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Veterans and Agent Orange: Previous IOM Reports

BACKGROUND

Public Law 102–4, the “Agent Orange Act of 1991,” was enacted on February 6, 1991. This legislation, codified as 38 USC Sec. 1116, directed the Secretary of Veterans Affairs to request that the National Academy of Sciences conduct a comprehensive review and evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and their components, including dioxin. In February 1992, the Institute of Medicine (IOM) of the National Academy of Sciences signed an agreement with the Department of Veterans Affairs (DVA) to review and summarize the strength of the scientific evidence concerning the association between herbicide exposure during Vietnam service and each disease or condition suspected to be associated with such exposure. The IOM was also asked to make recommendations concerning the need, if any, for additional scientific studies to resolve areas of continuing scientific uncertainty and to comment on four particular programs mandated in the law. Finally, P.L. 102–4 called for subsequent reviews of newly available information to be completed every 2 years after the initial report for a period of 10 years.

To carry out the mandate, the IOM established the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. The results of the original committee’s work were published in 1994 as Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as VAO) (IOM, 1994). Successor committees of the same name were formed to fulfill the requirement for subsequent reviews. These committees produced Vet-



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Veterans and Agent Orange: Update 2000 2 Veterans and Agent Orange: Previous IOM Reports BACKGROUND Public Law 102–4, the “Agent Orange Act of 1991,” was enacted on February 6, 1991. This legislation, codified as 38 USC Sec. 1116, directed the Secretary of Veterans Affairs to request that the National Academy of Sciences conduct a comprehensive review and evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and their components, including dioxin. In February 1992, the Institute of Medicine (IOM) of the National Academy of Sciences signed an agreement with the Department of Veterans Affairs (DVA) to review and summarize the strength of the scientific evidence concerning the association between herbicide exposure during Vietnam service and each disease or condition suspected to be associated with such exposure. The IOM was also asked to make recommendations concerning the need, if any, for additional scientific studies to resolve areas of continuing scientific uncertainty and to comment on four particular programs mandated in the law. Finally, P.L. 102–4 called for subsequent reviews of newly available information to be completed every 2 years after the initial report for a period of 10 years. To carry out the mandate, the IOM established the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. The results of the original committee’s work were published in 1994 as Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as VAO) (IOM, 1994). Successor committees of the same name were formed to fulfill the requirement for subsequent reviews. These committees produced Vet-

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Veterans and Agent Orange: Update 2000 erans and Agent Orange: Update 1996 (IOM, 1996) and Update 1998 (IOM, 1999). In 1999, in response to a request from DVA, IOM called together a committee to conduct an interim review of the scientific evidence regarding one of the conditions addressed in the Veterans and Agent Orange series of reports: Type 2 diabetes. The committee, which consisted of individuals responsible for the Update 1998 report plus recognized experts in the field of Type 2 diabetes, focused on information published since the deliberations of the Update 1998 committee. This effort resulted in the report Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (hereafter, Type 2 Diabetes) (IOM, 2000). Although limited to one health outcome, this report otherwise adhered to the format of the VAO series. In conducting their work, the committees responsible for these reports operated independently of the DVA and other government agencies. They were not asked to and did not make judgments regarding specific cases in which individual Vietnam veterans have claimed injury from herbicide exposure; this was not part of the congressional charge. Rather, the studies provide scientific information for the Secretary of Veterans Affairs to consider as the DVA exercises its responsibilities to Vietnam veterans. To fulfill their charge of judging whether each of a set of human health effects is associated with exposure to herbicides or dioxin, the committees concentrated on reviewing and interpreting human epidemiologic studies, as well as experimental investigations that may contribute to biologic plausibility. The committees began their evaluation presuming neither the presence nor the absence of association. They sought to characterize and weigh the strengths and limitations of the available evidence. These judgments have both quantitative and qualitative aspects. They reflect the nature of the exposures, health outcomes, and populations exposed; the characteristics of the evidence examined; and the approach taken to evaluate this evidence. To facilitate independent assessment of the committee’s conclusions, Chapter 5 of VAO describes as explicitly as possible the methodological considerations that guided the original committee’s review and its process of evaluation. This methodology was subsequently adopted by successor committees. It is briefly summarized in Chapter 4 of this report. To obtain additional information pertinent to the evaluation of possible health effects of herbicide exposure, the committees decided to review studies of other groups potentially exposed to the herbicides used in Vietnam (2,4,5-trichlorophenoxyacetic acid [2,4,5-T], 2,4-dichlorophenoxyacetic acid [2,4-D], cacodylic acid, and picloram), 2,3,7,8-tertachlorodibenzo-p-dioxin (2,3,7,8-TCDD, TCDD, or dioxin), phenoxy herbicides, chlorophenols, and other compounds. These 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. The committees felt that considering studies of other groups could help address the issue of whether these compounds might be associated with particular health

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Veterans and Agent Orange: Update 2000 outcomes, even though the results would have only an indirect bearing on the increased risk of disease in veterans themselves. Some of these studies, especially those of workers in chemical production plants, provide stronger evidence about health effects than studies of veterans because exposure was generally more easily quantified and measured. Furthermore, the general levels and duration of exposure to the chemicals were greater, and the studies were of sufficient size to examine the health risks among people with varying levels of exposure. Because of the great differences among studies, the committee concluded that it was inappropriate to use a quantitative technique such as meta-analysis to combine individual results into a single summary measure of statistical association. Using such a summary measure would also inappropriately focus attention on one piece of information used by the committee when, in fact, all the factors discussed above are important in evaluating the literature. CONCLUSIONS ABOUT HEALTH OUTCOMES VAO, Update 1996, and Update 1998 provide detailed reviews of the scientific studies evaluated by the committee and their implications for cancer, reproductive problems, neurobehavioral problems, and other health effects. The original report summarized the literature available in 1993; Update 1996 focused on research through mid-1995; and Update 1998 focused on work published through the fall of 1998. Type 2 Diabetes evaluated the evidence available through mid-2000 for that outcome only. This report focuses on research published since the Update 1998 committee’s work was completed and is current through the fall of 2000. The original committee addressed the statutory mandate to determine whether there is a statistical association between the suspect diseases and herbicide use by assigning each of the health outcomes under study to one of four categories on the basis of the epidemiologic evidence reviewed. The categories used by that committee were adapted from those used by the International Agency for Research on Cancer (IARC) in evaluating evidence for the carcinogenicity of various agents (IARC, 1977). Successor committees have adopted these categorizations in their evaluations. The definitions of the categories and the criteria for assigning a particular health outcome to them are discussed below. Health Outcomes with Sufficient Evidence of an Association The original committee found sufficient evidence of an association with herbicides and/or TCDD for three cancers—soft-tissue sarcoma, non-Hodgkin’s lymphoma, and Hodgkin’s disease—and two other health outcomes, chloracne and porphyria cutanea tarda (PCT). After reviewing the whole of the literature available in 1995, the committee responsible for the first update concluded that the statistical evidence still supported this classification for the three cancers and

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Veterans and Agent Orange: Update 2000 chloracne. However, new data regarding porphyria cutanea tarda combined with the studies reviewed in VAO justified moving PCT to the category of limited/ suggestive evidence of an association with herbicide exposure. Chapter 11 of Update 1996 details this decision. No changes were made to this category in Update 1998 or this report. For diseases in this category, a positive association between herbicides and the outcome must be observed in studies in which chance, bias, and confounding can be ruled out with reasonable confidence. The committee regarded evidence from several small studies that are free from bias and confounding, and show an association that is consistent in magnitude and direction, as sufficient evidence for an association. Health Outcomes with Limited/Suggestive Evidence of an Association The committee responsible for VAO found limited/suggestive evidence of an association for three cancers: respiratory cancers, prostate cancer, and multiple myeloma. The Update 1996 committee added three health outcomes to this list: PCT (explained above), acute and subacute transient peripheral neuropathy, and spina bifida in children of veterans. Transient peripheral neuropathies had not been addressed in VAO since, because of their transient nature, they were not amenable to epidemiologic study. In response to a request from DVA, the Update 1996 committee added them to the list of reviewed health outcomes and made its determination on the basis of evidence available from case histories. This classification is addressed in Chapter 10 of the 1996 report. A 1995 analysis of birth defects among the offspring of Ranch Hand veterans, in combination with earlier studies of neural tube defects in the children of Vietnam veterans published by the Centers for Disease Control and Prevention, led the Update 1996 committee to distinguish spina bifida from other adverse reproductive outcomes and classify it in the limited/suggestive category. Chapter 9 of Update 1996 discusses this decision in detail. Based on its evaluation of newly available scientific evidence as well as the cumulative findings of research reviewed in previous Veterans and Agent Orange reports, the committee responsible for the Type 2 Diabetes report found there was limited/suggestive evidence of an association between exposure to the herbicides used in Vietnam or the contaminant dioxin and that health outcome. Evidence reviewed in this report continues to support that finding. As detailed in Chapter 8 of the report, the present committee has added acute myelogenous leukemia in the children of veterans to this category. For diseases in this category, the evidence must be suggestive of an association between herbicides and the outcome considered, but the association may be limited because chance, bias, or confounding could not be ruled out with confi-

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Veterans and Agent Orange: Update 2000 dence. Typically, at least one high-quality study indicates a positive association, but the results of other studies may be inconsistent. Health Outcomes with Inadequate/Insufficient Evidence to Determine Whether an Association Exists Scientific data for many of the cancers and other diseases reviewed by the VAO, Update 1996, and Update 1998 committees were inadequate or insufficient to determine whether any association exists. There was one change in the health outcomes in this category between the first two reports: skin cancer was moved into this category in Update 1996 when available evidence no longer supported its classification as a condition with limited/suggestive evidence of no association. Based on an evaluation of all the epidemiologic evidence, including studies published since the release of Update 1996, the Update 1998 committee felt that urinary bladder cancer should be added to this category. Although there is no evidence that exposure to herbicides or dioxin is related to this cancer, newly available evidence weakened the committees’ prior conclusion that there was positive evidence of no association. The present committee has not made any changes to the list of health outcomes in this category. For diseases in this category, 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 may fail to control for confounding or have inadequate exposure assessment. Health Outcomes with Limited/Suggestive Evidence of No Association For a small group of cancers, the VAO committee found a sufficient number and variety of well-designed studies to conclude that there is limited/suggestive evidence of no association between these cancers and TCDD or the herbicides under study. This group included gastrointestinal tumors (colon, rectal, stomach, and pancreatic), skin cancer, brain tumors, and bladder cancer. As noted above, the Update 1996 committee removed skin cancer from this category and the Update 1998 committee removed urinary bladder cancer because the evidence no longer supported a no-association classification for these health outcome. No further changes to the categorizations were made for this report. For outcomes in this category, several adequate studies covering the full range of levels of exposure that human beings are known to encounter are mutually consistent in not showing a positive association between exposure to herbicides and the outcome at any level of exposure, and have relatively narrow confidence intervals. A conclusion of “no association” is inevitably limited to the

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Veterans and Agent Orange: Update 2000 conditions, levels of exposure, and length of observation covered by the available studies. In addition, the possibility of a very small elevation in risk at the levels of exposure studied can never be excluded. INCREASED RISK OF DISEASE AMONG VIETNAM VETERANS The second of the committee’s three statutory mandates calls on it to determine, to the extent that available scientific data permit meaningful determinations, the increased risk of disease among individuals exposed to herbicides during service in Vietnam. Although there have been numerous health studies of Vietnam veterans, many have been hampered by relatively poor measures of exposure to herbicides or TCDD, in addition to other methodological problems. Most of the evidence on which the findings regarding associations are based comes from studies of people exposed to dioxin or herbicides in occupational and environmental settings, rather than from studies of Vietnam veterans. The VAO, Update 1996, and Update 1998 committees found this body of evidence sufficient for reaching their conclusions about statistical associations between herbicides and health outcomes. However, the lack of adequate data on Vietnam veterans per se complicates consideration of the second part of the statutory charge. To estimate the magnitude of risk for a particular health outcome among herbicide-exposed Vietnam veterans, quantitative information about the dose-time-response relationship for each health outcome in humans, information on the extent of herbicide exposure among Vietnam veterans, and estimates of individual exposure are needed. The large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the studies that have been reviewed, the sometimes-inadequate control for important confounders, and uncertainty about the nature and magnitude of exposure to herbicides in Vietnam— all combine to make quantitative risk assessments problematic. Thus, the committees have found that in general, it is not possible to quantify the degree of risk likely to be experienced by veterans because of their exposure to herbicides in Vietnam. The existing evidence about herbicide exposure among various groups studied does suggest that most Vietnam veterans (except those with documented high exposures, such as participants in Operation Ranch Hand) had lower exposure to herbicides and TCDD than did the subjects in many occupational and environmental studies. However, individual veterans who had very high exposures to herbicides could have risks approaching those described in the occupational and environmental studies. The committees do offer observations regarding increased risk in specific veteran populations where data are available. EXISTENCE OF A PLAUSIBLE BIOLOGIC MECHANISM OR OTHER EVIDENCE OF A CAUSAL RELATIONSHIP Toxicological information forms the basis of the committee’s response to the

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Veterans and Agent Orange: Update 2000 third part of the statutory charge—to determine whether there is a plausible biologic mechanism or other evidence of a causal relationship between herbicide exposure and a disease. This information is summarized in general terms in separate toxicology chapters in previous reports: Chapter 4 of VAO and Chapter 3 of Update 1996, Update 1998, and this report. Specific findings for each health outcome are also given in the chapters that review the epidemiologic literature. RESEARCH RECOMMENDATIONS The IOM was also asked to make recommendations concerning the need, if any, for additional scientific studies to resolve areas of continuing scientific uncertainty concerning the health effects of the herbicides used in Vietnam. Based on its review of the epidemiologic evidence and a consideration of the quality of exposure information available in existing studies, especially of Vietnam veterans, the committee responsible for VAO concluded that a series of epidemiologic studies of veterans could yield valuable information if a new, valid exposure reconstruction model could be developed. The original committee also saw value in continuing the existing Ranch Hand study and expanding it to include Army Chemical Corps veterans. The committee’s research recommendations emphasized studies of Vietnam veterans, rather than general toxicologic or epidemiologic studies of occupationally or environmentally exposed populations. A substantial amount of research on the toxicology and epidemiology of herbicides and herbicide components is under way in the United States and abroad. Indeed, many of the studies on which the committee’s conclusions are based have been published since 1991. Although this research is not targeted specifically to Vietnam veterans, it probably will also contribute to the knowledge of potential health effects in this population. The committees responsible for VAO, Update 1996, Update 1998, Type 2 Diabetes, and this report have also made observations on research needs and opportunities regarding specific health outcomes and have offered advice on the conduct of future studies. The reports detail the committees’ comments on these topics. REFERENCES IARC (International Agency for Research on Cancer). 1977. Some Fumigants, the Herbicides 2,4-D and 2,4,5-T, Chlorinated Dibenzodioxins and Miscellaneous Industrial Chemicals. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man, Vol. 15. Lyon, France: World Health Organization, IARC. IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press. IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. IOM. 2000. Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes. Washington, DC: National Academy Press.