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Introduction

Public Law 102-4, the Agent Orange Act of 1991, was enacted on February 6, 1991. That legislation, codified as 38 USC Sec. 1116, directed the secretary of veterans affairs to request that the National Academy of Sciences (NAS) conduct an independent, comprehensive review and evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange (a 50:50 mixture of the herbicides 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid), and other chemical compounds in the herbicides, including the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, one form of dioxin). The legislation also called for reviews of newly available information to be completed every 2 years after the initial report for a period of 10 years. In addition, the NAS was asked to recommend, as appropriate, additional scientific studies to resolve continuing scientific uncertainties and to comment on particular programs mandated in the law.

In response to the request from the Department of Veterans Affairs (VA), the Institute of Medicine (IOM) of the NAS convened 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 (hereafter referred to as VAO; IOM, 1994). Successor committees were formed to fulfill the requirement for updated reviews. Those committees produced Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), and Update 2000 (IOM, 2001). In 1999, in response to a request from the VA, IOM convened a committee to conduct an interim review of type 2 diabetes. That effort resulted in the report Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (hereafter referred to as referred Type 2 Diabetes; IOM, 2000).



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Veterans and Agent Orange: Update 2002 1 Introduction Public Law 102-4, the Agent Orange Act of 1991, was enacted on February 6, 1991. That legislation, codified as 38 USC Sec. 1116, directed the secretary of veterans affairs to request that the National Academy of Sciences (NAS) conduct an independent, comprehensive review and evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange (a 50:50 mixture of the herbicides 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid), and other chemical compounds in the herbicides, including the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, one form of dioxin). The legislation also called for reviews of newly available information to be completed every 2 years after the initial report for a period of 10 years. In addition, the NAS was asked to recommend, as appropriate, additional scientific studies to resolve continuing scientific uncertainties and to comment on particular programs mandated in the law. In response to the request from the Department of Veterans Affairs (VA), the Institute of Medicine (IOM) of the NAS convened 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 (hereafter referred to as VAO; IOM, 1994). Successor committees were formed to fulfill the requirement for updated reviews. Those committees produced Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), and Update 2000 (IOM, 2001). In 1999, in response to a request from the VA, IOM convened a committee to conduct an interim review of type 2 diabetes. That effort resulted in the report Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (hereafter referred to as referred Type 2 Diabetes; IOM, 2000).

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Veterans and Agent Orange: Update 2002 In 2001, VA requested that IOM convene a committee to conduct an interim review of acute myelogenous leukemia (AML). Its review of the literature, including literature available since its review for Update 2000, is published in Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leukemia in the Children of Vietnam Veterans (hereafter, Acute Myelogenous Leukemia; IOM, 2002). In conducting their work, the committees responsible for those reports operated independently of VA 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. The reports are intended to provide scientific information for the secretary of veterans affairs to consider as VA exercises its responsibilities to Vietnam veterans. CHARGE TO THE COMMITTEE In accordance with PL 102-4, the committee 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. Details of how the committee approached its charge and the methods it used in reaching its conclusions are discussed in Chapter 2. CONCLUSIONS OF PREVIOUS VETERANS AND AGENT ORANGE REPORTS Health Outcome Conclusions VAO, Update 1996, Update 1998, Update 2000, Type 2 Diabetes, and Acute Myelogenous Leukemia provide detailed reviews of the scientific studies evaluated by the committees and their implications for cancer, reproductive and developmental effects, neurobehavioral disorders, and other health effects. The original committee addressed the statutory mandate to determine whether there is a statistical association between a given health effect and herbicide use by assigning each of the health outcomes under study to one of four categories on the

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Veterans and Agent Orange: Update 2002 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 in evaluating evidence of the carcinogenicity of various agents (IARC, 1977). Successor committees have adopted those categories in their evaluations. The categories, the criteria for assigning a particular health outcome to a category, and the health outcomes that have been assigned to the categories in past updates are discussed below. Table 1-1 summarizes the most recent categorization of the health effects based on the conclusions of Update 2000 (IOM, 2001) and AML (IOM, 2001). It should be noted that the categories of association described 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. Health Outcomes with Sufficient Evidence of an Association For effects 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. For example, the committee might regard evidence from several small studies that are free of bias and confounding and that show an association that is consistent in magnitude and direction to be sufficient evidence of an association. The original committee found sufficient evidence of an association between herbicides and three cancers—soft-tissue sarcoma, non-Hodgkin 's lymphoma, and Hodgkin's disease—and two other health outcomes, chloracne and porphyria cutanea tarda (PCT) (IOM, 1994). After reviewing all the literature available in 1995, the committee responsible for Update 1996 concluded that the statistical evidence still supported that classification for the three cancers and chloracne but that the evidence of an association with PCT warranted its being placed in the category of limited or suggestive evidence of an association with exposure; Chapter 11 of Update 1996 details the decision. No changes were made in this category in Update 1998 or Update 2000. Health Outcomes with Limited or Suggestive Evidence of an Association For effects in this category, the evidence must suggest an association between herbicides and the outcome considered, but the evidence of the association may be limited by the inability to rule out chance, bias, or confounding with confidence. Typically, at least one high-quality study indicates a positive association, but the results of other studies could be inconsistent. The committee responsible for VAO found limited or suggestive evidence of an association between herbicides and 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 periph-

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Veterans and Agent Orange: Update 2002 TABLE 1-1 Summary of Combined Conclusions on Specific Health Outcomes and Exposure to Herbicidesa from Update 2000 and AML Sufficient Evidence of an Association Soft-tissue sarcoma Non-Hodgkin's lymphoma Hodgkin's disease Chloracne Limited or Suggestive Evidence of an Association Respiratory cancers (or 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 children of veterans Inadequate or Insufficient Evidence to Determine Whether an Association Exists Hepatobiliary cancers Nasal or nasopharyngeal cancer Bone cancer Skin cancers (melanoma, basal, and squamous cell) Breast cancer Female reproductive cancers (cervical, uterine, and ovarian) Testicular cancer Urinary bladder cancer Renal cancer Leukemia Spontaneous abortion Birth defects (other than spina bifida) Neonatal or infant death and stillbirth 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, ulcers) Immune system disorders (immune suppression, autoimmunity) Circulatory disorders Respiratory disorders AL-type primary amyloidosis Limited/Suggestive Evidence of No Association Gastrointestinal tumors (stomach, pancreas, colon, rectum) 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.

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Veterans and Agent Orange: Update 2002 eral neuropathy, and spina bifida in children of veterans. Transient peripheral neuropathies had not been addressed in VAO—because, owing to their transient nature, they are not amenable to epidemiologic study—but in response to a request from VA, the committee responsible for Update 1996 reviewed these neuropathies and based its determination on case histories (see Chapter 10 of Update 1996). A 1995 analysis of birth defects among the offspring of veterans of operation Ranch Hand, 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 or suggestive-evidence category (see Chapter 9 of Update 1996). No changes were made in this category in Update 1998. Following the publication of Update 1998, on the basis of its evaluation of newly available scientific evidence and the cumulative findings of research reviewed in previous Veterans and Agent Orange reports, the committee responsible for Type 2 Diabetes found that there was limited or suggestive evidence of an association between exposure to the herbicides used in Vietnam or the contaminant TCDD and type 2 diabetes. The evidence reviewed in Update 2000 supported that finding. The committee responsible for Update 2000 reviewed the material in earlier Veterans and Agent Orange reports and newly available published literature and determined that there was limited or suggestive evidence of an association between exposure to herbicides used in Vietnam or the contaminant TCDD and acute myelogenous leukemia in the children of Vietnam veterans. After release of that report, researchers from one of the studies reviewed in Update 2000 discovered an error in their published data. After reconvening to reevaluate the previously reviewed and new literature regarding that illness, the Acute Myelogenous Leukemia report was produced; it reclassified acute myelogenous leukemia in children from “limited or suggestive evidence of an association ” to “inadequate evidence to determine whether an association exists.” Health Outcomes with Inadequate or Insufficient Evidence to Determine Whether an Association Exists For outcomes 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 might fail to control for confounding or have inadequate exposure assessment. Scientific data on many of the cancers and other health effects reviewed by the VAO and Update 1996, 1998, and 2000 committees were inadequate or insufficient to determine whether any association exists between the exposures of interest and a health outcome (see Table 1-1). There was one change in the health outcomes in this category between the first two reports: skin cancer was moved

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Veterans and Agent Orange: Update 2002 into this category in Update 1996 when available evidence no longer supported its classification as a condition with limited or suggestive evidence of no association. On the basis of an evaluation of all the epidemiologic evidence, the Update 1998 committee felt that urinary bladder cancer should be moved from the category of sufficient evidence of no association to this category. Although there was no evidence that exposure to herbicides or TCDD is related to this cancer, newly available evidence weakened the evidence of no association. No data reviewed in Update 2000 resulted in a change in that classification. The committee responsible for Acute Myelogenous Leukemia concluded that there was inadequate or insufficient evidence to determine whether an association exists between the exposures and acute myelogenous leukemia in the offspring of Vietnam veterans. Health Outcomes with Limited or Suggestive Evidence of No Association For an outcome in this category, several well conducted studies covering the full range of exposure that human beings are known to encounter are consistent in not showing a positive association between exposure to herbicides and the outcome at any exposure and have relatively narrow confidence intervals. A conclusion of “no association” is inevitably limited to the conditions, exposures, and length of observation covered by the available studies. The possibility of a very small increase in risk at the exposures studied can never be excluded. The VAO committee found a sufficient number and variety of well-designed studies to conclude that there is limited or suggestive evidence of no association between a small group of cancers and TCDD or the herbicides under study. That group included gastrointestinal tumors (colon, rectum, stomach, and pancreas), 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 from this category because the evidence no longer supported a no-association classification. No further changes in this category were made in Update 2000. Determining Increased Risk in Vietnam Veterans The second part of the committee's charge is to determine, to the extent permitted by available scientific data, the increased risk of disease among people exposed to herbicides during service in Vietnam. As discussed in previous VAO reports, although there have been numerous health studies of Vietnam veterans, many of them were hampered by relatively poor measures of exposure to herbicides or TCDD and other methodologic problems. Most of the evidence on which the findings regarding associations are based, therefore, comes from studies of people exposed to TCDD or herbicides in occupational and environmental set-

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Veterans and Agent Orange: Update 2002 tings rather than from studies of Vietnam veterans. The VAO and Update 1996, 1998, and 2000 committees found that body of evidence sufficient for reaching conclusions about statistical associations between herbicides and health outcomes, but the lack of adequate data on Vietnam veterans themselves complicated their consideration of the second part of the charge. Estimating the magnitude of risk of a particular health outcome among herbicide-exposed Vietnam veterans requires 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. The large uncertainties that remain regarding the magnitude of potential risk posed by 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 make quantitative risk assessments problematic. Therefore, 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 of herbicide exposure among various groups studied suggests 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. Individual veterans who had very high exposures to herbicides, however, could have risks approaching those described in the occupational and environmental studies. In their reports, the committees offer observations regarding increased risk in specific veteran populations on which relevant data are available. Existence of a Plausible Biologic Mechanism or Other Evidence of a Causal Relationship Toxicologic data form the basis of the committee's response to the third part of its charge—to determine whether there is a plausible biologic mechanism or other evidence of a causal relationship between herbicide exposure and a health effect. That information is summarized in general terms in separate toxicology chapters in previous reports: Chapter 4 of VAO and Chapter 3 of Update 1996, 1998, and 2000. Specific findings on each health outcome are also given in the chapters that review the epidemiologic literature. ORGANIZATION OF THIS REPORT The remainder of this report is organized into nine chapters. Chapter 2 briefly describes the considerations that guided the committee's review and evaluation of the scientific evidence. Chapter 3 updates the toxicology data on the effects of 2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram; these

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Veterans and Agent Orange: Update 2002 data contribute to the biologic plausibility of potential health effects in human populations. Chapter 4 provides an overview of the design of many of the epidemiologic studies reviewed by the committee. Chapter 5 addresses exposure-assessment issues and the exposure assessments conducted in the studies of the major cohorts. The committee's evaluation of the epidemiologic literature and its conclusions regarding associations between the exposures of interest and cancer, reproductive and developmental effects, neurobehavioral disorders, and other health effects are discussed in Chapters 6, 7, 8, and 9, respectively. The committee's research recommendations are presented in Chapter 10. 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. IOM. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press. IOM. 2002. Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leukemia in the Children of Vietnam Veterans. Washington, DC: National Academy Press.