Executive Summary

From 1962 to 1971, US military forces sprayed herbicides over Vietnam to strip the thick jungle canopy that helped conceal opposition forces, to destroy crops that enemy 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 majority of the herbicides sprayed. The herbicide mixtures used were named according to the color of an identification band painted on the storage drums; one of the main chemical mixtures 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, one form of dioxin) was an unintended contaminant from the production of 2,4,5-T and was present in Agent Orange and some other formulations sprayed in Vietnam.

In 1991, because of continuing uncertainty about the long-term health effects on Vietnam veterans of the herbicides sprayed, Congress passed Public Law 102-4 (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 chemical components of those herbicides, including TCDD. The secretary was also to ask that NAS conduct updates at least 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 request, the Institute of Medicine (IOM) of NAS convened a committee, whose conclusions IOM published in 1994 in Veterans and Agent



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Veterans and Agent Orange: Update 2002 Executive Summary From 1962 to 1971, US military forces sprayed herbicides over Vietnam to strip the thick jungle canopy that helped conceal opposition forces, to destroy crops that enemy 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 majority of the herbicides sprayed. The herbicide mixtures used were named according to the color of an identification band painted on the storage drums; one of the main chemical mixtures 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, one form of dioxin) was an unintended contaminant from the production of 2,4,5-T and was present in Agent Orange and some other formulations sprayed in Vietnam. In 1991, because of continuing uncertainty about the long-term health effects on Vietnam veterans of the herbicides sprayed, Congress passed Public Law 102-4 (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 chemical components of those herbicides, including TCDD. The secretary was also to ask that NAS conduct updates at least 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 request, the Institute of Medicine (IOM) of NAS convened a committee, whose conclusions IOM published in 1994 in Veterans and Agent

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Veterans and Agent Orange: Update 2002 Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as VAO). The work of later committees resulted in the publication of biennial updates (Update 1996, Update 1998, and Update 2000) and focused reports reviewing the scientific evidence regarding type 2 (non-insulin dependent) diabetes (Type 2 Diabetes), and acute myelogenous leukemia in children (Acute Myelogenous Leukemia). This report is the fourth review of recently published scientific evidence regarding associations between health outcomes and exposure to TCDD and other chemical compounds in herbicides used in Vietnam. THE CHARGE TO THE COMMITTEE In accordance with PL 102-4, the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Fourth Biennial Update) was asked “to determine (to the extent that available data permit meaningful determinations)” the following regarding associations between specific health outcomes and exposure to TCDD and other chemical compounds in herbicides: A) 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; B) the increased risk of the disease among those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era; and C) whether there exists a plausible biological mechanism or other evidence of a causal relationship between herbicide exposure and the disease. In conducting its study, this committee operated independently of the Department of Veterans Affairs (VA) and other government agencies. The committee was not asked to 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'S APPROACH TO ITS CHARGE To fulfill its charge of assessing whether a given human health effect is associated with exposure to at least one of the herbicides or TCDD, the committee concentrated on reviewing and interpreting epidemiologic studies. Experimental investigations that might contribute to biologic plausibility that the chemicals of interest might be related to a given effect were also reviewed. The committee began its evaluation presuming neither the presence nor the absence of associations. To obtain all information potentially relevant to the evaluation of health effects related to herbicide exposure, the present committee, in addition to re-

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Veterans and Agent Orange: Update 2002 viewing studies of Vietnam veterans, reviewed studies of other groups potentially exposed to the herbicides used in Vietnam (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram), other phenoxy herbicides, chlorophenols, and other compounds. Those groups include chemical production and agricultural workers, people possibly exposed heavily to herbicides or dioxins as a result of residing near the site of an accident or near areas used to dispose of toxic waste, and residents of Vietnam. 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 in VAO on the basis of diseases and conditions that had been mentioned in the scientific literature or in other documents identified through 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 public and commercial databases covering biologic, medical, toxicologic, chemical, historical, and regulatory information. Literature identification continued through July 1, 2002. More than 9,000 potentially relevant studies were identified in those searches, and more than 1,000 were reviewed. Input received from veterans and other interested persons at public hearings and in written submissions served as a valuable source of additional information. To provide data on whether an association between an exposure and a health outcome exists, epidemiologists estimate the magnitude of an appropriate quantitative measure (such as the relative risk or the odds ratio) that describes the relationship between exposure and disease in defined populations or groups. In deciding the strength of the evidence of an association between herbicide exposure and a particular outcome, the committee examined such estimates of risk and evaluated whether they might be due to error, bias, confounding, or chance, or were likely to represent true associations. The committee recognized that an absolute conclusion about the absence of association may never be attained, because, as is generally the case in science, studies of health outcomes after herbicide exposure are not capable of demonstrating that a purported effect is impossible. THE COMMITTEE'S EVALUATION Toxicology Data Since Update 2000, many experimental studies have been published on the herbicides used in Vietnam or their contaminant TCDD. Some of those studies look at particular disease outcomes in animals after exposure to the chemicals, and others focus more on how the chemicals cause effects in cells, tissues, or

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Veterans and Agent Orange: Update 2002 animals (the mechanism or mode of action of the chemicals). Toxicologic information on disease outcomes in animals can support a finding that an effect seen in an epidemiologic study is a true effect. Data on the mechanism of toxicity can also add information indicating that an effect is or is not plausible. Many health effects have been seen in animals after exposure to the herbicides used in Vietnam or their contaminant TCDD. None of those chemicals is thought to act directly by mutating DNA to lead to cancer, but some animal experiments have shown that some of the chemicals can cause some kinds of cancers alone or in conjunction with other treatments. Those effects, and their relevance to human health outcomes, are discussed as part of the biologic plausibility of outcomes. TCDD is thought to be the most toxic of the chemicals sprayed, and a large amount of recent experimental research has focused on how it causes its effects. Although a great deal is known about the cellular effects of TCDD, the exact mechanism by which it causes the various effects seen in humans and animals remains unknown. Cacodylic acid is an organic form of arsenic; arsenic has two methyl groups attached to it. It is not known, however, whether the effects observed following exposure to inorganic arsenic are relevant to exposure to cacodylic acid. The present committee therefore did not consider the effects of inorganic arsenic relevant, and the literature on it was not reviewed. Exposure Assessment Assessment of human exposure to a chemical is a key element in determining whether specific health outcomes are linked to that chemical. Ideally exposure assessment would characterize the dose at the site of action of a chemical, but in human studies that is rarely possible. Exposure estimates, therefore, should be viewed as surrogates for dose. Many methods of estimating exposure are available for epidemiologic research; different methods have advantages and disadvantages that should be considered when evaluating the results of studies. Exposure can be characterized by measurement of chemical contact at various body barriers (for example, the lungs, skin, gastrointestinal tract). It can also be estimated through measurement of chemicals in biological samples. In epidemiologic studies exposure is often characterized by less quantitative methods such as questionnaires or job titles. Update of the Scientific Literature The health outcomes reviewed by the committee are categorized as cancer, reproductive and developmental effects, neurobehavioral disorders, and other health effects. This section briefly summarizes the relevant epidemiologic studies published on those health outcomes since Update 2000.

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Veterans and Agent Orange: Update 2002 Cancer Three major epidemiologic studies have been published since Update 2000 that look at cancer outcomes: a study of residents of Chapaevsk, a Russian industrial community with documented contamination by TCDD and other chemicals; an update of a cohort of Dow Chemical Company workers; and a study of Swedish lumberjacks exposed to pesticides. The study in Russia showed some, mostly small, increases in lung and urinary bladder cancer in males, and nasal–nasopharyngeal, laryngeal, skin, lung, breast, and cervical cancer in females. It is difficult to draw conclusions regarding the association between exposure to the herbicides used in Vietnam and TCDD and health outcomes on the basis of that study because exposures to other chemicals in the Russian town could underlie any effects seen and because of the small number of cases. A small increase in deaths from lymphopoietic cancers was seen in the study of Dow workers, one case of skin cancer and a slight increase in non-Hodgkin's lymphoma were seen in the Swedish lumberjack study; again, the size of the study populations limits their usefulness. In addition to those cohort studies that looked at numerous cancer end points, some smaller studies that are relevant to the exposures of interest and cancer were conducted. Effects were seen in two: an increase in soft-tissue sarcoma in a cohort living near a chemical factory in northern Italy, and an association between exposure to phenoxy herbicides (such as 2,4-D) and non-Hodgkin's lymphoma in a case–control study in Canada. Reproductive and Developmental Effects The study of residents of Chapaevsk, Russia, also looked at reproductive and developmental outcomes. An increase in congenital morphogenetic birth defects and a slight decrease in birth weight were seen. As discussed above, the usefulness of that study for drawing conclusions regarding the association between the exposures of interest and health outcomes is small. Evidence of an increase in birth defects was also seen in the study of US women Vietnam veterans (unspecified birth defects), in a study of residents of an area of Amsterdam thought to be contaminated with TCDD and other chemicals (unspecified birth defects), and in a study of infants in Baltimore and Washington, DC (effects on the developing cardiovascular system). A study of Ontario farm families showed some indication of an increase incidence of spontaneous abortion in farm families. Some evidence of an increased risk of childhood cancer (neuroblastoma) was seen in a case–control study in New York City. Other studies reviewed in this report, however, did not demonstrate reproductive or developmental effects of the herbicides used in Vietnam or TCDD. Thus, evidence regarding any effects of those chemicals on reproductive and developmental end points is inconsistent.

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Veterans and Agent Orange: Update 2002 Neurobehavioral Disorders An update of the Air Force Health Study (AFHS), which looked at cognitive effects on people involved in the aerial spraying of Agent Orange (the Ranch Hands) has been published, as has a study of cognitive effects on Czech workers exposed to TCDD during the production of 2,4,5-T. A case–control study of possible factors contributing to Alzheimer's disease, including pesticides, has also been published. Inconsistent effects on cognitive endpoints were seen in the AFHS and the Czech study. No significant relationship was seen between exposure to pesticides and Alzheimer's disease. The relationship between exposure to pesticides and Parkinson's disease or parkinsonism has been investigated in two studies of agricultural cohorts, in both of which an association was seen: a study of agricultural workers in Iowa and North Carolina and a study of agricultural workers on sugarcane and pineapple plantations in Hawaii. No specific information on herbicide use is available in those studies. Amyotrophic lateral sclerosis (ALS) was investigated in four case –control studies and in the update of the Dow chemical-plant cohort. An increased relative risk was seen in the Dow cohort on the basis of three cases of ALS, but no statistically significant associations were seen in the case–control studies. No other consistent neurobehavioral or neurological effects were seen, and there was no consistent increase in chronic peripheral neuropathy in the AFHS. Other Health Effects A number of studies have investigated other health effects. The update of the Dow chemical-plant cohort looked at respiratory and circulatory disorders and saw no effects. A cross-sectional survey of residents of rural Saskatchewan did not indicate an increased prevalence of diabetes or circulatory disorders. The update of the AFHS showed an increase in hepatomegaly but no other liver effects. The study of residents of Chapaevsk, Russia, demonstrated an increase in mortality from cardiovascular disease, but the committee questioned the usefulness of that study for this report because of the use of different control populations, the likelihood of other exposures, the lack of individual confounding data, and demographic and socioeconomic confounders. A cross-sectional study that investigated diabetes, lipid and lipoprotein disorders, and circulatory disorders in people working at a municipal waste incinerator in Japan showed an increase in self-reported lipoprotein disorders. Health-Outcome Conclusions The present committee weighed the strengths and limitations of all the epidemiologic evidence reviewed in this report and in previous Veterans and Agent

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Veterans and Agent Orange: Update 2002 Orange reports and reached its conclusions by interpreting the new evidence in the context of the entire body of literature. It assigned each health outcome being considered to one of four categories on the basis of that evidence. The definitions of the categories and the criteria for assigning particular health outcomes to them are described in Table ES-1; the health outcomes assigned to each category are also listed in the table. The present committee made one change in the categorization of health outcomes in this report compared with the Update 2000 and Acute Myelogenous Leukemia reports. Previously, the evidence of all forms of leukemia was considered together. In this update, however, the committee was asked by the VA to consider whether the evidence of chronic lymphocytic leukemia could be assessed separately from evidence of other forms of leukemia. Because of the available data and the etiology of chronic lymphocytic leukemia, the present committee made conclusions for that leukemia separately. On the basis of all the evidence reviewed, the committee concluded that there is sufficient evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and chronic lymphocytic leukemia. As mandated by PL 102-4, the distinctions between categories are based on statistical association, not on causality. It should be noted that the committee is charged with reviewing the scientific data, not with making recommendations regarding VA policy; therefore, conclusions reported in Table ES-1 are not intended to imply or suggest policy decisions. Furthermore, the conclusions are related to associations between exposure to chemicals and health outcomes in human populations, not to the likelihood that any individual's health problem is associated with or caused by the herbicides in question. Increased Risk of Disease Among 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 conclusions regarding associations between exposure to TCDD or herbicides and disease are based on studies of people exposed in occupational and environmental settings rather than on studies of Vietnam veterans. The committee believes that there is sufficient evidence to reach general conclusions about associations between herbicide exposure and the health outcomes, but the lack of adequate data on Vietnam veterans themselves makes it difficult to reach conclusions about increased risk of disease among Vietnam veterans. The lack of data on Vietnam veterans, the large uncertainties about the magnitude of potential risk posed by exposure to herbicides in epidemiologic studies, the inadequate control for other important risk factors in many epidemiologic studies, and the uncertainty about the nature and magnitude of exposure to herbicides in Vietnam add

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Veterans and Agent Orange: Update 2002 TABLE ES-1 Summary of Findings in Occupational, Environmental, and Veterans Studies Regarding the Association Between Specific Health Outcomes and Exposure to Herbicidesa Sufficient Evidence of an Association Evidence is sufficient to conclude that there is a positive association. That is, a positive association has been observed between herbicides and the outcome in studies in which chance, bias, and confounding could be ruled out with reasonable confidence. For example, if several small studies that are free from bias and confounding show an association that is consistent in magnitude and direction, there may be sufficient evidence of an association. There is sufficient evidence of an association between exposure to herbicides and the following health outcomes: Chronic lymphocytic leukemia (CLL) (category change from Update 2000) Soft-tissue sarcoma Non-Hodgkin's lymphoma Hodgkin's disease Chloracne Limited or Suggestive Evidence of an Association Evidence is suggestive of an association between herbicides and the outcome but is limited because chance, bias, and confounding could not be ruled out with confidence. For example, at least one high-quality study shows a positive association, but the results of other studies are inconsistent. There is limited or suggestive evidence of an association between exposure to herbicides and the following health outcomes: Respiratory cancer (of lung and bronchus, larynx, and trachea) Prostate cancer Multiple myeloma Acute and subacute transient peripheral neuropathy Porphyria cutanea tarda Type 2 diabetes Spina bifida in the children of veterans Inadequate or Insufficient Evidence to Determine Whether an Association Exists The available 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 whether an association exists between exposure to herbicides and the following health outcomes: Hepatobiliary cancer Nasal or nasopharyngeal cancer Bone cancer Skin cancers (melanoma, basal, and squamous cell) Breast cancer Female reproductive cancer (cervical, uterine, and ovarian) Testicular cancer Urinary bladder cancer Renal cancer Leukemia (other than CLL) Spontaneous abortion Birth defects (other than spina bifida) Neonatal or infant death and stillbirth

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Veterans and Agent Orange: Update 2002 Low birthweight Childhood cancer in offspring, including acute myelogenous leukemia Abnormal sperm characteristics and infertility Cognitive and neuropsychiatric disorders Motor or coordination dysfunction Chronic peripheral nervous system disorders Gastrointestinal, metabolic, and digestive disorders (changes in liver enzymes, lipid abnormalities, and ulcers) Immune system disorders (immune suppression and autoimmunity) Circulatory disorders Respiratory disorders AL-type primary amyloidosis Endometriosis Effects on thyroid homeostasis Limited or Suggestive Evidence of No Association Several adequate studies, covering the full range of levels of exposure that human beings are known to encounter, are consistent in not showing a positive association between any magnitude of exposure to herbicides and the outcome. A conclusion of “no association” is inevitably limited to the conditions, exposure, 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 herbicides and the following health outcomes: Gastrointestinal tumors (stomach cancer, pancreatic cancer, colon cancer, and rectal cancer) Brain tumors aHerbicides refers to the major herbicides used in Vietnam: 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 is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. up to the unavailability of the information that would be necessary to measure the risk to people exposed to herbicides during service in Vietnam during the Vietnam conflict. Despite those limitations, some general conclusions can be drawn regarding the risks to Vietnam veterans, depending on the category of the association between exposure and a given health outcome. Even for outcomes for which there is “sufficient” or “limited or suggestive” evidence of an association with herbicide exposure, it is not possible to calculate precise estimates of risk, if any, among Vietnam veterans because of the lack of exposure information for this population. Such estimates are also not possible when there is “inadequate or insufficient” evidence of an association. But, when there is “limited or suggestive evidence of

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Veterans and Agent Orange: Update 2002 no association” between herbicide exposure and a health outcome, the evidence suggests that there is no increased risk of the outcome among Vietnam veterans. That conclusion is limited to the conditions, exposures, and lengths of observation covered by the studies reviewed by the committee. RESEARCH RECOMMENDATIONS IOM has also 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. Progress had been made over the last several years in understanding the health effects of exposure to the herbicides used in Vietnam and TCDD and in elucidating the mechanisms underlying the effects, but there are still important gaps in our knowledge. On the basis of its review of the epidemiologic evidence and consideration of the quality of exposure information available in existing studies, especially of Vietnam veterans, the present committee concludes that continuation of epidemiologic studies of veterans could yield valuable information, especially as the Vietnam-veteran population ages and as a new exposure-reconstruction model is developed and validated. The committee sees value in continuing the AFHS, expanding studies of Army Chemical Corps veterans, and following the experience of Vietnam veterans as they age, with emphasis on diseases associated with aging. Continued study of other exposed cohorts (for example, the cohort studied by the National Institute for Occupational Safety and Health) could also provide information on diseases of aging. The AFHS is an epidemiologic study whose purpose is to determine whether exposure to the herbicides used in Vietnam might be responsible for any adverse health conditions observed in a cohort of Air Force personnel responsible for conducting aerial spray missions (the Ranch Hands). Five health assessments have been conducted, and, in accordance with the study protocol, one additional assessment is under way and will be completed in April 2003. The AFHS is one of the few primary sources of information on the health of Vietnam veterans. An assessment of herbicide exposure of the AFHS participants and other Vietnam veterans is under revision, and more accurate and precise data are expected in the near future. In addition, the AFHS cohorts are now reaching the age where several health outcomes of interest may be expected to manifest, such as cancers and diseases related to aging. Therefore, the committee recommends continuing the study past its planned completion date. The committee further recommends retaining and maintaining medical records and samples on the AFHS cohort so that—with proper respect for the privacy of the study participants —they could be available for future research. It also recommends that the federal government examine whether and how the various forms of data and specimens collected in the course of the AFHS could be retained and maintained and what form of oversight should be established for their future use.

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Veterans and Agent Orange: Update 2002 Members of the Army Chemical Corps (ACC) constitute the largest cohort of Vietnam veterans exposed directly to the herbicides and TCDD, and preliminary studies on this cohort have demonstrated increased TCDD concentrations in ACC veterans who reported spraying herbicides as part of their duties. Some research on the health effects in this population has been and is being conducted. The committee recommends continued and expanded long-term study of this cohort. Veterans have raised concerns about glioblastomas and possibly astrocytomas. The committee considers those tumors worthy of further investigation despite previous evidence of no association. They are extremely rare tumors, and investigating them in epidemiologic studies is difficult. Recording or monitoring trends in those tumors, as well as other diseases of aging, in Vietnam veterans could be useful for indicating which diseases might warrant further study. The committee is aware that an assessment of herbicide exposure of Vietnam veterans is nearing completion. That assessment should provide more accurate and precise data on the potential exposure of individuals to herbicides sprayed in Vietnam, and the data could be used in epidemiologic studies to increase their power to detect health effects associated with exposure to the herbicides in Vietnam. In light of the anticipated availability of this database, it is even more important to continue research into the health effects of the herbicides in Vietnam veterans themselves, making use of this potentially valuable tool. The federal government should consider the actions that might best facilitate such research and ensure the scientific validity of any such studies of Vietnam veterans. Another population that has been understudied is the Vietnamese. Anecdotal evidence and studies published in non-English-language journals suggest an array of long-term health effects that are potentially related to the chemicals used by US troops in Vietnam. Although collaborative research by scientists in the two countries presents challenges, such research has the potential to fill a number of gaps in our understanding of the long-term health consequences of exposures to TCDD and herbicides used in Vietnam. The committee supports steps that would continue development of collaborative programs of research. The possibility of using the newly established exposure database for assessing exposures of the Vietnamese also warrants consideration.