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Veterans and Agent Orange: Update 2014 (2016)

Chapter: Summary

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

From 1962 to 1971, the US military sprayed herbicides over Vietnam to strip the thick jungle canopy that could conceal opposition forces, to destroy crops that those forces might depend on, and to clear tall grasses and bushes from the perimeters of US base camps and outlying fire-support bases. Mixtures of 2,4-di-chlorophenoxyacetic 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 herbicide mixtures used were named according to the colors of identification bands painted on the storage drums; 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 as well as some other formulations sprayed in Vietnam. It is important to recognize that Agent Orange is not synonymous with TCDD or dioxin.1

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 from animal studies and some positive findings from epidemiologic studies resulted in sustained controversy for many years. In 1991, because of continuing uncertainty about long-term health effects of the sprayed herbicides in Vietnam veterans, Congress passed Public Law (PL)

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

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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102-4, the Agent Orange Act of 1991. This legislation directed the Secretary of Veterans Affairs to ask the National Academy of Sciences (NAS) 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. The legislation also instructed the Secretary to ask the NAS to conduct updates every 2 years for 10 years from the date of the first report to review newly available literature and draw conclusions from the overall evidence.

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

Enacted in 2002, PL 107-103, the Veterans Education and Benefits Expansion Act of 2001, mandated that the VAO biennial updates continue through 2014. Update 2006, Update 2008, Update 2010, and Update 2012 were published under that legislation. The current update presents this committee’s review of peer-reviewed scientific reports concerning associations between health outcomes and exposure to TCDD and other chemicals in the herbicides used in Vietnam that were published between October 1, 2012, and September 30, 2014, and the committee’s integration of this information with the previously established evidence database.

CHARGE TO THE COMMITTEE

The Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Tenth Biennial Update) was assembled to produce the final report mandated by PL 102-4 and PL 107-103. It 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 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, Section 3 (d)]
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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In addition, the committee for Update 2014 was asked to address the specific question of whether all neurodegenerative diseases with Parkinson-like symptoms should be considered service-related under the association identified between Parkinson disease and herbicide exposure by the committee for Update 2006. As for all previous updates, the committee was instructed to recommend additional scientific studies and research initiatives to resolve areas of continuing scientific uncertainty.

Judicial history and the congressional mandate, quoted above, dictated that the committee’s statement of task be framed in terms of “association” between exposure and health outcomes. This and all prior committees fully recognized that an association does not establish a causal relationship and that the rigor of the evidentiary database needed to support a finding of statistical association is weaker than that needed to establish causality. Nonetheless, any positive evidence supporting a causal relationship would enhance the conviction that an observed statistical association is reliable. Such scientific evidence, of course, would include any information assembled in relation to plausible biologic mechanisms as directed in Article C. In accordance with its charge, the committee examined outcome measures commonly used to evaluate statistical associations while assessing the adequacy of control for bias and confounding and the likelihood that an observed association could be explained by chance. The committee also assessed evidence of biologic plausibility derived from laboratory findings in cell culture or animal models. In particular, associations found to have multiple supportive lines of evidence were interpreted as having stronger scientific support for reflecting causal effects.

In conducting its study, the present committee operated independently of the US Department of Veterans Affairs (VA) and other government agencies. The committee was not asked to make and did not make judgments regarding specific cases in which individual Vietnam veterans have claimed injury from herbicide exposure. This report provides scientific information for the Secretary of Veterans Affairs to consider as VA exercises its responsibilities to Vietnam veterans. The committee was not charged to focus on broader issues, such as the potential costs of compensation for veterans or policies regarding such compensation.

COMMITTEE’S APPROACH TO ITS CHARGE

Following the pattern established by prior VAO committees, the present committee concentrated its review on epidemiologic studies 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 considered controlled laboratory investigations that provided information on whether a scientifically relevant association between the chemicals of interest and a given effect is biologically plausible.

The process of evaluation of the evidence presumes neither the presence nor the absence of association for any particular health outcome. Over the sequence

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

of reviews, evidence of various degrees of association, lack of association, or persistent indeterminacy with respect to a wide array of disease states has accrued. For many conditions, however, particularly those that are very uncommon, any association with the chemicals of interest has remained unaddressed in the medical research literature. For these conditions, unless the condition is logically subsumed under a broader disease category that has been evaluated, the committee remains neutral, abiding by the maxim that “absence of evidence is not evidence of absence.”

In accordance with Congress’s mandated presumption of herbicide exposure of all Vietnam veterans, VAO committees have treated Vietnam-veteran status as a proxy for some herbicide exposure when no more specific exposure information is available. To anticipate health conditions associated with aging that might differentially affect Vietnam veterans 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 (2,4-D, 2,4,5-T, TCDD, cacodylic acid, and picloram). In addition to retrieving articles identified on the basis of keywords specifying the chemicals and chemical classes of interest, literature searches for the earliest reports in the VAO series were structured to retrieve all studies of several occupational groups, including chemical, agricultural, pulp and paper, sawmill, and forestry workers. To the extent that studies of those workforces were recovered in new searches directed at particular agents of exposure, they have continued to be incorporated into the database. Some occupational and environmental cohorts that received exceptionally high exposures—such as the International Agency for Research on Cancer (IARC) and Seveso cohorts discussed in this report—are now well characterized and have produced a stream of informative results. The Agricultural Health Study, a continuing prospective cohort study of agricultural populations with specific information on the chemicals of interest, has also been steadily contributing new findings to the database. As the information in the database on populations that had established exposures to the chemicals of interest has grown, VAO committees have come to depend less on data from studies that yielded nonspecific exposure information and have been able to focus more on findings of studies that have refined exposure specificity. With advancing age, the Vietnam veterans themselves are now able to provide substantial information on chronic health conditions directly.

Tables on individual health outcomes contain the results of epidemiologic studies that have been evaluated over the entire series of VAO reports. The results for a particular endpoint are grouped by study population to emphasize and clarify the relationships among successive publications based on repeated study of particular exposed populations. Studies of cohorts have been ordered to reflect the hierarchic nature of many of the study populations—for example, the group of workers in the Dow Chemical Company plant in Midland, Michigan, are one of several cohorts making up the National Institute for Occupational Safety and

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Health (NIOSH) cohort, which in turn is one of the many international cohorts making up the IARC cohort—with citations indicating the source of particular results presented in the final column. The exposure of interest in each study population is noted in the tables to facilitate judgments about when consistency might be expected among populations that experience the same exposure. Unless case-control studies are nested within study populations that have been investigated with cohort or cross-sectional design protocols, case-control studies are gathered in a separate section at the end of the results tables, because they may investigate both occupational and environmental factors as potential risk factors for a specific health outcome.

The original legislation, PL 102-4, did not provide a list of specific diseases and conditions suspected of being associated with herbicide exposure. Such 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 has been augmented in response to literature reporting assessments of additional health endpoints for association with exposure to the chemicals of interest, 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. More than 7,600 potentially relevant citations were identified during searches of literature published between the date of the literature cut-off for Update 2012 and the current update deadline, that is, between October 1, 2012, and September 30, 2014. After the citation abstracts were screened for relevance, about 1,100 were retained for closer consideration. Ultimately, about 70 papers on epidemiologic studies and several score of toxicologic studies and exposure evaluations contributed new information to this updated review. Additional information came from veterans and other interested people who testified at public hearings and offered written submissions.

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 associations. Although not required, data supporting biologic plausibility can strengthen confidence that an association is not spurious and 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 several international review boards, the Agent Orange Act requires

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

that a finding of association 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 herbicide exposure cannot demonstrate that a purported outcome is impossible, only that it is statistically improbable.

EVIDENCE REVIEWED BY THE COMMITTEE

The sections below summarize new epidemiologic information evaluated in this update and integrated with that previously assembled. The epidemiologic studies have been divided, both here and in the health-outcome chapters, into four categories—Vietnam-veteran, occupational, environmental, and case-control—depending on the population addressed and the study design.

Vietnam-Veterans Studies

With interest in posttraumatic stress disorder (PTSD) renewed by recent military engagements, almost all recent studies concerning the impact of deployment on Vietnam veterans have addressed psychological endpoints. However, psychological endpoints are not within the scope of VAO, and therefore no conclusions about them are presented in these reports. The Vietnam veterans themselves are advancing in age and are therefore able to provide substantial information on chronic health conditions directly. Nonetheless, the intensity of research on physical health outcomes in this target population seems to have been waning in recent years. While no comprehensive new information on male US Vietnam veterans was published during the review period, several new publications were available on other groups of Vietnam veterans—from Australia, Korea, and New Zealand, plus women in the US military. It is noteworthy that the very large and comprehensive epidemiology study of Korean Vietnam veterans made use for the first time of the Exposure Opportunity Index (EOI) model developed with the encouragement of earlier VAO committees. Estimates of potential herbicide exposure were calculated for each veteran on the basis of military records of the movements of the individual service units merged with a model of location and time of US herbicide spray missions reconstructed from the records of Operation Ranch Hand. At this late date, there is no standard to which the EOI scores generated for this cohort could be compared for verification or validation, but the committee was pleased to have the opportunity to review the results obtained based on the use of individualized exposure estimates.

In addition, several studies based on samples gathered at VA medical centers have appeared (details provided in Chapter 14). It is gratifying to learn that VA

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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has been interested in mobilizing resources to support research on health outcomes in Vietnam veterans. Future efforts should emphasize that Agent Orange exposures abstracted from a patient’s VA medical records are not definitive and therefore undue confidence should not be placed on these results.

Occupational Studies

The literature search for this update found a study on just one new occupational cohort exposed to the chemicals of interest, but the study population was so small that mortality results could be presented for only three types of cancer. A few other publications provided additional information on previously studied populations, primarily participants in the Agricultural Health Study and subcohorts of the IARC cohort.

Environmental Studies

This committee reviewed a considerable number of studies of the effects of environmental exposures to the chemicals of interest. Most involved measurements of compounds with dioxin-like activity in blood samples for association with various health outcomes. Several new publications of this sort were generated from the data of the US National Health and Nutrition Examination Surveys, the Seveso Woman’s Health Study, and the Prospective Investigations of the Vasculature in Uppsala Seniors. A multitude of cohorts of mother–child birth pairs have been established internationally, and they are generating reports on various aspects of child growth and development in conjunction with levels of dioxin-like compounds in maternal blood during gestation, cord blood, or maternal milk.

Case-Control Studies

Additional articles evaluating exposures to pesticides and phenoxy herbicides in particular came from the Cross-Canada Study of Pesticides and Health, which focuses on lymphoid neoplasms, and from the National Birth Defects Prevention Study. Four new separate case-control studies also addressed lymphohematopoietic conditions in relation to the chemicals of interest, while a final case-control study was concerned with male infertility.

THE COMMITTEE’S CONCLUSIONS

Health Outcomes

In Update 2014 (as listed in Table S-1), the committee changed the categorization of three health outcomes and clarified the breadth of the previous finding of “limited or suggestive” evidence of an association for Parkinson disease. The

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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TABLE S-1 Summary of Tenth Biennial Update of Findings on Vietnam-Veteran, Occupational, and Environmental Studies Regarding Scientifically Relevant Associations Between Exposure to Herbicides and Specific Health Outcomesa

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, then 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
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 (category change from Inadequate or Insufficient in Update 2012)
  * Multiple myeloma
  * AL amyloidosis
  Early-onset peripheral neuropathy
  Parkinson disease (including Parkinsonism and Parkinson-like syndromes) (category clarification from Update 2012)
  Porphyria cutanea tarda
  Hypertension
  Ischemic heart disease
  Stroke
  Type 2 diabetes (mellitus)
  Hypothroidism (category change from Inadequate or Insufficient in Update 2012)
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:
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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  Cancers 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 cancer
  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 B-cell leukemias, including chronic lymphocytic leukemia and hairy cell leukemia)
  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 (category change from Limited or Suggestive in Update 2012 for spina bifida)
  Childhood cancer (including acute myeloid leukemia) 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, lipid abnormalities, and ulcers)
  Kidney disease
  Immune system disorders (immune suppression, allergy, and autoimmunity)
  Circulatory disorders (other than hypertension, ischemic heart disease, and stroke)
  Endometriosis
  Disruption of endocrine function (other than hypothyroidism) (category modification from Update 2012)
  Eye problems
  Bone conditions
This committee used a classification that spans the full array of cancers. However, reviews for nonmalignant 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.
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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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 component 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 occupational, environmental, and veteran 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 at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109529/table/T1, accessed December 2, 2015).

specific birth defect spina bifida was moved from the “limited or suggestive” category back into the “inadequate or insufficient” category with all other birth defects. Bladder cancer and hypothyroidism were moved to the “limited or suggestive” category from their previous positions in the default “inadequate or insufficient” category; findings from the reports on the cohort of Korean veterans who served in Vietnam provided the impetus for the committee to scrutinize the previously assembled evidence on these two conditions.

Bladder Cancer

Assessment of the full body of evidence on bladder cancer had also been encouraged by representatives of Vietnam veterans, who asserted that the recognized effect of inorganic arsenic should apply for these veterans because of their presumed exposure to the organic arsenical cacodylic acid, which constituted a relatively small portion of the herbicides sprayed in Vietnam. The toxicologic information regarding exposure to methylated forms of arsenic indicate these metabolites of inorganic arsenic are potentially carcinogenic, but literature searches have not identified any publications concerning epidemiologic investigations of a possible role for direct exposure to cacodylic acid in the development of bladder or any other cancers. As such, any cacodylic acid in the herbicide mix could not be assumed to be responsible for the two-fold increase in mortality from bladder cancer observed in those Korean veterans whose movements while in Vietnam

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

indicated high potential for herbicide exposure as compared to those with low potential for exposure. Among the previously reviewed epidemiology studies concerning bladder cancer and exposure to the chemicals of interest, the most comprehensive pooled analyses of workers who produced dioxin-contaminated phenoxy herbicides was published by IARC in 1997. It reported a modest increase in mortality from bladder cancer that was not extreme enough to be considered significant by usual statistical standards. The committee noted, however, a distinct pattern of elevated mortality from bladder cancer among worker groups updated for mortality after their earlier findings were incorporated in the IARC analysis. Considering that bladder cancer is predominantly a cancer of old age, it is plausible that such suggestive findings would only become apparent as the cohorts became older.

Hypothyroidism

In addition to the notable increase in the prevalence of hypothyroidism associated with estimates of potential herbicide exposure individually modeled for the large cohort of Korean veterans who served in Vietnam, consistent supporting evidence was seen in several other publications new to this update. In the Agricultural Health Study, hypothyroidism among male pesticide applicators was found to be significantly associated with exposure to each of the phenoxy herbicides analyzed, and for 2,4-D, the most commonly used of these, and a dose–response relationship was observed with intensity of use. A new report from the Seveso Women’s Health Study found an inverse relationship between total thyroxine levels and serum TCDD levels measured in 1996 in women who were younger than 40 years of age at the time of the industrial accident, but not with their serum TCDD levels in 2008. In addition to these highly relevant new findings, several reports of inverse relationships of dioxin-like polychlorinated biphenyls with thyroid hormones in environmentally exposed populations were added to the existing evidence, which was largely consistent with reduced thyroid activity.

Spina Bifida

The birth defect spina bifida has been in the “limited or suggestive” category of association for the children of all Vietnam veterans since Update 1996. The original VAO committee concluded that there was little and inconsistent evidence for an association between paternal exposure and birth defects in general. At the time of the first VAO update, the only additional information the committee had to consider was a publication from the Air Force Health Study (AFHS) noting more cases of spina bifida among the Operation Ranch Hand personnel than in the control group. Data gathering for the AFHS was completed in 2002, but no additional cases of spina bifida have been reported in that study population. Since Update 1996, no new analyses of the birth defect data from the AFHS or any

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

other study finding increased rates of spina bifida among children of men exposed to the chemicals of interest have become available. It has long been challenging to hypothesize feasible biologic mechanisms by which paternal exposure might generate adverse effects in offspring, and, since Update 1996, epigenetic modification has increasingly been considered a possible mode of action by which paternal exposure to toxic agents might produce such effects. To date, however, epigenetic research has addressed paternal exposure only to a very limited extent and has demonstrated transmission of harm from father to offspring only in the circumstance where the father himself was exposed in utero, when his mother was directly exposed. As yet, however, it has not been convincingly established that harm to offspring may arise from paternal exposures experienced as an adult. Because biologic plausibility remains uncertain for paternal transmission following adult exposure (as would be the case for Vietnam veterans), this committee deemed that the “limited or suggestive” category is inappropriate for the children of male Vietnam veterans. On the other hand, epigenetic research has further strengthened certainty that maternal exposures have the potential to alter the development of offspring. For the chemicals of interest, however, there are no supportive epidemiologic results for increases specifically in spina bifida among the children of exposed women. Consequently, spina bifida in the offspring of Vietnam veterans has been moved to the category of “inadequate or insufficient” evidence of an association with herbicide exposure along with all other types of birth defects. (This is only the second time that a VAO committee has demoted a health outcome to a weaker category of association than it had been in before; the first instance was the move of porphyria cutanea tarda from the “sufficient” category to the “limited or suggestive” category by the committee for Update 1998.)

Conditions with Parkinson-like Symptoms

VA charged this committee to address the specific question of whether various conditions with Parkinson-like symptoms should be considered covered under the assignment of Parkinson disease to the “limited or suggestive” category of association with herbicide exposure. The committee noted that the diagnostic standards for this condition cannot be assumed to have been uniform in the epidemiologic studies that are the basis for this association or in the claims submitted by veterans, so there is no rational basis for an exclusion of those with Parkinson-like symptoms from the service-related category denoted as Parkinson disease. To exclude a claim for a condition with Parkinson-like symptoms, the onus should be on VA on a case-by-case basis to definitively establish the role of a recognized etiologic factor other than the herbicides sprayed in Vietnam.

The changes in classification made by the committee for Update 2014 are indicated in boldface in Table S-1.

The above conclusions and the decision not to modify any other findings from earlier VAO committees were made after the present committee weighed

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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the strengths and limitations of the epidemiologic evidence reviewed in this report and in previous VAO reports. Although the studies published since Update 2012 are the subject of detailed evaluation in this report, the committee drew its conclusions in the context of the entire body of literature. The contribution of recent publications to the evidence database was substantial, but the committee did not weigh these findings more heavily merely because they were new. Epidemiologic methods and analytic capabilities have improved, but many of the recent studies were particularly useful for this committee’s purpose also because they produced results in terms of serum TCDD concentrations or the amount of exposure to dioxin-like chemicals. Of course, observations on the health of our population of primary concern, Vietnam veterans, are increasingly informative as they age.

Table S-1 defines four categories of association and gives criteria for assigning health outcomes to them. On the basis of its evaluation of case-control studies and studies of veteran, occupational, and environmentally exposed populations, the committee allocated particular health outcomes to categories of relative certainty of association with 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 committee notes that experimental data related to the biologic plausibility of conditions statistically associated with exposure to Agent Orange have gradually emerged since the beginning of this series of VAO reports and that these findings can inform decisions about how to categorize the degree of association of individual conditions; Table S-1 includes a footnote to this effect.

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 human populations, not to the likelihood that any individual’s health problem is associated with or caused by the herbicides in question.

Risk in Vietnam Veterans

There have been numerous health studies of Vietnam veterans, but most have been hampered by relatively poor measures of exposure to herbicides or TCDD and by other methodologic problems. Exposures were not intentionally monitored during the Vietnam War, but there have been concerted efforts over the nearly 50 years since the end of the conflict to reconstruct the herbicide exposures experienced by US veterans during their service in Vietnam. Nonetheless, we remain completely out of range of the ideal of having reliable estimates of the intensity and duration of every soldier’s exposure to each of the five chemicals of interest, and with the passage of time, it has become increasingly unlikely that even semi-quantitative group estimates will ever be obtained.

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Because of its international reputation as an exceptionally toxic substance and the fact that it is retained in tissues long after exposure, measurement of TCDD has been the object of considerable technological advance. Unfortunately, as sampling techniques became much more sensitive and somewhat more affordable, the blood levels of TCDD remaining after many half-life cycles in even highly exposed Vietnam veterans have become increasingly indistinguishable from those of the general population. It is also very challenging to extrapolate back with confidence from measured serum TCDD levels to what original exposure levels would have been, even with continually refined, physiologically based pharmacokinetic models.

The encouragement of VAO committees and substantial resources have gone into the development of an exposure opportunity model built using detailed records of the herbicide spraying mission conducted in Vietnam. Exposure estimates derived by merging this exposure opportunity model with temporal records of movement by individual military units could then serve as input to epidemiologic investigations of health outcomes available on an individual basis. An important aspect of this update has been reviewing the application of this exposure opportunity model in the comprehensive studies of disease incidence and mortality in a very large population of Korean men who are veterans of the Vietnam War. Regrettably, American service records needed to apply this exposure estimation model to individual American Vietnam veterans have not been located.

In light of those challenges, many conclusions regarding associations between exposure to the chemicals of interest and disease have been based on studies of people exposed in various occupational and environmental settings rather than on studies of Vietnam veterans. More recent studies of health consequences in the maturing veterans themselves, however, have generated more informative findings than were available to earlier VAO committees.

The committee believes that there is sufficient evidence to reach general or qualitative conclusions about associations between herbicide exposure and health outcomes, but the lack of adequate exposure data on Vietnam veterans themselves makes it difficult to estimate the degree of increased risk of disease in Vietnam veterans as a group or individually. Without information on the extent of herbicide exposure of Vietnam veterans and quantitative information about the dose–and time–response relationships for each health outcome in humans, estimation of the risks experienced by veterans exposed to the chemicals of interest during the Vietnam War is not possible.

Because of those limitations, only general assertions can be made about the risks to Vietnam veterans, depending on the category of association into which a given health outcome has been placed. If there were “limited or suggestive evidence of no association” between herbicide exposure and a health outcome, then the evidence would suggest that no increased risk of the outcome in Vietnam veterans was attributable to exposure to the chemicals of interest (at least given the conditions, exposures, and lengths of observation covered by the studies

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

reviewed). Even qualitative estimates are not possible when there is “inadequate or insufficient” evidence of an association. For outcomes categorized as having “sufficient” or “limited or suggestive” evidence of an association with herbicide exposure, the lack of exposure information on Vietnam veterans prevents the calculation of precise risk estimates.

The present committee agrees with the assessment of previous committees that it is not now possible to derive quantitative estimates of any increased risks of various adverse health effects that Vietnam veterans may have experienced in association with exposure to the herbicides sprayed in Vietnam. Given the amount of time that has passed since the Vietnam era, it is extremely unlikely that the situation will improve.

COMMITTEE RECOMMENDATIONS

The IOM has been asked to make recommendations concerning the need, if any, for additional scientific studies to resolve continuing scientific uncertainties about the health effects of the herbicides used in Vietnam and their contaminants. Although advances have been made over the past several years in understanding the health effects of exposure to the herbicides used in Vietnam and to TCDD, as well as in elucidating the mechanisms that underlie the effects, there are still subjects on which increased knowledge could be useful.

The committee again notes that the earlier investment in establishing cohorts of exposed populations can continue to produce useful findings with continued study; the NIOSH, Seveso, AFHS, and US Army Chemical Corps (ACC) cohorts all merit continuing follow-up or more comprehensive analysis. Longitudinal analyses of cancers, cardiovascular, and reproductive outcomes represented in the complete database assembled in the course of the AFHS are especially important, and further research using the valuable assemblage of biological samples is encouraged. The committee was disappointed that the anticipated results from the investigation into the relationship of herbicide exposure during the Vietnam War with hypertension and chronic obstructive pulmonary disease (COPD) in ACC veterans were not yet ready for evaluation. The committee is encouraged that VA is completing plans for a survey of the present health status of Vietnam veterans and has provided several suggestions about how this large effort could generate more useful findings.

As summarized in greater detail in Table S-2, this committee recommends that VA continue to query its own medical databases more actively to identify potential associations between Vietnam service and specific health outcomes, particularly outcomes that are so specific that they are infrequently addressed in epidemiology studies. Cohort studies often do not have enough cases to break out risk for particular types of cancer in a given organ, as is the case for squamous cell carcinomas of the head and neck. For such relatively uncommon conditions, a case-control approach would be recommended, but only rarely do such studies

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

TABLE S-2 Suggested Activities to Follow Completion of the Veterans and Agent Orange Report Series Mandated by the Agent Orange Act

OVERSIGHT OF LONG-TERM HEALTH STATUS OF DEPLOYED SERVICE MEMBERS
  A single overarching body is needed to review all deployment-related issues of veteran’s health regularly and in a uniform fashion. (Numerous points concerning appointment of members and other procedural matters would need to be addressed in advance.)
  Very careful review of evidence concerning whether paternal exposure to any toxicant has definitively been demonstrated to result in abnormalities in even the first generation of offspring.
  Careful assessment of the risks to offspring that may arise from maternal exposure is also merited given the greatly increased number women now serving in the military.
DATA COLLECTION
  Department of Defense (DOD) should create and maintain rosters of individuals deployed on every mission.
  DOD should create and maintain a matrix of potentially toxic exposures by time and location for every deployment.
  DOD’s collection of biological specimens should be expanded to occur at regular intervals for all service members, as well as before and after deployments. Storage should be established on a permanent basis, with samples being accessible to researchers.
  Documentation of vaccination and other medical procedures performed during service need to be included in the records of each service person, and automatically transferred to VA upon discharge from the military.
DATA MANAGEMENT
  DOD and VA databases should be linked to systematically identify, record, and/or monitor trends in diseases of soldiers and veterans for evaluation of possible associations with military service deployments.
  VA should routinely (probably quarterly) obtain frequency distributions of health conditions treated at its medical facilities for participants in each deployment in contrast to those observed among their non-deployed contemporaries.
  It would be worthwhile to conduct similar monitoring of VA claims data even though it might be less objective than treatment records and does not have an obvious comparison group.
EPIDEMIOLOGIC STUDIES
  Air Force Health Study (AFHS)
  Comprehensive longitudinal analysis of the AFHS data collected in the six intensive medical-cycle examinations (particularly concerning medical interventions, cancer incidence, mortality, birth defects in veterans’ offspring) making use of the available exposure data.
  Use AFHS samples for study of epigenetic changes and definition of biomarkers of exposure and effect. (See Table 14-4 from the recent report of the Committee on the Management of the Air Force Health Study Data and Specimens [IOM, 2015])
  Dedicated funding should be continued for focused analyses by independent investigators.
Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
  Army Chemical Corps (ACC)
  Analysis and release of findings gathered by following up on the ACC mortality study to assemble clinical information on morbidity associated with COPD and hypertension.
  Vietnam Era-Health Evaluation Retrospective Observational Study (VE-HEROeS)
  VA should continue epidemiologic studies (morbidity and mortality) of Vietnam veterans, especially as this population grows older and the incidence of many health outcomes increases with age.
  Clinical examination and collection of biologic specimens from a subsample would provide a basis for establishing the reliability of self-reported information and deepen the value of hypotheses that could be explored.
  Foster cooperation with veterans’ service organizations in conducting studies.
  Other Epidemiology Goals
  Pursue development of protocols that could feasibly and efficiently investigate paternal transmission of adverse effects to offspring at birth or manifesting with maturation that have sufficient power for convincing findings. The logistics of attempting to detect adverse effects in the grandchildren of Vietnam veterans would be considerably more challenging.
  Design a study to focus on specific manifestations in humans of dioxin exposure and compromised immunity, which has been so clearly demonstrated in animal models.
TOXICOLOGIC RESEARCH
  Foster investigation of epigenetic changes in both somatic tissues and germ cells and during gestation.
  Without sophisticated and specific markers of environmentally induced epigenetic activity, epidemiologic investigations will not be able to distinguish the mechanisms inducing any observed adverse health effects in exposed people or their offspring. Fully investigate whether paternally transmitted adverse effects occur in animal models.
  Continue exploration of the constellation of effects involved with the metabolic syndrome, which appear to represent a node of dioxin-related conditions.
  Explore the role of B-cell responses to dioxin-like activity.
  Resolve whether toxicology results for direct exposure to organic arsenic compounds are applicable to human exposure to such compounds.

assess exposure to include the chemicals of interest to VAO committees. Consideration of the experience of VA’s own patients might also provide insight into the role of exposures unique to military service in common conditions that are recognized to have a multitude of contributing etiologic factors. Moreover, if a perceived conflict of interest exists for VA in surveying its own databases, it is recommended that an external advisory group be formed to determine the best mechanism for mining the information so that these medical databases can be available for external study.

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

As in previous years, this committee recommends the pursuit of additional research in toxicology. The development of animal models of neurologic outcomes and of various chronic health conditions and their progression would be useful for understanding the possible contributions of the chemicals of interest to compromising the health of aging Vietnam veterans. Specifically, determining the mechanism by which dioxin-like chemicals induce B-cell cancers and how such exposure alters the susceptibility to obesity and components of metabolic syndrome would fill important knowledge gaps. Health problems, such as metabolic syndrome, COPD, and measurement of biomarkers of immune or inflammatory disease, merit study in human populations.

There is a growing body of evidence from animal models that TCDD can induce epigenetic changes, a mechanism that may contribute to health problems in both the veterans and their children. Vietnam veterans have been concerned for decades that wartime exposures may cause harm in their offspring, but there remain extremely limited data on the risk that paternal exposure to xenobiotics in general, and the VAO chemicals of interest in particular, may pose for future generations. Although animal studies have shown epigenetic modifications to be passed along through the male germline, as yet, this has only been the result of perinatal exposure (in utero and by lactation) in which the exposed parent is the mother. The perinatal period clearly represents a period of susceptibility for impacts on the development of both male and female fetuses and on their germlines, but this exposure scenario is not relevant for the offspring of male Vietnam veterans who were adults when the exposure of concern would have taken place. Consequently, this committee continues to recommend that laboratory research be conducted to characterize TCDD’s potential for inducing epigenetic modifications and for producing adverse outcomes in offspring specifically following exposure of adult males. Because the biological plausibility of paternal transmission of adverse effects remains to be established, effort should be invested in the development of epidemiologic protocols to address the logistical challenge of tracing adverse effects in the adult children and grandchildren of Vietnam veterans that are sufficiently robust to detect any actual effect associated specifically with exposures experienced by male veterans.

It is the committee’s conviction that work needs to be undertaken promptly to resolve questions regarding several health outcomes, such as COPD, tonsil cancer, melanoma, Alzheimer disease, and paternally transmitted effects in offspring. Creative analysis of VA’s own data resources and further work on cohorts that have already been established may well be the most effective way to address those outcomes and to gain a better understanding of the role of herbicide exposure in development of stroke, prostate cancer, and Parkinson disease in Vietnam veterans.

Suggested Citation:"Summary." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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From 1962 to 1971, the US military sprayed herbicides over Vietnam to strip the thick jungle canopy that could conceal opposition forces, to destroy crops that those forces might depend on, and to clear tall grasses and bushes from the perimeters of US base camps and outlying fire-support bases. Mixtures of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid made up the bulk of the herbicides sprayed. The main chemical mixture sprayed was Agent Orange, a 50:50 mixture of 2,4-D and 2,4,5-T. At the time of the spraying, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic form of dioxin, was an unintended contaminant generated during the production of 2,4,5-T and so was present in Agent Orange and some other formulations sprayed in Vietnam.

Because of complaints from returning Vietnam veterans about their own health and that of their children combined with emerging toxicologic evidence of adverse effects of phenoxy herbicides and TCDD, the National Academy of Sciences was asked to perform a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and the various components of those herbicides, including TCDD. Updated evaluations were conducted every two years to review newly available literature and draw conclusions from the overall evidence. Veterans and Agent Orange: Update 2014 is a cumulative report of the series thus far.

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