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Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: 10.17226/25137.
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Summary

From 1962 to 1971, the U.S. 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 U.S. 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 (collectively, the “chemicals of interest” or COIs) made up the bulk of the herbicides sprayed. The herbicide mixtures used were named according to the colors of identification bands painted on the storage drums. The most-used chemical mixture sprayed was Agent Orange,1 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 as well as some of the other formulations sprayed in Vietnam.

Concerns from returning Vietnam veterans about their own health and that of their children combined with emerging toxicologic evidence of the adverse effects of phenoxy herbicides and TCDD exposure from animal studies and some positive findings from epidemiologic studies led Congress to pass Public Law (PL) 102-4, the Agent Orange Act of 1991. This legislation directed the Secretary of Veterans Affairs to ask the National Academies of Sciences, Engineering, and Medicine (the “National Academies”) to perform a comprehensive evaluation

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1 Despite loose usage of “Agent Orange” as a collective term for all of the herbicides sprayed by U.S. forces during the Vietnam War—including in the title of this publication—it was only one of the formulations used. The text of the report uses “herbicides” or “COIs” to refer to the full range of herbicide agents, while “Agent Orange” is reserved for that specific formulation.

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: 10.17226/25137.
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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. The legislation also instructed the Secretary to ask the National Academies to conduct updates every 2 years for 10 years from the date of the first report in order to review newly available literature and draw conclusions from the overall evidence.

In response to the first request, the Institute of Medicine convened a committee whose conclusions were published in 1994 in Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (VAO). The work of later committees resulted in a series of biennial updates (Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004) and focused reports on the scientific evidence regarding type 2 diabetes, acute myeloid leukemia in the children of veterans, and the latent period for respiratory cancers.

Enacted in 2002, PL 107-103, the Veterans Education and Benefits Expansion Act of 2001, mandated a continuation of the VAO biennial updates. Update 2006, Update 2008, Update 2010, Update 2012, and Update 2014 were published under that legislation and subsequent extensions to the Department of Veterans Affairs’ (VA’s) authority to request reports. The current update presents this committee’s review of peer-reviewed scientific reports concerning associations between various health outcomes and exposure to TCDD and other chemicals in the herbicides used in Vietnam that were published between September 30, 2014, and December 31, 2017, and the committee’s integration of this information with the previously established evidence database.

CHARGE TO THE COMMITTEE

The committee was asked to “determine (to the extent that available scientific data permit meaningful determinations)” the following regarding associations between specific health outcomes and exposure to TCDD and other chemicals present in the herbicides used by the military in Vietnam:

  1. whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemiological methods used to detect the association;
  2. the increased risk of disease among those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era; and
  3. whether there exists a plausible biological mechanism or other evidence of a causal relationship between herbicide exposure and the disease. [PL 102-4, § 3(d)]

In addition, the committee was asked to address the current research available on possible generational health effects that may be the result of exposures to these

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: 10.17226/25137.
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chemicals, including the biologic plausibility or potential for exposures to lead to an increased risk of birth defects or other adverse conditions in the descendants of male veterans; on myeloproliferative neoplasms (MPN) as part of its consideration of the literature concerning leukemias and related diseases; and on glioblastoma multiforme in its review of brain cancers.

In conducting its work, the committee operated independently of VA and other government agencies. It was not asked to make and did not make judgments regarding specific cases in which individual Vietnam veterans have claimed injury from herbicide exposure or such broader issues as the potential costs of compensation for veterans or policies regarding such compensation.

COMMITTEE’S APPROACH TO ITS CHARGE

Following the pattern established by previous VAO committees, the present committee concentrated its review on epidemiologic studies so as to fulfill its charge of assessing whether specific human health effects are associated with exposure to at least one of the herbicides sprayed in Vietnam or to TCDD. The committee also examined controlled laboratory investigations that provided information on whether a scientifically relevant association between the COIs and a given effect is biologically plausible. Information on dioxins other than TCDD and dioxin-like chemicals was considered because of the common mode of action underlying biologic effects.

The evidence evaluation process presumes neither the presence nor the absence of association for any particular health outcome. Over the sequence of reviews, evidence has accrued of various degrees of association, lack of association, or persistent indeterminacy with respect to a wide array of disease states. For many conditions, however, particularly ones that are very uncommon, any association with the COIs has remained unaddressed in the medical research literature. The committee does not offer a conclusion for these conditions unless the condition is logically subsumed under a broader disease category that has been evaluated, abiding by the maxim that “absence of evidence is not evidence of absence.”

In accord with Congress’s mandated presumption of herbicide exposure of all Vietnam veterans, VAO committees have treated Vietnam-veteran status as a proxy for herbicide exposure when no more specific exposure information is available. To anticipate the health conditions associated with aging and to obtain additional information potentially relevant to the evaluation of health effects in Vietnam veterans, the committees have reviewed studies of other groups potentially exposed to the constituents present in the herbicide mixtures used in Vietnam.

The original legislation calling for the report series, PL 102-4, did not provide a list of specific diseases and conditions suspected of being associated with herbicide exposure. Instead, a list was developed on the basis of diseases and conditions that had been mentioned in the scientific literature or in other documents identified through the original VAO’s extensive literature searches. The VAO list

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: 10.17226/25137.
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has since been augmented in response to new scientific findings, requests by VA, and concerns of Vietnam veterans.

The information that the present committee reviewed was identified through a comprehensive search of relevant databases, including databases covering epidemiologic, biologic, medical, toxicologic, chemical, historical, and regulatory information. To determine whether there is a scientifically relevant association between exposure and a health outcome, epidemiologists estimate the magnitude of an appropriate measure (such as the relative risk or the odds ratio) that describes the relationship between exposure and disease in a defined population or group. In evaluating the strength of the evidence linking herbicide exposure with a particular outcome, the committee considered whether such estimates of risk might not be consistent with a causal association (because of confounding, chance, or bias related to errors in selection and measurement) or might be an indication of a true association. Although they are not required, data supporting biologic plausibility can increase the confidence that an association is not spurious, and such data are presented in each of the sections. In this regard, it is important to note that while the biologic plausibility for a particular effect has been considered sufficient evidence of association by other bodies that have reviewed the health effects of environmental exposures, PL 102-4 specifies that the scientific determinations concerning the association between exposures and outcomes be supported by epidemiologic evidence. It has been the practice of all VAO committees to evaluate all studies according to the same criteria and then to weight findings of similar strength and validity equivalently, whether or not the study subjects are Vietnam veterans, when drawing conclusions. The committee recognizes that an absolute conclusion about the absence of association might never be attained, because—as is generally the case in science—studies of health outcomes after an exposure cannot demonstrate that a purported outcome is impossible, only that it is statistically improbable.

Tables on individual health outcomes summarizing the salient results of epidemiologic studies that have been evaluated over the entire series of VAO reports have been compiled and are available in digital form from www.nap.edu/catalog/25137. The results for a particular endpoint are grouped by study population to emphasize and clarify the relationship among successive publications based on the repeated study of particular exposed populations.

EVIDENCE REVIEWED BY THE COMMITTEE

The sections below describe the epidemiologic information that was newly evaluated for this update and illustrate the broad scope and nature of that information. The studies are divided, both here and in the report’s health-outcome chapters, into four categories—Vietnam-veteran, occupational, environmental, and case-control—reflecting the committee’s judgement of their relative relevance to the exposures of interest. Details of these publications are presented in Chapters 511.

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: 10.17226/25137.
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Vietnam-Veterans Studies

There has been an upswing of research interest in studies of the health of veterans of the Vietnam War, with publications addressing both U.S. and other populations. The committee considered analyses of the data and biospecimens collected in the course of the Air Force Health Study—a 20-year study of personnel involved in wartime aerial herbicide spray missions and a matched comparison group—to be particularly valuable because of the large amount of health and other information collected over an extended time period and because of the availability of measured serum dioxin levels. Since Update 2014, investigators have published studies of monoclonal gammopathy of undetermined significance (MGUS) and testosterone levels (which influence type 2 diabetes risk) in the cohort. A new study of hypertension in Army Chemical Corps personnel, who managed ground spraying operations, was also reviewed. Researchers using data from VA’s Agent Orange Registry, a database containing health information on Vietnam veterans who voluntarily undergo examinations in a VA medical center, produced papers on various health outcomes that relied on surrogates of herbicide exposure such as self-reports. Studies of health outcomes for Australian, Korean, and New Zealand Vietnam veterans were also released.

Occupational Studies

In contrast with Update 2014, which found few studies of health outcomes in workers occupationally exposed to the COIs, there were several new publications available for the current committee to consider. The subjects of these included chemical manufacturing workers in the United States, New Zealand agrochemical production personnel, waste incineration workers in Japan, and employees of an electric arc furnace facility in Italy, a transformer and capacitor recycling plant in Germany, and five factories in the United Kingdom manufacturing or formulating phenoxy herbicides.

The Agricultural Health Study—a longstanding examination how agricultural, lifestyle, and genetic factors affect the health of U.S. farming populations being conducted by the National Institutes of Health (NIH)—has yielded numerous papers reviewed in the VAO series of reports. New studies of asthma, body mass index (a risk factor for type 2 diabetes), end-stage renal disease, lung cancer, prostate cancer, and rheumatoid arthritis were reviewed by this committee.

Environmental Studies

The committee reviewed a considerable number of studies of the effects of environmental exposures to the COIs. Most involved measurements of compounds with dioxin-like activity in blood samples and their association with a diverse set of health outcomes. The U.S. efforts included analyses of data

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: 10.17226/25137.
×

from Centers for Disease Control and Prevention’s (CDC’s) National Health and Nutrition Examination Surveys and NIH’s Longitudinal Investigation of Fertility and the Environment study cohorts. The large body of international work examined included the Danish Fetal Origins 1988–1989 Cohort, Duisburg (Germany) Birth Cohort Study, Hokkaido Study on Environment and Children’s Health and its Sapporo companion study, the (Chapaevsk) Russian Children’s Study, the Seveso (Italy) Woman’s Health Study, and publications concerning populations in Belgium, Brazil, Canada, China, Finland, France, Greece, Hong Kong, Italy, Korea, Nicaragua, Norway, Spain, and Taiwan. Ten newly published studies of birth and other health outcomes in the Vietnamese population were also identified and reviewed.

Case-Control Studies

Several new publications using case-control methodology from the CDC’s National Birth Defects Prevention Study were identified for the current update. These included studies of parental exposure to the COIs and spina bifida, congenital heart defects, gastroschisis, and a series of defects including anotia/microtia, anorectal atresia/stenosis, transverse limb deficiency, craniosynostosis, and diaphragmatic hernia in offspring.

A number of case-control studies in various other populations that examined forms of cancer (including cutaneous melanoma, female breast cancer, hepatocellular carcinoma, infiltrating ductal carcinomas, non-Hodgkin lymphoma, pancreatic cancer, prostate cancer, soft tissue sarcoma, and testicular cancer) and other health outcomes including Parkinson disease, amyotrophic lateral sclerosis, and kidney and urinary disorders were also reviewed.

THE COMMITTEE’S CONCLUSIONS

General Observations Regarding Findings

VAO committees classify the evidence regarding exposure to the COIs and health outcomes into four categories: sufficient, limited or suggestive, inadequate or insufficient, and no association. Table S-1 sets forth the criteria for assigning categorizations and summarizes the committee’s conclusions, with the changes in classification made since the previous volume (Update 2014) indicated in boldface. The classifications are based on the committee’s evaluation of the epidemiologic literature and reflect the committee members’ judgement of the relative certainty of the association between the outcome and exposure to the herbicides that were used in Vietnam or to any of their components or contaminants (with no intention of specifying particular chemicals).

The changes and the decisions not to modify other findings from earlier VAO committees were made after the present committee weighed the strengths and

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: 10.17226/25137.
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TABLE S-1 Summary of the Eleventh Biennial Update Findings on Vietnam-Veteran, Occupational, and Environmental Studies Regarding Scientifically Relevant Associations Between Exposure to Herbicides and Specific Health Outcomes

Sufficient Evidence of an Association

Epidemiologic evidence is sufficient to conclude that there is a positive association. That is, a positive association has been observed between exposure to herbicides and the outcome in studies in which chance, bias, and confounding could be ruled out with reasonable confidence.b For example, if several small studies that are free of bias and confounding show an association that is consistent in magnitude and direction, there could be sufficient evidence of an association. There is sufficient evidence of an association between exposure to the chemicals of interest and the following health outcomes:

Soft-tissue sarcoma (including heart)

* Non-Hodgkin lymphoma

* Chronic lymphocytic leukemia (including hairy cell leukemia and other chronic B-cell leukemias)

* Hodgkin lymphoma

Chloracne

Hypertension (category change from Limited or Suggestive in Update 2014)

Monoclonal gammopathy of undetermined significance (MGUS) (newly considered condition)

The committee did not reach consensus on whether the evidence regarding type 2 diabetes (mellitus) was more properly classified as Sufficient or Limited or Suggestive.

Limited or Suggestive Evidence of an Association

Epidemiologic evidence suggests an association between exposure to herbicides and the outcome, but a firm conclusion is limited because chance, bias, and confounding could not be ruled out with confidence.b For example, a well-conducted study with strong findings in accord with less compelling results from studies of populations with similar exposures could constitute such evidence. There is limited or suggestive evidence of an association between exposure to the chemicals of interest and the following health outcomes:

Laryngeal cancer

Cancer of the lung, bronchus, or trachea

Prostate cancer

Cancer of the urinary bladder

* Multiple myeloma

* AL amyloidosis

Early-onset peripheral neuropathy

Parkinson disease (including Parkinsonism and Parkinson-like syndromes)

Porphyria cutanea tarda

Ischemic heart disease

Stroke

Hypothyroidism

The committee did not reach consensus on whether the evidence regarding type 2 diabetes (mellitus) was more properly classified as Sufficient or Limited or Suggestive.

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: 10.17226/25137.
×

Inadequate or Insufficient Evidence to Determine an Association

The available epidemiologic studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association. For example, studies fail to control for confounding, have inadequate exposure assessment, or fail to address latency. There is inadequate or insufficient evidence to determine association between exposure to the chemicals of interest and the following health outcomes that were explicitly reviewed:

Cancers of the oral cavity (including lips and tongue), pharynx (including tonsils), or nasal cavity (including ears and sinuses)

Cancers of the pleura, mediastinum, and other unspecified sites in the respiratory system and intrathoracic organs

Esophageal cancer

Stomach cancer

Colorectal cancer (including small intestine and anus)

Hepatobiliary cancers (liver, gallbladder, and bile ducts)

Pancreatic cancer

Bone and joint cancers

Melanoma

Non-melanoma skin cancer (basal-cell and squamous-cell)

Breast cancer

Cancers of reproductive organs (cervix, uterus, ovary, testes, and penis; excluding prostate)

Renal cancer (kidney and renal pelvis)

Cancers of brain and nervous system (including eye)

Endocrine cancers (thyroid, thymus, and other endocrine organs)

Leukemia (other than chronic lymphocytic leukemia, including hairy-cell leukemia and other chronic B-cell leukemias)

Other myeloid diseases (including myeloproliferative neoplasms)

Cancers at other and unspecified sites

Infertility

Spontaneous abortion (other than after paternal exposure to TCDD, which appears not to be associated)

Neonatal or infant death and stillbirth in offspring of exposed people

Low birth weight in offspring of exposed people

Birth defects in offspring of exposed people, including spina bifida

Childhood cancer (including acute myeloid leukemia) or other adverse health outcomes in offspring of exposed people

Neurobehavioral disorders (cognitive and neuropsychiatric)

Neurodegenerative diseases, excluding Parkinson disease

Chronic peripheral nervous system disorders

Hearing loss

Respiratory disorders (wheeze or asthma, chronic obstructive pulmonary disease, and farmer’s lung)

Gastrointestinal, metabolic, and digestive disorders (changes in hepatic enzymes, liver disorders including cirrhosis, lipid abnormalities, and ulcers)

Immune system disorders (immune suppression, allergy, and autoimmunity)

Circulatory disorders (other than hypertension, ischemic heart disease, and stroke)

Endometriosis

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: 10.17226/25137.
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Disruption of thyroid homeostasis (other than hypothyroidism)

Eye problems

Bone conditions

Kidney and urinary disorders (including chronic kidney disorder, differences in kidney function, nephropathy, and end stage renal disorder)

Chronic skin disorders (including skin infections and changes in skin pigmentation)

The committee used a classification that spans the full array of cancers. However, reviews for non-malignant conditions were conducted only if they were found to have been the subjects of epidemiologic investigation or at the request of the Department of Veterans Affairs. By default, any health outcome on which no epidemiologic information has been found falls into this category.

Limited or Suggestive Evidence of No Association

Several adequate studies, which cover the full range of human exposure, are consistent in not showing a positive association between any magnitude of exposure to a component of the herbicides of interest and the outcome. A conclusion of “no association” is inevitably limited to the conditions, exposures, and length of observation covered by the available studies. In addition, the possibility of a very small increase in risk at the exposure studied can never be excluded. There is limited or suggestive evidence of no association between exposure to the herbicide components of interest and the following health outcome:

Spontaneous abortion after paternal exposure to TCDD

aHerbicides indicates the following chemicals of interest: 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 or dioxin), cacodylic acid, and picloram. The evidence regarding association was drawn from veteran, occupational, and environmental cohort studies in which people were exposed to the herbicides used in Vietnam, to their components, or to their contaminants.

bEvidence of an association is strengthened by experimental data supporting biologic plausibility, but its absence would not detract from the epidemiologic evidence.

*The committee notes the consistency of these findings with the biologic understanding of the clonal derivation of lymphohematopoietic cancers that is the basis of the World Health Organization classification system (Campo et al., 2011; see table here: www.ncbi.nlm.nih.gov/pmc/articles/PMC3109529/table/T1, accessed May 17, 2018).

limitations of the epidemiologic evidence reviewed in this report and in previous VAO reports. Although the studies published since Update 2014 are the subject of detailed evaluation in this report, the committee drew its conclusions in the context of the entire body of literature, and the committee did not weigh new findings more heavily than past research.

As mandated by PL 102-4, the distinctions among categories are based on statistical association and not on strict causality. The committee was directed to review the scientific data, not to recommend VA policy; therefore, the conclusions reported in Table S-1 are not intended to imply or suggest policy decisions. The conclusions are related to the associations between exposure and outcomes in

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: 10.17226/25137.
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human populations, not to the likelihood that any individual’s health problem is associated with or caused by the herbicides in question.

Hypertension

The committee concluded that the information now assembled constitutes sufficient evidence of an association between exposure to at least one of the COIs and hypertension. The decision to change the classification from limited or suggestive evidence of an association was motivated in large part by the work of Cypel and colleagues (2016). These investigators conducted a study on the population of interest, U.S. Vietnam veterans (specifically, the Army Chemical Corps), that was characterized by a large sample size, appropriate controls, and validated health endpoints. The statistical analyses conducted were robust, used state-of-the-art methods, and adjusted for relevant confounders. The study clearly showed that self-reported hypertension rates were the highest among those military personnel with the greatest opportunity for exposure to the COIs. Among Vietnam-deployed veterans, there was a statistically significantly elevated association between the odds of hypertension for sprayers versus nonsprayers that remained after an adjustment for potential confounders. Similarly, for those veterans who did not deploy to Vietnam, self-reported hypertension was significantly elevated among sprayers compared with nonsprayers. Earlier studies reviewed in previous updates consistently reported increased hypertension with increasing levels of serum dioxin in Vietnam veterans as well as increased prevalence in veterans with higher presumed exposure to the COIs. When considered in light of other new research and earlier studies that demonstrated a consistency in the direction and magnitude of this effect, the committee found that this body of literature constitutes sufficient evidence of an association.

Monoclonal Gammopathy of Undetermined Significance (MGUS)

The committee also concluded that there was sufficient evidence of an association between exposure to at least one of the COIs and MGUS. MGUS is a precursor to multiple myeloma, although only an estimated 1% of MGUS cases progress to multiple myeloma each year. It is a clinically silent condition defined by the presence of a monoclonal antibody, antibody heavy chain, or antibody light chain in the blood or urine of a person lacking symptoms or signs of a more serious plasma cell dyscrasia. The foundation of this finding was a well-conducted study by Landgren and colleagues (2015) that examined data and biospecimens from a population of veterans that included participants with known exposure to herbicides in Vietnam: the Air Force Health Study cohort. The study used previously measured serum levels of TCDD and performed a new assay of serum samples to detect MGUS. Known confounders including age, race, body mass index, smoking and drinking history, and a history of radiation therapy or

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: 10.17226/25137.
×

chemotherapy were considered. The investigators found a statistically significant higher prevalence of MGUS in veterans involved in herbicide spray operations than in comparison veterans. Although no previous study directly addressed MGUS incidence, the direct relevance of the exposure and exposed population and the high quality of the study and underlying database were persuasive in finding sufficient evidence of an association.

Type 2 Diabetes

Finally, the committee—after extensive deliberations—could not come to a consensus on whether the available evidence regarding exposure to the COIs and type 2 diabetes continued to be limited or suggestive or merited elevation to sufficient. Both newly reviewed and previously reviewed studies quite consistently show a relationship between well-characterized exposures to dioxin and dioxin-like chemicals and measures of diabetes health outcomes in diverse cohorts, including Vietnam veteran populations. However, the lack of exposure specificity and the potential for uncontrolled confounding that characterized many of these studies complicates any attribution of the outcome to the COIs. Thus, a case can be made that the body of literature regarding the exposure to the COIs and diabetes meets the criteria for sufficient evidence of an association, but it was not clear to the committee as a whole whether a category change was appropriate, given its limitations.

Findings on Health Outcomes Identified for Special Focus by VA

As noted, VA asked the committee to specifically address three health outcomes: possible generational health effects that may be the result of herbicide exposure among male Vietnam veterans, myeloproliferative neoplasms, and glioblastoma multiforme.

Research on the effects of paternal chemical exposures on their descendants is burgeoning. Few studies address Vietnam veterans, however, and almost all of them that were conducted on other populations have weaknesses—prominently, different exposures than those experienced by veterans and poor exposure characterization—that limit their usefulness when assessing the risks for veterans. Some find associations between exposures and various outcomes, but there are no circumstances where there is a consistent and compelling body of evidence that would lead the committee to conclude that there might be limited or suggestive or sufficient evidence of an association between an exposure to a COI and a particular outcome. Transgenerational effects—those that might occur in descendants when gestational exposure did not take place—are of great interest to veterans, but no literature exists to evaluate whether the COIs might have an influence on outcomes. Given these gaps in the knowledge base, the committee strongly believes that more work in this area is warranted. It concurs with the

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: 10.17226/25137.
×

Update 2014 committee that there is a critical need for this research to include animal studies in order to elucidate whether and which mechanisms for intergenerational and transgenerational effects might exist. It is in principle possible to do studies on the health of children and grandchildren of veterans, but it must be understood up front that such complex studies will need to be carefully planned and conducted if they are to yield meaningful results. Voluntary participation surveys and registries relying on self-reported information will not be helpful.

Myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes are diseases of the blood cells and bone marrow. VA asked that MPNs be explicitly examined as part of the consideration of the literature concerning leukemias and related diseases. However, after conducting a targeted search of science and medical databases, the committee was able to identify only one relevant paper, which assessed cancer incidence among Korean veterans who had served in Vietnam during 1964–1973 and was evaluated by the Update 2014 committee. The paper’s authors reported non-significant and imprecise increased risks of myeloproliferative disease and of myelodysplastic syndromes in internal comparisons of high- and low-exposure groups. The committee observes that, in general, those studies that have looked at the correlation between exposure to the COIs and hematological outcomes have generated much more compelling results for abnormalities of lymphoid development and immune function, such as non-Hodgkin lymphoma, chronic lymphocytic leukemia, multiple myeloma, and MGUS, than have those that examined myeloid neoplasms of granulocytic lineage such as MPN. Given the absence of new studies, the paucity of epidemiologic studies in general, and the lack of information on the biologic plausibility of a connection between exposures to the COIs and abnormalities of hematopoietic cells, the committee concluded there was inadequate or insufficient evidence of an association between exposure to the COIs and MPN. Because the outcome has not been subject to previous research attention and is of interest to veterans, the committee recommends that investigators examine existing databases on myeloid diseases to determine whether there are data available that would allow for an evaluation of MPN in Vietnam veterans and others who have been exposed to dioxin and the other COIs.

The scientific literature regarding exposure to the COIs and brain and other nervous system cancers, including glioblastoma, has been examined since the first VAO report. The body of evidence that has been developed has not found statistically significant associations between exposure and any relevant outcome in studies performed on Vietnam-veteran, occupational, or environmental cohorts. These studies have by and large been underpowered because of the relative rarity of these cancers. Given the limited epidemiologic data available on glioblastoma, the committee heard invited presentations from two experts on the disease. While their presentations to the committee were helpful and impressive, demonstrating that the biological understanding of glioblastoma in particular is rapidly advancing, they reinforced the absence of clear data suggesting that the COIs are associated with the occurrence of brain cancers. Information on

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: 10.17226/25137.
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glioblastomas in Vietnam veterans submitted for the committee’s consideration by the Sierra Valley Cancer Registry Services, Inc., was, in part, anecdotal and without documented levels of exposure and was therefore of limited usefulness for the purpose of drawing conclusions. Furthermore, the committee did not identify any animal studies that have reported an association between exposure to the COIs and any brain cancer. While some studies have put forward mechanisms that might explain why dioxin exposure would be associated with glioblastoma, the information reviewed by the committee along with the presentations it received from experts in the field were not sufficient to alter the conclusion of previous reports that the evidence is inadequate or insufficient to determine whether there is an association between exposure to the COIs and brain 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 it observes that the outcome is so rare and the information concerning herbicide exposures so imprecise that it is doubtful that any logistically and economically feasible epidemiologic study of veterans—no matter how well designed or executed—would produce meaningful results. The committee therefore recommends that epidemiologic studies of glioblastoma in Vietnam veterans should not be pursued and that VA should instead focus on fostering advancements in other areas that may be used to inform improved treatment options.

Risk in Vietnam Veterans

Part of the committee’s charge was to determine, to the extent permitted by available scientific data, the increased risk of disease among veterans exposed to herbicides or the contaminant TCDD during service in Vietnam. Estimating the magnitude of risk of each particular health outcome among herbicide-exposed Vietnam veterans requires quantitative information about the dose–time–response relationship for the health outcome, information on the extent of herbicide exposure among Vietnam veterans, and estimates of individual exposure. Vietnam veterans were exposed to other agents and stresses—such as tobacco smoke, insecticides, therapeutics, drugs, diesel fumes, alcohol, hot and humid conditions, and combat—that may have independent effects or increase or decrease the ability of chemicals in herbicides to produce a particular adverse health outcome. Few, if any, studies either in humans or in experimental animals have examined those interactions. The committees that produced the first VAO report and the updates found that the body of evidence was sufficient for reaching conclusions about statistical associations between herbicide exposures and health outcomes but that the lack of adequate data on Vietnam veterans themselves complicated the consideration of this part of the charge. The committees responsible for the VAO report series have therefore concluded that, in general, it is impossible to quantify the risk posed to veterans by their exposure to herbicides in Vietnam.

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: 10.17226/25137.
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COMMITTEE RECOMMENDATIONS

As part of their charge, all VAO committees have been asked to offer recommendations concerning the need for additional scientific studies and research to resolve areas of continuing scientific uncertainty concerning the health effects of the COIs. The previous (tenth; Update 2014) update of the VAO series was originally understood to be the last of the reports mandated by Congress. The committee responsible for that update thus considered it appropriate to compile the recommendations made by prior VAO committees and, in light of the lessons learned in this process, to consider what would be the most important activities to undertake in the future. That committee produced a compendium of the recommendations of prior committees condensed and sorted into topic areas, with comments on what response these recommendations had received from VA, Department of Defense (DoD), and other parties along with a summary of the future activities that the committee considered most important for monitoring and evaluating the health issues of Vietnam veterans and other veterans who might experience service-related health problems long after discharge.

Generally speaking, the recommendations of previous VAO committees fell into four primary areas: better management of veterans’ health information; additional epidemiologic studies; improvement of exposure estimation; and priority areas for toxicologic research. Suggested future activities included these areas plus initiatives related to the collection and analysis of additional information on Vietnam veterans’ service, exposures, and health.

While there have been a few laudable exceptions—notably, the initiation of additional epidemiologic studies on Vietnam veterans, the development of a herbicide exposure assessment model for use in studies of Vietnam veterans, and the fostering of additional research on the data and biospecimens collected in the course of the Air Force Health Study2—there has been no known follow-up to the vast majority of recommendations that have been offered. The current committee did not choose to revisit this issue in general, concluding that the Update 2014 committee had effectively covered it. It does observe, though, that the very first VAO (1994) indicated that “carefully conducted epidemiologic studies—with adequate sample size to detect elevated associations—of the reproductive history of individuals with occupational or environmental exposure to herbicides and dioxin are . . . needed” (p. 731). Several subsequent volumes have echoed and expanded on this. The current committee is in agreement with these sentiments and therefore recommends further specific study of the health of offspring of male Vietnam veterans.

The Update 2014 committee also offered suggestions for research activities that should follow the end of the VAO report series. Several of these addressed

___________________

2 The Institute of Medicine publications Disposition of the Air Force Health Study (2006) and The Air Force Health Study Assets Research Program (2015) provide details of this work.

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: The National Academies Press. doi: 10.17226/25137.
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reproductive outcomes. As that committee noted, although progress has been made in understanding the health effects of exposure to the COIs and the mechanisms underlying these effects, significant gaps in our knowledge remain. Many additional opportunities for progress via continuing and new toxicologic, mechanistic, and epidemiologic research exist. Such work should include efforts to gain new knowledge through the integration of existing DoD and VA databases. While they were mentioned in previous VAO updates, that committee restated them to emphasize their conviction that more progress should be made in the fields noted. This committee concurs in this assessment and endorses the recommendations offered in Table 12-3, noting that research in the rapidly advancing field of epigenetics appears to hold particular promise.

FINAL OBSERVATIONS

In the course of carrying out its Statement of Task, the committee has offered myriad criticisms of the conduct of studies of Vietnam veterans’ health, pointing out specific weaknesses and shortcomings in particular papers and widespread (although not universal) issues such as poor exposure characterization, failure to fully control for confounding influences on outcomes, and sample sizes that are inadequate to draw statistically meaningful results. It wishes to make clear, though, that the difficulty in conducting research on Vietnam veteran health issues should not act as a barrier to carrying out such work. There are many questions regarding veterans’ health that cannot be adequately answered by examining superficially analogous exposures and outcomes in other populations. It is only through research on veterans themselves that the totality of the military service experience can be properly accounted for.

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From 1962 to 1971, the U.S. 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 Academies of Sciences, Engineering, and Medicine 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 11 (2018) examines peer-reviewed scientific reports concerning associations between various health outcomes and exposure to TCDD and other chemicals in the herbicides used in Vietnam that were published between September 30, 2014, and December 31, 2017, and integrates this information with the previously established evidence database.

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