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-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 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 and some other formulations sprayed in Vietnam. It is important to remember that Agent Orange is not synonymous with TCDD or dioxin.

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. In 1991, because of continuing uncertainty about long-term health effects of the sprayed herbicides in Vietnam veterans, Congress passed Public Law (PL) 102-4, the Agent Orange Act of 1991. That 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



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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 and some other formulations sprayed in Vietnam. It is important to remember that Agent Orange is not synonymous with TCDD or dioxin. 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. In 1991, because of continuing uncertainty about long-term health effects of the sprayed herbicides in Vietnam veterans, Congress passed Public Law (PL) 102-4, the Agent Orange Act of 1991. That 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 1

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2 VETERANS AND AGENT ORANGE: UPDATE 2012 to ask 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 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 cancer. Enacted in 2002, PL 107-103, the Veterans Education and Benefits Expan- sion Act of 2001, mandated that the VAO biennial updates continue through 2014. Update 2006, Update 2008, and Update 2010 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 pub- lished in October 2010–September 2012 and the committee’s integration of this information with the previously established evidence database. CHARGE TO THE COMMITTEE In accordance with PL 102-4 and PL 107-103, the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Ninth Biennial Update) was asked to “determine (to the extent that available scientific data per- mit meaningful determinations)” the following regarding associations between specific health outcomes and exposure to TCDD and other chemicals in herbi- cides used by the military in Vietnam: A)  hether a statistical association with herbicide exposure exists, taking w into account the strength of the scientific evidence and the appropriate- ness of the statistical and epidemiological methods used to detect the association; B) he increased risk of disease among those exposed to herbicides during t service in the Republic of Vietnam during the Vietnam era; and C)  hether there exists a plausible biological mechanism or other evidence w of a causal relationship between herbicide exposure and the disease. [PL 102-4, Section 3 (d)] Judicial history and the congressional mandate, quoted above, dictated that the committee’s statement of task is 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

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SUMMARY 3 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 in- clude any information assembled in relation to plausible biologic mechanisms as directed in Article C. In accord 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 ani- mal 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 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 scientifically relevant association between the chemicals of interest and a given effect is biologically plausible. The VAO committees began their evaluation presuming neither the pres- ence nor the absence of association for any particular health outcome. Over the sequence 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 ones that are very uncommon, any association with the chemicals of interest has remained unaddressed in the medical research literature; for these (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 accord 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

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4 VETERANS AND AGENT ORANGE: UPDATE 2012 is available. To obtain information potentially relevant to the evaluation of health effects related to herbicide exposure in addition to that available from studies of Vietnam veterans, the committee reviewed studies of other groups potentially exposed to the constituents of 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 had been structured to retrieve all studies of several occupational groups, including chemi- cal, 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 were 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 are producing a stream of informative results. The Agricultural Health Study (AHS), a continuing pro- spective cohort study of agricultural populations with specific information on the chemicals of interest, is also steadily contributing new findings to the database. The Vietnam veterans themselves are advancing in age and, when studied, are ca- pable of providing substantial information on chronic health conditions directly; however, the intensity of research on this target population has waned in recent years. As the information in the database on populations that had established exposures to the chemicals of interest has grown, the committee has come to depend less on data from studies that yielded nonspecific exposure information and has been able to focus more on findings of studies that had refined exposure specificity. As in Update 2010, the results tables in this report are grouped by study population rather than by the update in which the studies were originally re- viewed. That change was made to emphasize and clarify the relationship among successive publications that have provided insight into the health responses of particular exposed populations that have been studied for many years. Studies of cohorts have been ordered in a given table to reflect the hierarchic nature of many of the study populations—for example, workers in the Dow Chemical Company plant in Midland, Michigan, are one of several cohorts composing the National Institute for Occupational Safety and Health (NIOSH) cohort, which in turn is one of the many international cohorts making up the IARC cohort—and the citations indicating the source of particular results have been moved to the last column of the table. To allow for the possibility that a case-control study may investigate the relationship of a health outcome to both occupational and environ- mental factors and in recognition of the difference between this protocol and that of cohort and cross-sectional studies, case-control studies have been gathered into a separate section in the results tables. Finally, the exposure of interest in each study population has been explicitly noted in the tables to facilitate judgments

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SUMMARY 5 about when consistency might be expected between populations that experience the same exposure. 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 men- tioned 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 developments in the literature, 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 epi- demiologic, biologic, medical, toxicologic, chemical, historical, and regulatory information. More than 6,800 potentially relevant citations were identified dur- ing searches of literature published between the date of the literature cut-off for Update 2010 and the current update deadline, September 30, 2010–September 30, 2012. After screening of the citation abstracts for relevance, about 1,100 were retained for closer consideration. Ultimately, about 60 papers on epidemiologic studies and several score of toxicologic studies and exposure evaluations ulti- mately contributed new information to this 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 par- ticular outcome, the committee considered whether such estimates of risk might not reflect a causal association (because of confounding, chance, or bias related to errors in selection and measurement) or might accurately represent true as- sociations; although they are not required, data supporting biologic plausibility strengthen confidence that an association is not spurious. It has been the practice of all VAO committees to evaluate all studies according to the same criteria and then to weigh findings of similar strength and validity equivalently, whether or not the study subjects are Vietnam veterans, when drawing conclusions. The commit- tee 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

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6 VETERANS AND AGENT ORANGE: UPDATE 2012 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 Notably few studies concerning the health of Vietnam veterans were identi- fied as having been published since the three evaluated in Update 2010, and almost all addressed psychological endpoints, which are not within the scope of this report. There were no new studies of Vietnam-veteran cohorts and only a single, largely uninformative case-control study on Korean veterans with cardiac disease, which assessed hypertension and hyperlipidemia in terms of whether or not they had served in Vietnam. Occupational Studies The committee reviewed several occupational studies published since Up- date 2010. Researchers reported on cancer mortality in pentachlorophenol (PCP) workers who are part of the NIOSH cohort and cancer incidence in a NIOSH subcohort of chemical workers in a Dow plant in Michigan. Plasma dioxin con- centrations and cause-specific mortality were investigated in German production workers in a plant included in the IARC cohort in Hamburg, Germany, and three new studies of IARC subcohorts in the Netherlands reported on cancer mortality, ischemic heart disease, humoral immunity, atopic disease, and immune suppres- sion in herbicide workers. An examination of pesticide appliers and gliomas in participants in the Upper Midwest Health Study was reviewed, and eight recent reports from the AHS examined cancer incidence, body-mass index, amyotrophic lateral sclerosis, and mortality in private pesticide applicators (farmers), their spouses, and commercial pesticide applicators in Iowa and North Carolina. Environmental Studies Several new studies of the effects of environmental exposure to the chemi- cals of interest have been published since Update 2010. Cancer incidence and reproductive factors were investigated in people who lived near the site of the industrial accident in Seveso, Italy. Five new studies published by the Prospective Investigations of the Vasculature in Uppsala Seniors (PIVUS) group reported on stroke, atherosclerosis, diabetes, and obesity. Several new studies from Taiwan examined hypertension, cardiovascular disease, and insulin resistance in people who lived in the vicinity of a closed PCP factory. Hypertension and bone min- eral density and environmental exposures were investigated via the National Health and Nutrition Examination Survey, and diabetes and hypertension were examined in the Anniston (Alabama) Community Health Survey. Reproductive

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SUMMARY 7 outcomes—including birth weight, onset of puberty, infant growth, immune func- tion, leukemia, and congenital cryptorchidism—were studied in mother–infant pairs exposed to TCDD and other chemicals that have dioxin-like biologic activ- ity in Japan, Finland, the Netherlands, the United States, and Vietnam. Case-Control Studies New case-control studies examined the possible association of occupational exposures with prostate cancer, lymphoid neoplasms, myelodysplastic syn- dromes, and Parkinson disease. Additional new case-control studies examined environmental exposures to the chemicals of interest and breast cancer, mela- noma, non-Hodgkin lymphoma, endometriosis, menstrual cycles, and Parkinson disease. And a large Canadian study published papers investigating both catego- ries of exposure as related to several cancers. THE COMMITTEE’S CONCLUSIONS Health Outcomes In Update 2012, the committee has elected to change the categorization of one health outcome listed in Table S-1. The committee voted unanimously to move stroke to the “limited and suggestive” category because of new evidence showing a statistically significant association in the well-designed PIVUS study; evidence of an overall increase in stroke and cerebrovascular disease associated with exposure to the chemicals of interest in environmental, occupational, and Vietnam-veteran populations in the most relevant of previously considered stud- ies; demonstrated biological plausibility from human and animal studies; and the strong connection between stroke and hypertension, cardiovascular disease, and diabetes (three conditions already in the limited and suggestive category). The published data did not permit the committee to distinguish hemorrhagic from ischemic stroke, but given that only a small percentage of strokes are of the hemorrhagic type in Western populations, this was not seen to be an impediment. That single change in the classifications made in previous updates is in boldface in Table S-1. This conclusion and the decision not to modify any other findings from earlier VAO committees were made after the present committee weighed the strengths and limitations of the epidemiologic evidence reviewed in this report and in previous VAO reports. Although the studies published since Update 2010 are the subject of detailed evaluation in this report, the committee drew its con- clusions 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 them more heavily merely because they were new. Epidemiologic methods and analytic capabilities have improved, but many of the recent studies were par-

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8 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE S-1  Summary of Ninth Biennial Update of Findings on Vietnam- Veterans, Occupational, and Environmental Studies Regarding Scientifically Relevant Associationsa Between Exposure to Herbicides and Specific Health Outcomesb 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. c 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 *  hronic lymphocytic leukemia (including hairy cell leukemia and other chronic B-cell C 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 * Multiple myeloma * AL amyloidosis Early-onset peripheral neuropathy Parkinson disease Porphyria cutanea tarda Hypertension Ischemic heart disease Stroke (category change from Update 2010) Type 2 diabetes (mellitus) Spina bifida in offspring of exposed people 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

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SUMMARY 9 TABLE S-1  Continued 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 Nonmelanoma skin cancer (basal-cell and squamous-cell) Breast cancer Cancers of reproductive organs (cervix, uterus, ovary, testes, and penis; excluding prostate) Urinary bladder cancer 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 (other than spina bifida) in offspring of exposed people 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) Immune system disorders (immune suppression, allergy, and autoimmunity) Circulatory disorders (other than hypertension, ischemic heart disease, and stroke) Endometriosis Disruption of thyroid homeostasis 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. 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 continued

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10 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE S-1  Continued 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 aThis change in wording was made to emphasize the scientific nature of the VAO task and proce- dures and reflects no change in the present committee’s criteria from those used in previous updates. bHerbicides 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. cEvidence 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. ticularly 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 assign- ing health outcomes to them. (Although the committee for this update did not modify the criteria used by previous VAO committees for assigning categories of association to health outcomes, it has inserted “scientifically relevant” before “as- sociation” in the title of Table S-1 to clarify that the strength of evidence evalu- ated, based on the quality of the scientific studies reviewed, was a fundamental component of the committee’s deliberations to address the imprecisely defined legislative target of “statistical association.”) 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 compo- nents or contaminants (with no intention of specifying particular chemicals). The committee notes that experimental data related to 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 find- ings can inform decisions about how to categorize the degree of association of individual conditions; Table S-1 includes a footnote to this effect.

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SUMMARY 11 As mandated by PL 102-4, the distinctions among categories are based on statistical association, not on strict causality. The committee was directed to review the scientific data, not to recommend VA policy; therefore, conclusions reported in Table S-1 are not intended to imply or suggest policy decisions. The conclusions are related to associations between exposure and outcomes in human populations, not to the likelihood that any individual’s health problem is associ- ated 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. In light of those problems, many conclu- sions 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, although more recent studies of health consequences in the maturing veterans themselves have generated more informative findings than originally available to VAO com- mittees. 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–time–response relationship 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 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, the evidence would suggest that no increased risk of the outcome in Vietnam veterans was at- tributable to exposure to the chemicals of interest (at least given the conditions, exposures, and lengths of observation covered by the studies 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 calculation of precise risk estimates. The information needed for assigning risk estimates continues to be absent despite concerted efforts to model the exposure of the troops in Vietnam, to measure serum TCDD concentrations of individual veterans, and to model the dynamics of retention and clearance of TCDD in the human body. Accordingly,

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12 VETERANS AND AGENT ORANGE: UPDATE 2012 several successive VAO committees have stated as a general conclusion that, at least for the present, it was not 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, the present committee agreed with the assessment of previous committees that the neces- sary information to perform such estimation for Vietnam veterans is extremely unlikely ever to become available. COMMITTEE RECOMMENDATIONS 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. Al- though advances have been made over the last several years in understanding the health effects of exposure to the herbicides used in Vietnam and to TCDD and in elucidating the mechanisms that underlie the effects, there are still subjects on which increased knowledge could be very useful. This committee recommends that VA query its own medical databases more actively to identify potential associations between Vietnam service and specific health outcomes, particularly outcomes that are so common or so specific that they are infrequently addressed in epidemiology studies. Moreover, if a perceived conflict of interest exists in surveying its own databases, it is recommended that an external advisory group be formed to determine the best mechanism for min- ing the information so that these medical databases can be available for external study. The committee for Update 2008 concluded that it was possible that epigen- etic changes arising from exposure to the herbicides sprayed in Vietnam might cause paternally mediated effects in offspring, and such potential would most likely be attributable to the TCDD contaminant in Agent Orange. There is a growing body of evidence that TCDD—and arsenicals—can induce epigenetic changes in animal models, but there remain extremely limited data on the risk that paternal exposure to xenobiotics in general, and the VAO chemicals of inter- est in particular, will result in adverse effects on their offspring. Consequently, this committee continues to recommend that laboratory research be conducted to characterize TCDD’s potential for inducing epigenetic modifications. The committee also recommends development of epidemiologic protocols to address the logistical challenge of determining whether adverse effects are being manifested in the adult children and grandchildren of Vietnam veterans as a result of male veterans’ exposure. The best cohorts for revealing potential associations would be those on which there is well-characterized exposure information. An- other alternative would be to adopt a case-control approach and explore whether information about Vietnam exposure or specific herbicide exposure could be

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SUMMARY 13 ascertained in any of the many birth cohorts that have been established in the last several decades. To home in on a paternal effect, however, it will be necessary to establish that the mothers did not have the opportunity for exposure to the chemicals of interest above background levels. As in previous years, this committee recommends the pursuit of additional research in toxicology. The development of animal models of neurologic out- comes 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 meta- bolic syndrome, chronic obstructive pulmonary disease (COPD), and measure- ment of biomarkers of immune or inflammatory disease merit study in human populations. The committee notes that the earlier investment in studying several exposed populations has produced useful findings; the NIOSH, Seveso, Air Force Health Study (AFHS), and Army Chemical Corps (ACC) cohorts all merit continu- ing followup or more comprehensive analysis. Longitudinal analyses of cancer, cardiovascular, and reproductive outcomes represented in the complete database assembled in the course of the AFHS are especially important. The committee is encouraged that VA has reinitiated the National Vietnam Veterans Longitudinal Study and has launched the Army Chemical Corps Vietnam-Era Veterans Health study to investigate the relationship of herbicide exposure during the Vietnam War with hypertension and COPD in ACC veterans. Several of the committee’s recommendations are similar to those offered in previous updates because little activity has been seen in several critical topics. Proposals for studies that would use data and biologic samples from the AFHS have only recently been approved, and published results from these investiga- tions are still several years off. Meanwhile, critical integrative analyses, such as longitudinal evaluation of the cancer data, have not yet been made public, and the unique potential of this resource has languished. It is the committee’s conviction that work needs to be undertaken promptly to resolve questions regarding sev- eral health outcomes, among them 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 estab- lished 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.