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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 updated reviews to be completed every two years after the initial report for a period of ten years.

To carry out the study, 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 (henceforth called VAO) (IOM, 1994). This report contains a systematic review and evaluation of the then-available scientific evidence. Upon completion of VAO, a successor committee of the same name was formed that produced Veterans and Agent Orange: Update 1996 (hereafter referred to as Update 1996) (IOM, 1996).



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Veterans and Agent Orange: Update 1998 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 updated reviews to be completed every two years after the initial report for a period of ten years. To carry out the study, 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 (henceforth called VAO) (IOM, 1994). This report contains a systematic review and evaluation of the then-available scientific evidence. Upon completion of VAO, a successor committee of the same name was formed that produced Veterans and Agent Orange: Update 1996 (hereafter referred to as Update 1996) (IOM, 1996).

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Veterans and Agent Orange: Update 1998 The present report follows this model, summarizing the content of the two previous reports and providing detailed reviews of the most recent research. In conducting these studies, the committee operated independently of the DVA 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 was not part of its 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. Update 1996 contains a summary of the literature addressed in VAO and in-depth reviews of the scientific studies and other information developed during the intervening time. The present report follows this model, summarizing the content of the two previous reports and providing detailed reviews of the most recent research. In fulfilling its charge of judging whether each of a set of human health effects is associated with exposure to herbicides or dioxin, the committee concentrated primarily on reviewing and interpreting epidemiologic studies. The committee began its evaluation presuming neither the presence nor the absence of association. It 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 summarized in Chapter 4 of this report. In reviewing the literature, the committee found that the existing epidemiologic data base is severely lacking in quantitative measures of individual exposure to herbicides and dioxin. Assessment of the intensity and duration of individual exposures is a key component in determining whether specific health outcomes are associated with exposure to dioxin or other chemicals found in the herbicides used in Vietnam. Although different approaches have been employed to estimate exposure in Vietnam veterans and others exposed occupationally or environmentally, each approach is limited in its ability to determine precisely the degree and level of individual exposure. The available quantitative and qualitative evidence about herbicide exposure, summarized in Chapter 5, suggests that Vietnam veterans as a group had substantially lower exposure to herbicides and dioxin than the subjects in many occupational studies. Participants in Operation Ranch Hand are a known exception to this pattern, and it is likely that others among the approximately 3 million men and woman who served in Vietnam were exposed to herbicides at levels associated with health effects. Thus, in the committee's judgment, a sufficiently large range of exposures may exist among Vietnam veterans to conduct a valid epidemiologic study for certain health outcomes.

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Veterans and Agent Orange: Update 1998 To obtain additional information pertinent to the evaluation of possible health effects of herbicide exposure, the committee 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, residents of Vietnam, and 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. The committee felt that considering studies of other groups could help address the issue of whether these compounds might be associated with particular health 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 the studies, the committee concluded that it was inappropriate to use a quantitative technique such as metaanalysis to combine their individual results into a single summary measure of statistical association. Using such a summary measure would also inappropriately focus attention on one piece of the information used by the committee when, in fact, all the factors discussed above are important to evaluating the literature. Conclusions About Health Outcomes VAO and Update 1996 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 examined all research available through mid-1995, but concentrated on work published since the completion of VAO. The committee's statutory mandate is to determine, to the extent that available scientific data permit meaningful determinations, whether there is a statistical association between the suspect diseases and herbicide use, taking into account the strength of the scientific evidence and the appropriateness of the methods used to detect the association; the increased risk of disease among individuals exposed to herbicides during service in Vietnam; and

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Veterans and Agent Orange: Update 1998 whether there is a plausible biologic mechanism or other evidence of a causal relationship between herbicide exposure and a disease. The original committee addressed the first part of this charge by assigning each of the health outcomes under study 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 the evidence for 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. Consistent with the charge to the Secretary of Veterans Affairs in Public Law 102-4, the distinctions between categories are based on "statistical association," not on causality, as is common in scientific reviews. The committee was charged with reviewing the scientific evidence rather than making recommendations regarding DVA policy, and the findings reported do not imply or suggest any policy decisions; these must rest with the Secretary. 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 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. 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:

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Veterans and Agent Orange: Update 1998 PCT (as explained above), acute and subacute transient peripheral neuropathy, and spina bifida in the children of veterans. Transient peripheral neuropathies had not been addressed in VAO since, by virtue 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 Hands, in combination with earlier studies of neural tube defects in the children of Vietnam veterans published by the Centers for Disease Control and Prevention (CDC), 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 the 1996 report discusses this decision in detail. 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 confidence. 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 and Update 1996 committees were inadequate or insufficient to determine whether any association exists. There was one change in the health outcomes in this category between the 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. 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. The Update 1996 committee came to the same conclusions in all but one circumstance. It concluded that studies on skin cancer published since VAO, considered in combination with the evidence addressed in that report, no longer

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Veterans and Agent Orange: Update 1998 supported the classification of this health outcome in the no-association category. 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 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 in 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. Both the VAO and Update 1996 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 complicated their 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 VAO and Update 1996 committees found that in general, it was 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

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Veterans and Agent Orange: Update 1998 had very high exposures to herbicides could have risks approaching those described in the occupational and environmental studies. 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 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 the previous reports: Chapter 4 of VAO and Chapter 3 of Update 1996. Specific findings for each health outcome are also given in the chapters that reviewed the epidemiologic literature. Research Recommendations The Academy 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 committee responsible for Update 1996 did not make any further research recommendations. IMPACT OF THE REPORTS On July 27, 1993, the Institute of Medicine released Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam to the news media and the public. Immediately following the press conference, the Senate Committee on Veterans Affairs held a hearing on the report. Testifying at the hearing, Secretary

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Veterans and Agent Orange: Update 1998 of Veterans Affairs Jesse Brown announced that the Department of Veterans Affairs was already compensating Vietnam veterans exposed to herbicides for soft-tissue sarcoma, Hodgkin's disease, and chloracne. Based on the findings of the IOM committee, the DVA decided to begin immediately to compensate Vietnam veterans for non-Hodgkin's lymphoma and porphyria cutanea tarda (Category I diseases) (U.S. DVA, 1994). In September 1993, Secretary Brown announced that the DVA would also begin to compensate Vietnam veterans for respiratory cancers and multiple myeloma (Category II diseases) (U.S. DVA, 1993). Veterans and Agent Orange: Update 1996 was publicly released on March 14, 1996. The next day, DVA formed a task force to review the findings, which reported its recommendations for action on May 16 of that year. The following subsections focus on impacts of the Update 1996 report. A more detailed discussion of the impacts of VAO is contained in Chapter 2 of the 1996 report. DVA Task Force The DVA task force made four specific recommendations to Secretary Brown in the wake of the Update 1996 report: that the Secretary establish a presumption of service connection for prostate cancer based on exposure to an herbicide agent; that the Secretary establish a presumption of service connection for acute and subacute peripheral neuropathy based on exposure to an herbicide agent if manifested within one year of exposure to the agent; that the Secretary support increased research efforts to learn more about the possible relationship between exposure to herbicides and the development of birth defects, including spina bifida and other health problems in veterans' offspring; and that the Secretary establish a presumption of service connection for spina bifida in offspring of veterans based on exposure to an herbicide agent if statutory authority was enacted granting such authority (U.S. DVA, 1996). In a May 28, 1996, news conference, President Clinton and Secretary Brown announced the Administration's intention to implement all four recommendations. DVA proposed amending its regulations regarding presumptive service connection for prostate cancer and for acute and subacute peripheral neuropathy on August 8, 1996 (61 FR 41368-71), and announced a final rule concerning these conditions on November 7, 1996 (61 FR 57586-89). Legislation regarding the authority to grant compensation for spina bifida was proposed in July 1996. Section 421 of Public Law 104-204, which was signed on September 26, 1996, changed Title 38 of the U.S. Code to provide certain benefits, including a monthly monetary allowance, to children born with spina bifida (except spina bifida occulta) who are the natural children of veterans who served in Vietnam during

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Veterans and Agent Orange: Update 1998 the Vietnam era. DVA then proposed (62 FR 23724-31, May 1, 1997) and finalized (62 FR 51274-96, September 30, 1997) regulations implementing the law. Subsequently, Section 404 of Public Law 105-114, signed on November 21, 1997, made technical corrections to some of the definitions in the original act. FEDERAL GOVERNMENT'S RESPONSE TO CONCERNS OVER THE MILITARY USE OF HERBICIDES IN VIETNAM The federal government has been involved with international and domestic policy issues related to the health effects associated with the military use of herbicides, particularly Agent Orange, since the defoliation program began in Vietnam. On December 16, 1974, the U.S. Senate ratified the Geneva Protocol, which broadly sought an international commitment from all governments that they would never use chemical or biological weapons (including herbicides) in war. In April 1975, President Ford issued Executive Order 11850 renouncing future use of herbicides in war. U.S. Congress Congressional interest concerning Vietnam veterans' health falls primarily into three categories: (1) health care (provision of services at VA medical centers); (2) scientific research (primarily, epidemiologic research on veterans); and (3) compensation issues (for disabilities that might have resulted from exposure to herbicides). As documented in VAO and Update 1996, congressional committees have for many years held informational and oversight hearings and introduced bills on these topics, and Congress has passed several laws dealing with the human health effects of exposure to the herbicides used in Vietnam. This section focuses on congressional action since the release of Update 1996. Hearings on the Update 1996 Report Two congressional hearings were conducted to review the finding of Update 1996. The first of these was held on April 16, 1996, by the Subcommittee on Hospitals and Health Care of the House Committee on Veterans' Affairs (U.S. Congress, House, 1996). The IOM committee responsible for the report was represented by committee chair Dr. David Tollerud and member Dr. Andrew Olshan. Representatives of DVA and researchers involved in the CDC and the Ranch Hands studies of Vietnam veterans also participated. On September 19, 1996, the Senate Committee on Veterans Affairs heard testimony from Dr. Tollerud, Secretary of Veterans Affairs Brown, and others regarding the committee's classification of spina bifida into the limited/suggestive evidence of an association category (U.S. Congress, Senate, 1996).

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Veterans and Agent Orange: Update 1998 Legislation Regarding Herbicide Exposure and the Health of Vietnam Veterans In 1970, Congress enacted the first public law dealing with the military use of herbicides. Congress has since promulgated legislation to appropriate funds for herbicide exposure research, to provide clarification of payments received from the Agent Orange settlement fund, and to specify the conditions under which Vietnam veterans and their families may receive disability compensation for medical conditions. Health Care. Public Law 97-72, enacted on November 3, 1981, expanded eligibility for health care services to include veterans exposed to Agent Orange in Vietnam. The effect of this legislation was to provide health care for Vietnam veterans for conditions that require treatment and may have resulted from exposure to Agent Orange. Veterans need not demonstrate any direct link with Agent Orange; rather, care is provided unless the condition is shown to be due to something other than exposure (e.g., congenital or developmental conditions or conditions resulting from postservice trauma) (Conway, 1993). Public Law 103-452 extended the program through June 30, 1995. A further extension through December 31, 1997, was authorized in P.L. 104-110. The Veterans' Health Care Eligibility Reform Act of 1996—which became P.L. 104-262 on October 9, 1996—significantly revamped VA medical care eligibility requirements for all veterans and superseded the provisions of previous acts with regard to Vietnam veterans. As mentioned earlier, the 1997 appropriations for the Department of Veterans Affairs (P.L. 104-204) included provisions extending health care benefits to the children of Vietnam veterans who are born with spina bifida. Epidemiologic Studies. Public Law 96-151, enacted on December 20, 1979, ordered the Veterans Administration (VA) to conduct an epidemiologic study of the possible health effects in veterans of exposure to dioxin found in the herbicides used in Vietnam. The legislation also required the Office of Technology Assessment to review and approve the protocol for the study. In 1981, Public Law 97-72 expanded the scope of the epidemiologic study to include an evaluation of the impact on the health of Vietnam veterans of other environmental factors existing in Vietnam; this study was later transferred from the VA to the CDC and is referred to as the "Vietnam Experience Study." On April 7, 1986, President Reagan signed Public Law 99-272, which included provisions directing the VA to conduct an epidemiologic study of the long-term health effects of herbicide exposure on women who served in Vietnam. The Women Veterans Health Programs Act of 1992 (P.L. 102-585) expanded the program for women veterans. Compensation. On October 24, 1984, Congress enacted Public Law 98-542, the Veterans' Dioxin and Radiation Exposure Compensation Standards Act, to address

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Veterans and Agent Orange: Update 1998 the issue of compensation for disabilities that might have resulted from exposure to Agent Orange in Vietnam. This law "provided for payment, during a two-year interim period from October 1, 1984, to September 30, 1986, of disability and death benefits for Vietnam veterans with chloracne and porphyria cutanea tarda (an uncommon disorder of urinary porphyrin metabolism manifest in patients by thinning and blistering of the skin) which became manifest within one year after service in Vietnam and the survivors of veterans with such conditions" (U.S. Congress, Senate, 1989). Public Law 102-4, the Agent Orange Act of 1991, was enacted on February 6, 1991, to grant disability compensation payments for chloracne, non-Hodgkin's lymphoma, and soft-tissue sarcoma (other than osteosarcoma, chondrosarcoma, Kaposi's sarcoma, or mesothelioma) associated with Agent Orange. As discussed earlier, this law also mandated the review of the scientific literature that resulted in the Veterans and Agent Orange series of reports. Department of Veterans Affairs The Department of Veterans Affairs is responsible for providing health care, compensation, and benefits to veterans of the Vietnam era. DVA has also been involved in conducting and assessing research and in monitoring studies on the health effects of herbicide exposure in veterans. Health Care The DVA provides certain health care services to veterans of the Vietnam era (defined as January 9, 1962, through May 7, 1975, in P.L. 105-114) who were possibly exposed to herbicides as a result of their service in Southeast Asia. Prior to receiving health care services, veterans must provide proof of service in Vietnam. When a veteran requests DVA medical care, he or she undergoes a physical examination and appropriate diagnostic studies, which may serve as the Agent Orange examination (U.S. DVA, 1992). Research Efforts The DVA's Environmental Epidemiology Service (EES) has conducted several research studies on Vietnam veterans. The Agent Orange Registry (AOR) serves as a health surveillance data base; it contains records on approximately 10 percent of the entire Vietnam veteran population (self-selected) and is reviewed routinely for changes in health outcomes and mortality patterns. Since completion of the Update 1996 report, DVA has published studies regarding Hodgkin's disease incidence (Dalager et al., 1995), the risk of death from trauma and selected cancers among Marine veterans (Watanabe and Kang, 1995), mortality patterns among Army and Marine veterans (Watanabe and Kang, 1996), mortality among Army Chemical Corps veterans (Dalager and Kang, 1997), and lung

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Veterans and Agent Orange: Update 1998 cancer incidence (Mahan et al., 1997). These studies are reviewed in subsequent sections of this report. EES is also conducting or managing ongoing epidemiologic studies of women Vietnam veterans and Army Chemical Corps veterans. Compensation and Benefits The DVA compensates veterans for certain diseases related to exposure to dioxin-containing herbicides during their service in Vietnam. Whenever the Secretary determines that there is sound medical and scientific evidence indicating a positive association between exposure to an herbicide agent and occurrence of a disease in humans, DVA issues regulations stating that a presumption of service connection is warranted for the disease. DVA's compensation policy provides that the Secretary take into account reports from the National Academy of Sciences and all other sound medical and scientific information and analysis in making determinations. In evaluating any study, the Secretary must take into consideration whether the results are statistically significant, are capable of replication, and can withstand peer review [38 USC 1116 (b)(2)]. An association between the occurrence of a disease in humans and exposure to an herbicide agent is considered positive if the credible evidence for the association is equal to or outweighs the credible evidence against the association [38 USC 1116 (b)(3)]. Proposed regulations regarding compensation or denial of compensation for these diseases are published in the Federal Register, and DVA solicits comments from the public before final regulations are issued. Outreach Activities The DVA's Environmental Agents Service (EAS) is responsible for developing and implementing national medical policies and procedures regarding the exposure of military veterans to possible environmental hazards, including Agent Orange. EAS maintains the Agent Orange Registry, a computerized index of Agent Orange medical examinations. As of December 29, 1997, there were 259,554 veterans in the Registry (Rosenblum, 1998). In addition to diagnostic data, the AOR also contains a variety of self-reported demographic and military characteristics (U.S. DVA, 1992). The registry's participants (all self-selected) receive the Agent Orange Review, a newsletter that provides updated information about Agent Orange and related matters. EAS also compiles fact sheets, called Agent Orange Briefs, about Agent Orange and related concerns; copies of these briefs are available through the Agent Orange Coordinator at all DVA medical centers. Department of the Air Force In 1979, the Air Force began an epidemiologic study of Operation Ranch Hand personnel who participated in the aerial spraying of herbicides in Vietnam.

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Veterans and Agent Orange: Update 1998 The Ranch Hand study, formally known as the "Air Force Health Study," is designed to assess whether long-term adverse health effects exist and can be attributed to occupational exposure to Agent Orange and other herbicides and dioxins. It is managed by the Population Research Branch of the Air Force Armstrong Laboratory. The study population consists of approximately 1,000 Ranch Hand personnel and approximately 1,300 Air Force personnel involved in aircraft missions in Southeast Asia during the same period that the Ranch Hand unit was active. Comparison veterans were not involved with spraying herbicides. The study includes periodic analyses of postservice mortality, physical examinations, in-person interviews, medical record retrievals, and psychological testing. Examinations were administered in 1982, 1985, 1987, and 1992. The 1997 follow-up examinations began in May 1997 and were scheduled to be completed in March 1998. A final follow-up is planned for 2002. Numerous reports and papers regarding the Ranch Hand study population have been published. Many of these are reviewed in the earlier Veterans and Agent Orange reports. A complete listing of research publications is available at the study's Web site: http://www.brooks.af.mil/AFRL/HED/hedb/afhs.html. The National Technical Information Service maintains copies of the reports and publicly available data files. Environmental Protection Agency In 1991, the Environmental Protection Agency (EPA) began a scientific reassessment of the risks of exposure to the dioxin 2,3,7,8-TCDD and chemically similar compounds. EPA undertook this project in response to newly emerging scientific knowledge about the mechanisms of action of dioxin (U.S. EPA, 1992). The reassessment is part of EPA's efforts to improve the research and scientific base of the agency and to incorporate solid research and science into its decisions. In 1994, the EPA released a draft report on the project seeking comment on its technical accuracy and policy implications (U.S. EPA, 1994). The draft stated there was the potential for adverse impacts on human metabolism, developmental biology, reproductive biology and possibly other effects in the range of current human exposures to TCDD. According to the draft, evidence also suggested that dioxin and related compounds were likely to present a cancer hazard to humans. It was noted that there were significant data gaps and that additional information was needed to reduce uncertainty in these conclusions. The EPA Science Advisory Board (SAB) submitted its evaluation of the draft in September 1995 (SAB, 1995). It faulted the draft for its reliance on the standard EPA default assumption of a linear non-threshold model for carcinogenic risk. The SAB asserted that the report's presentation of scientific findings concerning possible risks was not balanced, with a tendency to overstate the possibility for danger; and that important uncertainties associated with the conclusions were not fully identified. However, it also noted almost all the SAB reviewers concurred with EPA's draft

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Veterans and Agent Orange: Update 1998 judgment that dioxin, under some conditions of exposure, was likely to increase human cancer incidence. The EPA report was undergoing revision at the end of 1998. International Agency for Research on Cancer IARC was established in 1965 by the World Health Organization to coordinate and conduct research on the causes of human cancer and to develop scientific strategies for cancer control. One of IARC' s primary efforts is a program to evaluate the carcinogenic risk of chemical, radiation, and other exposures to humans. This work is conducted by international working groups of experts who review and evaluate the scientific literature. To date, more than 800 agents (including chemicals, groups of chemicals, complex mixtures, occupational exposures, and biological or physical agents) have been examined. A working group of 25 scientists from 11 countries was convened in 1997 to review evidence for the potential carcinogenicity of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (IARC, 1997). The working group reviewed published scientific data on the occurrence of cancer in human populations known to have been exposed to high levels of dioxins, assessed the evidence for carcinogenic effects of dioxins in experimental animals, and evaluated possible biologic mechanisms of carcinogenesis for these substances. The IARC working group concluded on the basis of its review that 2,3,7,8-TCDD is carcinogenic to humans. It cited three major categories of supporting evidence: 2,3,7,8-TCDD is a multi-site carcinogen in experimental animals that has been shown by several lines of evidence to act through a mechanism involving the Ah Receptor. This receptor is highly conserved in an evolutionary sense and functions the same way in humans as in experimental animals. Tissue concentrations are similar both in heavily exposed human populations in which an increased overall cancer risk has been observed and in rats exposure to carcinogenic dosage regimens in bioassays. REFERENCES Conway F. 1993. Memorandum to the Institute of Medicine Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. Washington: Department of Veterans Affairs. May 18. Dalager NA, Kang HK. 1997. Mortality among Army Chemical Corps Vietnam veterans. American Journal of Industrial Medicine 31:719-726. Dalager NA, Kang HK, Burt VL, Weatherbee L. 1995. Hodgkin's disease and Vietnam service. Annals of Epidemiology 5:400-406. Institute of Medicine (IOM). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press.

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