeled incidence rate as calculated on the site https://seer.cancer.gov/faststats/selections.
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Update of the Epidemiologic Literature No new studies of Vietnam veterans (U.S. or international)
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Other Identified Studies Three other studies were identified that reported on the outcomes of melanoma or skin cancer. The first was a mortality study of an occupational cohort of capacitor manufacturers exposed to mixed PCBs as well as several other chemicals and metals; this study lacked sufficient exposure specificity to be included as contributing to the evidence base of the potential effect of the COIs and melanoma (Ruder et al., 2014)
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(2009) examined the physiologic role of the AHR in human skin and theorized that over-activation can lead to skin cancers, but they provided no evidence that melanoma incidence is increased after TCDD exposure.
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; radiation exposure, HPV,immune suppression, and a family history of non-melanoma skin cancers have also been identified as potential risk factors (Dubas and Ingraffea, 2013)
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This study does not support an association between pheonxy herbicide exposure and non-melanoma/other skin cancer. Other Identified Studies One other study that reported on the mortality of nonmelanoma skin cancers was identified, but it lacked sufficient exposure specificity to be included as contributing to the evidence base of the potential effect of the COIs (Ruder et al., 2014)
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. The age-adjusted modeled incidence rate of breast cancers for women 50–64 years old of all races combined was 265.5 per 100,000 for 2000–2014 and increased to 448.6 for 65- to 74-yearolds and drops to 412.1 for women over 75 years.10 The roughly 5,000–8,000 female Vietnam veterans who were potentially exposed to herbicides in Vietnam would now be menopausal.
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Established risk factors for women other than age include a personal or family history of breast cancer, alcohol consumption, and some characteristics 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)
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and the inconsistent findings of risk in studies of the incidence of breast cancer in several occupational cohorts and the Seveso study, the committees have maintained that breast cancer should remain in the category of inadequate or insufficient evidence to determine whether there is an association. Update of the Epidemiologic Literature No studies of breast cancer among Vietnam veterans or occupational cohorts of exposure to the COIs and breast cancer have been published since Update 2014.
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Thus, in adjusted models that account for known risk factors for breast cancer, dioxin-like PCB were not associated with increased risk. Danjou et al.
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There was no increased risk for breast cancer in this primarily post enopausal group of women who were m apporoximate the age of the female Vietnam veterans. Most of the women had low levels of exposure (below what WHO has reported as safe)
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Heptachlor has dioxin-like properties and is the chemical in this study most related to the COIs, but it was not associated with increased odds of breast cancer in the most rigorous model, and therefore, this analysis does not add sufficient data to the weight of the evidence regarding the association between exposure to the COIs and female breast cancer.
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Other Identified Studies Four other studies that reported outcomes of breast cancer were identified, but all lacked sufficient exposure specificity to be included as contributing to the evidence base of the potential effect of the COIs. The first study examined breast cancer mortality in an occupational cohort of both women and men who worked in capacitor manufacturing and who were exposed to mixed PCBs as well as several other chemicals and metals, but no additional information was provided regarding the specific PCBs or objective measures of exposure (Ruder et al., 2014)
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. 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.
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(2016) found that TCDD and other AHR agonists suppressed pro-metastatic SOX4 in breast cancer cell lines.
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Some well-designed environmental and case-control studies with good expo sure assessment found statistically significant increased risk of breast cancer (Bertazzi et al., 1993; Pesatori et al., 2009; Reynolds et al., 2005; Viel et al.,
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TEQ data were not presented for the dioxin-like PCBs, and of the dioxin-like PCBs measured, PCB 118, a mono-ortho is given low consideration as it contributes less than 10% to total TEQs. Biological mechanistic data from cell lines and non-primate animal models have provided insight into a number of ways in which TCDD and related chemicals may interact with AHR, ER, aromatase enzyme, inflammatory cytokines, DNA repair genes, and the stroma to modulate events leading to breast cancer.
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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.
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In comparison with non-deployed female Vietnam-era veterans, those who served in Vietnam had no excess cervical cancer mortality. A further analysis restricted to female nurses, again using the non-deployed cohort as the referent, yielded virtually the same nonstatistically significant risk of mortality from cervical cancer.
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Other Identified Studies Three studies that reported outcomes of uterine or ovarian cancer were identified, but all lacked sufficient exposure specificity to be included as contributing to the evidence base of the potential effect of the COIs. The first study examined mortality from malignant neoplasms of female genital organs in an occupational cohort of capacitor manufacturers who were exposed to mixed PCBs as well as to several other chemicals and metals, but no additional infor ation was pro m vided regarding the specific PCBs or objective measures of expo ure (Ruder et s al., 2014)
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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 llustrates the role of cell context and organ specificity in responses i to TCDD by cancer cells (Labrecque et al., 2012)
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. That makes prostate cancer the second most common cancer in men (after non-melanoma skin cancers)
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From page 293... ...
Additional information from various epidemiologic studies -- including the AFHS and ACC, veterans seen in VA medical facilities, and occupational cohorts of phenoxy chemical factory workers and pesticide applicators from the AHS -- reviewed in subsequent updates has not changed that conclusion. Four studies of prostate cancer and Vietnam veterans were reviewed in Update 2014, two among veterans at VA medical facilities and two international cohort studies of male Vietnam veterans from New Zealand and Korea.
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reported an inverse association between the EOI scores and prostate cancer incidence, which was based on 53 cases in the high-exposure category.
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The study's negative results may be applicable to the relationship between Agent Orange and prostate cancer progression, but do not directly address initiation and incidence. Occupational Studies Among the Dow Midland, Michigan, worker cohort that was compared with the standardized U.S.
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Prostate cancer was slightly elevated but was not statistically significant for any of the groups of workers: all workers (n = 120; SMR = 1.10, 95% CI 0.91–1.32) , workers exposed to herbicide levels above background (n = 89; SMR = 1.14, 95% CI 0.92–1.14)
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(2017) conducted a case-cohort study to evaluate the relationship between serum concentrations of persistent organic pollutants and the incidence of prostate cancer using the Korean Cancer Prevention Study-II cohort.
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Other Identified Studies Several other studies of prostate cancer were identified. Among occupational cohorts, one examined mortality (Ruder et al., 2014)
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The small number of participants, uncertainty about length of residence in the study areas, unknown response rate, and uncertainty on how the blood draw 2 years apart might have affected the results further limit this study's utility to the committee. Biologic Plausibility In prostate cells and prostate cancer cell lines TCDD can lead to the induc tion of various genes, including those involved in drug metabolism.
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. As with breast cancer, these studies suggest that the timing of an exposure may be critical, with early-life exposures increasing prostate cancer susceptibility or risk and adult Ahr activation reducing it (recently demonstrated in TRAMP mice by Moore et al.
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Ranch Hands and Australian Vietnam veterans that used better exposure assessment support an association between exposure to the herbicides used in Vietnam and prostate cancer. Several positive associations between exposure to specific herbicides or their contaminants and prostate cancer have been reported from previously reviewed occupational studies.
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Conclusion Based on 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. TESTICULAR CANCER NCI estimated that 9,310 men would receive diagnoses of testicular cancer (ICD-9 186; ICD-10 C62)
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Update of the Epidemiologic Literature No studies of testicular cancer in Vietnam veterans (U.S. or those of other countries)
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Other Identified Studies An Italian environmental study was identified that performed an ecological analysis of testicular cancer incidence rates at 14 Italian priority contaminated sites and compared the rates among those sites (Benedetti et al., 2017) ; however, the study lacked sufficient exposure specificity to be included as contributing to the evidence base of the potential effect of the COIs.
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Based on the findings from studies r eviewed in the current and previous updates and the lack of supporting mechanistic data, the committee maintains the conclusion of inadequate or insufficient evidence for an association between exposure to at least of the COIs and testicular cancer. Conclusion Based on 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.
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From page 306... ...
and the con sistently inconclusive results from studies of additional occupationally exposed cohorts, environmentally exposed populations, and two small studies of Vietnam veterans. Updates of the IARC cohort, augmented with 12 additional cohorts and updated through 1992 (Kogevinas et al., 1997)
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Update of the Epidemiologic Literature No studies of U.S. or international cohorts of Vietnam veterans have been published since Update 2014.
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From page 308... ...
workers exposed to mixed PCBs (Ruder et al., 2014) , and the other examined risk factors among Egyptian agricultural workers (Amr et al., 2015)
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From page 309... ...
Vietnam veterans (including AFHS Ranch Hands, Army veterans in the CDC Vietnam Experience Study, and state-specific studies of veterans) have not reported statistically significant increased risks of bladder cancer.
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In the age groups that include most Vietnam veterans, the age-adjusted modeled incidence rate of kidney and renal pelvis cancers for men 50–64 years old of all races combined was 45.3 per 100,000 in 2014 and increased to 93.1 for 65–74-year-olds and 105.1 for men over 75 years. The incidence rate for men is about twice as high as it is for women of the same race.
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. A non-significant increased risk of ureter cancer (ICD-10 C66)
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. Other Identified Studies Two other studies that reported outcomes of renal cancer were identified, but both lacked sufficient exposure specificity to be included as contributing to the evidence base of the potential effect of the COIs (Akahane et al., 2017; Ruder et al., 2014)
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From page 313... ...
Synthesis The available analyses of an association between exposure to the COIs and renal cancer risk have been limited by the small number of cases and a lack of exposure specificity. Studies of Vietnam veterans have not found statistically significant associations between deployment and presumed exposure to the herbicides and incidence or mortality of renal cancers.
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From page 314... ...
. In the age groups that include most Vietnam veterans, the age-adjusted modeled incidence rate of brain and other nervous-system cancers for men 50–64 years old of all races combined was 11.5 per 100,000 in 2014 and increased to 20.2 for 65- to 74-year-olds and 26.2 for men over 75 years.17 In reviewing the descriptive epidemiology of these cancers, it is important to recognize the variation with which specific cancers are included in published r eports, many of which distinguish between benign and malignant tumors.
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The U.S. Vietnam veterans nurses study is limited by the issue of multiple comparisons, the possibility of false positives, and imprecise risk estimates.
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From page 316... ...
Both studies are summarized in this section. No new published literature of Vietnam veterans that addressed exposure to the COIs and brain cancers was identified by the committee for the current update.
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From page 317... ...
Therefore, while these data are consistent with some other studies that suggest an agricultural chemical exposure risk for brain cancer, they are very nonspecific and must be considered exploratory. Other Identified Studies Three other studies of brain cancer were identified, but all lacked sufficient exposure specificity to be included as contributing to the evidence base of the potential effect of the COIs.
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From page 318... ...
Accepted non-genetic risk factors include exposure to ionizing radiation and a history of respiratory allergies and atopic disease,
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In the final part of its presentation, VA representatives informed the committee of the department's current and planned studies of brain cancer in Vietnam veterans. The planned studies included an update of the causes of mortality of deployed and Vietnam-era veterans from 1979 through 2014 and an exploratory study of self-reported exposures and different types of brain cancer using information, in part, from the Agent Orange Registry.
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From page 320... ...
. Synthesis Studies of Vietnam veterans have not found statistically significant associations between deployment and presumed exposure to the herbicides and incidence or mortality of brain or other nervous-system cancers.
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From page 321... ...
Conclusion Based on 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. The committee believes it is appropriate for VA to be mindful of the concerns raised about the possible association between Vietnam service and glioblastoma but observes that the outcome is so rare and the information concerning herbicide exposures so imprecise that is doubtful that any logistically and economically feasible epidemiologic study of veterans -- no matter how well designed or executed would produce meaningful results.
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In the age groups that include most Vietnam veterans, the age-adjusted modeled incidence rate of thyroid cancer for men 50–64 years old of all races combined was 13.4 per 100,000 in 2014 and increased to 21.5 for 65- to 74-year-olds before decreasing to 16.5 for men over 75 years.18 The incidence rate of thyroid cancer is about three times higher in women than in men of the same race. Whites and Asian/Pacific Islanders have the highest incidence rates for both sexes (NCI, n.d.x)
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From page 323... ...
. The small number of cases and imprecise estimates did not change the conclusion that there was inadequate or insufficient evidence to determine whether there is an association between the COIs and endocrine cancers.
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From page 324... ...
With limited deaths, mortality risk estimates were imprecise and not statistically significant for any of the groups of workers. Other Identified Studies Four other studies were identified that reported outcomes of thyroid cancer, but all lacked sufficient exposure specificity to be included as contributing to the evidence base of the potential effect of the COIs.
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From page 325... ...
Synthesis The studies of Vietnam veterans and of occupational cohorts reviewed in previous updates did not provide compelling evidence to determine whether there is an association between exposure to the COIs and cancers of the endocrine organs. Although Le et al.
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From page 326... ...
, but the revised "blue book" has not yet been published. Stem cells arising in the bone marrow generate two major lineages of leukocytes: myeloid and lymphoid.
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From page 327... ...
On ncountering their cognate antigens, B cells differentiate into antibody-secreting e plasma cells involved in humoral immunity. LHCs originate in specific pluripotent or lineage-restricted cells at different stages in hematopoiesis and immune-cell development.
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From page 328... ...
. Multiple myeloma is a lymphohematopoietic malignancy derived from antibody secreting plasma cells, which also have a B-cell lineage, that accumu late primarily in the bone marrow but may also infiltrate extramedullary sites.
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From page 329... ...
(2012) assessed plasma TCDD concentrations at the time of the assumed last exposure and reported a modest but not statistically significant increase in the HR for LHC in the total cohort, but there was no increase in plant A, where workers were occupationally exposed to TCDD.
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From page 330... ...
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 but that did not provide support for an association of AML with exposure to the COIs.
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From page 331... ...
. In the age groups that include most Vietnam veterans, the age-adjusted modeled incidence rate of HL for men 50–64 years old of all races combined was 3.2 per 100,000 in 2014 and increased to 4.7 for 65–74-year-olds and 5.7 for men over 75 years.19 19 As calculated on the site https://seer.cancer.gov/faststats/selections.php?
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From page 332... ...
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)
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From page 333... ...
. Among a cohort of male Vietnam veterans from New Zealand, McBride et al.
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From page 334... ...
No deaths from HL were identified in Dow PCP workers in Midland, Michigan (Collins et al., 2009c; Ramlow et al., 1996) , and only two deaths from HL o ccurred among the TCP workers, resulting in imprecise risk estimates (Collins et al., 2009b)
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From page 335... ...
Update of the Epidemiologic Literature No new published literature of Vietnam veterans, environmental studies, or case-control studies that addressed exposure to the COIs and HL was identified by the committee for the current update. Reviews of the relevant studies are presented in the earlier reports.
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From page 336... ...
Conclusion Based on 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, 201, 202.0–202.2, 202.8–202.9; ICD-10 C82–85, C96.3)
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From page 337... ...
Most cases of CLL and NHL reflect the malignant transformation of germinal-center B cells, so these diseases could have a common etiology. As with HL, the epidemiologic data reviewed by previous VAO committees suggest that it is the phenoxy herbicides (including 2,4-D)
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From page 338... ...
. 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)
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From page 339... ...
agricultural workers that were reviewed showed increased risk ratios, and two NCI studies of farmers in Kansas and Nebraska (Hoar et al., 1986; Zahm et al., 1990) showed patterns of an increased risk linked to use of 2,4-D.
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From page 340... ...
. In studies of Vietnam veterans from New Zealand and Korea, no statistically significant increased risk of NHL was found in either group.
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From page 341... ...
Vietnam veterans was identified that examined CLL prognosis, treatment, and survival and their association with exposure to Agent Orange (determined by benefits and compensation officers who use service records to confirm if the locations and timeframes of deployment correspond to sprayed areas)
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From page 342... ...
Although a statistically significant excess of deaths from NHL was reported, the authors believe that greater weight should be given to the nested case-control analysis, which included both non-fatal and fatal cases and men with CLL as well as solid lymphomas. That analysis found no statistically significant increased risk with exposure to phenoxy herbicides; the highest risk estimate was for workers with high exposure (OR = 1.22, 95% CI 0.61–2.46)
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From page 343... ...
The 27 chemicals were not weighted equally in the index, overall or by site. The weighted quantile sum index was statistically significantly associated with NHL (OR = 1.30, 95% CI 1.08–1.56)
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From page 344... ...
, and other known or suspected risk factors. However, all these studies lacked sufficient exposure specificity to be included as contributing to the evidence base of the potential effect of the COIs.
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From page 345... ...
Nor has long-term exposure to phenoxy herbicides or cacodylic acid resulted in an increased incidence of lymphomas in laboratory animals. Thus, few laboratory animal data support the biologic plausibility of the 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.
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From page 346... ...
The mortality status of the entire subcohort was updated, and blood samples were gathered in 2007– 2008 from a small number of survivors -- 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., 2010)
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From page 347... ...
Vietnam veterans were reviewed. B aumann Kreuziger et al.
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From page 348... ...
. Plasma cell neoplasms are lymphoid neoplasms of terminally differentiated B cells, all of which exhibit the expansion of a single clone of Ig-secreting plasma cells.
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From page 349... ...
One published study that specifically examined the prevalence of MGUS in Vietnam veterans who were responsible for spraying herbicides was identified and reviewed; no other studies of MGUS and the COIs were identified. Table 27, which can be found at www.nap.edu/catalog/25137, summarizes the results of studies related to plasma cell dyscrasias and includes the studies of MGUS.
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From page 350... ...
In both Ranch Hand veterans and comparison veterans, the prevalence of MGUS increased with age. This study is the first to correlate objective measurement of levels of TCDD exposure with MGUS.
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From page 351... ...
In the age groups that include most Vietnam veterans, the age-adjusted modeled incidence rate of myeloma for men 50–64 years old of all races combined was 13.1 per 100,000 in 2014, increasing to 39.0 for 65- to 74-year-olds and 61.1 for men over 75 years.21 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)
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From page 352... ...
A statistically significant increased risk of multiple myeloma was observed with exposure to Mecoprop but not with exposure to 2,4-D. An evaluation of days per year of mixing or applying phenoxy herbicides was not statistically significant for any category (≤ 2 days per year, 2–5 days, and > 5 days)
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From page 353... ...
In both Ranch Hand veterans and comparison veterans, the prevalence of MGUS increased with age. This study is the first to provide objective evidence of an association between higher levels of TCDD exposure and MGUS, and therefore, possibly multiple myeloma.
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From page 354... ...
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, arcroglossia, carpal tunnel syndrome, and peri heral neuropathy. Bone marrow m p biopsies commonly show an increased density of plasma cells, which suggests a premalignant state.
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From page 355... ...
Epidemiologic results for amyloidosis 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.
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From page 356... ...
Therefore, based on 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 multiple myeloma and AL amyloidosis. The close association of these diagnoses to a previous diagnosis of MGUS strengthens this association; however, further study would be needed to establish definitively that the increased prevalence of MGUS will translate to higher levels of these clinically significant plasma cell neoplasms.
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From page 357... ...
and Down syndrome are asso ciated with an increased risk of AML, and tobacco use is thought to account for about 20% of AML cases. Vietnam veterans have expressed concern about whether myelodysplastic syndromes, which can transform to AML, are associated with Agent Orange exposure.
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From page 358... ...
. Update of the Epidemiologic Literature No studies of leukemia of any type in Vietnam veterans have been published since Update 2014.
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From page 359... ...
were identified that examined leukemia outcomes, but all lacked sufficient exposure specificity (e.g., mixtures to several chemicals with no concentrations measured, general herbicide exposure, or exposure determination based on broad categories of occupation with no further details collected) to be included further as contributing to the evidence base of the potential effect of the COIs (Akahane et al., 2017; Levine et al., 2016; Maryam et al., 2015; Poynter et al., 2017; Punjindasup et al., 2015; Ruder et al., 2014)
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From page 360... ...
, risk estimates have been mixed in direction, but most continue not to be statistically significant. No new studies of leukemia in Vietnam veterans were identified for the current update.
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From page 361... ...
An exception is the specific leukemia subtypes of chronic B-cell hemato proliferative diseases, including CLL and HCL, which are more appropriately grouped with lymphomas. Other Myeloid Diseases Myelodysplastic syndromes (MDSs)
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From page 362... ...
Yi and Ohrr (2014) assessed cancer incidence among Korean veterans who had served in Vietnam between 1964 and 1973 and reported a non-significant increased risk of MDS in the internal comparison of the high- and low-exposure groups, based on the EOI scores.
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From page 363... ...
Conclusion Based on the available information, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and other myeloid diseases including myelo proliferative neoplasms.
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Key Terms
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