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Executive Summary

Because of continuing uncertainty about the long-term health effects of exposure to the herbicides used in Vietnam, Congress passed Public Law 102–4 (P.L. 102–4), the “Agent Orange Act of 1991.” This legislation directed the Secretary of Veterans Affairs to request the National Academy of Sciences (NAS) to 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 the various chemical components of these herbicides, including dioxin. A committee convened by the Institute of Medicine (IOM) of the NAS conducted this review and in 1994 published a comprehensive report entitled Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as VAO) (IOM, 1994).

P.L. 102–4 also called for NAS to conduct subsequent reviews at least every 2 years for a period of 10 years from the date of the first report. NAS was instructed to conduct a comprehensive review of the evidence that had become available since the previous IOM committee report and to reassess its determinations and estimates of statistical association, risk, and biological plausibility. Committees were formed that produced Veterans and Agent Orange: Update 1996 (hereafter, Update 1996) (IOM, 1996) and Veterans and Agent Orange: Update 1998 (hereafter, Update 1998) (IOM, 1999). In 1999, in response to a request from the Department of Veterans Affairs (DVA), IOM convened a committee to conduct a focused review of the scientific evidence regarding Type 2 (adult-onset) diabetes. Although limited to one health outcome, its report, Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (hereafter, Type 2 Diabetes), otherwise adhered to the format of the Veterans and Agent Orange series (IOM, 2000).



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Veterans and Agent Orange: Update 2000 1 Executive Summary Because of continuing uncertainty about the long-term health effects of exposure to the herbicides used in Vietnam, Congress passed Public Law 102–4 (P.L. 102–4), the “Agent Orange Act of 1991.” This legislation directed the Secretary of Veterans Affairs to request the National Academy of Sciences (NAS) to 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 the various chemical components of these herbicides, including dioxin. A committee convened by the Institute of Medicine (IOM) of the NAS conducted this review and in 1994 published a comprehensive report entitled Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as VAO) (IOM, 1994). P.L. 102–4 also called for NAS to conduct subsequent reviews at least every 2 years for a period of 10 years from the date of the first report. NAS was instructed to conduct a comprehensive review of the evidence that had become available since the previous IOM committee report and to reassess its determinations and estimates of statistical association, risk, and biological plausibility. Committees were formed that produced Veterans and Agent Orange: Update 1996 (hereafter, Update 1996) (IOM, 1996) and Veterans and Agent Orange: Update 1998 (hereafter, Update 1998) (IOM, 1999). In 1999, in response to a request from the Department of Veterans Affairs (DVA), IOM convened a committee to conduct a focused review of the scientific evidence regarding Type 2 (adult-onset) diabetes. Although limited to one health outcome, its report, Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (hereafter, Type 2 Diabetes), otherwise adhered to the format of the Veterans and Agent Orange series (IOM, 2000).

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Veterans and Agent Orange: Update 2000 The present report is the third comprehensive review and evaluation of the newly published scientific evidence regarding associations between health outcomes and exposure to dioxin and other chemical compounds in herbicides used in Vietnam. In accordance with P.L. 102–4, the committee was asked to determine, to the extent that available data permitted meaningful determinations, (1) whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemiologic methods used to detect the association; (2) the increased risk of the disease among those exposed to herbicides during Vietnam service; and (3) whether there is a plausible biologic mechanism or other evidence of a causal relationship between herbicide exposure and the disease. DVA also asked the committee to examine the possible association between the herbicides of concern in this report and AL-type primary amyloidosis, a condition not examined in previous Veterans and Agent Orange reports. In conducting its study, the IOM 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. Rather, the study provides scientific information for the Secretary of Veterans Affairs to consider as the DVA exercises its responsibilities to Vietnam veterans. ORGANIZATION AND FRAMEWORK Chapter 2 provides an overview of the methods and conclusions of the previous Veterans and Agent Orange series reports. Chapter 3 updates the experimental toxicology data on the effects of the herbicides and 2, 3, 7, 8-TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin, commonly referred to as TCDD, or “dioxin”), a compound found as a contaminant in the herbicide 2,4,5-trichloro-phenoxyacetic acid (2,4,5-T). These data contribute to the biologic plausibility of potential health effects in human populations. Chapter 4 briefly describes the methodological considerations that guided the committee’s review and its evaluation. Chapter 5 addresses exposure assessment issues. Chapter 6 provides a general review of the epidemiologic studies used to assess the potential association between herbicides and specific health outcomes. The chapter is organized to reflect similarities and differences in the nature of exposure among three types of study populations: occupationally exposed, environmentally exposed, and Vietnam veterans. Health outcomes are addressed in the remaining chapters: Chapter 7 focuses on cancer outcomes; Chapter 8, on reproductive effects; Chapter 9, on neurobehavioral disorders; and Chapter 10, on other (noncancer) health effects including respiratory, immune system, metabolic, digestive, and circulatory disorders. Many epidemiologic studies assess multiple health outcomes. These chapters provide detailed information on and citations for the research discussed below.

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Veterans and Agent Orange: Update 2000 TOXICOLOGY SUMMARY The results of cellular and animal studies published since the release of Update 1998 that investigate the toxicokinetics, mechanism of action, and disease outcomes of the herbicides and TCDD are reviewed in Chapter 3. Although effects in such experiments cannot be translated directly to effects in humans at the same doses, these experiments provide important information on the biologic plausibility of toxic effects and the underlying mechanisms by which these effects occur. TCDD is considered more toxic than the uncontaminated components of the herbicides used in Vietnam. TCDD elicits a diverse spectrum of sex-, strain-, age-, and species-specific effects, including carcinogenicity, immunotoxicity, reproductive and developmental toxicity, hepatotoxicity, neurotoxicity, chloracne, and loss of body weight. Most species studied experimentally develop a “wasting syndrome,” characterized by a loss of body weight and fatty tissue, from acutely toxic doses. Liver necrosis (i.e., cell death) was seen at lethal doses. Effects on the morphology and function of the liver are seen at lower doses. TCDD affects the endocrine system of animals. Some experiments indicate that treating animals with TCDD alters thyroid hormone levels, but others do not, making the interpretation of effects on thyroid hormones difficult. In utero TCDD exposure decreased performance on certain learning and memory tasks in the offspring of rats and monkeys but improved performance on other tasks. However, animal studies to date suggest that the adult nervous system is sensitive to the effects of TCDD only at high doses. In experimental animals, one of the most sensitive systems to TCDD toxicity is the immune system. Recent studies have demonstrated that TCDD can alter the number and activity of immune cells and the ability of animals to fight off infection. Effects on the immune system, however, appear to be dependent on the species and strain of animal studied. Reproductive and developmental effects have been seen in animals exposed to TCDD. Effects on sperm counts, sperm production, and seminal vesicle weights have been seen in male offspring of rats and hamsters treated with TCDD during pregnancy. Effects on the female reproductive system have also been seen following in utero exposure to TCDD. Effects on the male and female reproductive systems, however, are not always accompanied by effects on reproductive outcomes. It is possible that effects on the reproductive system are secondary to effects on reproductive hormones. In recent studies, TCDD did not affect surgically induced endometrial lesions in rats, although effects were seen in earlier studies. Pre- and postnatal exposure of mice to TCDD increased sensitivity to endometrial lesion growth. TCDD is an extremely potent tumor promoter in laboratory rats. In a recent study there was an increase in hepatic foci at doses as low as 0.01 ng/kg/day. This is the lowest dose of TCDD to promote tumors to date. Recent data also suggest that promotion of liver tumors by TCDD in female rats depends on continuous exposure to TCDD.

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Veterans and Agent Orange: Update 2000 Over the past 10 years, much has been learned about the mechanisms by which the dioxins exert their toxic effects. Most information published to date is consistent with the hypothesis that TCDD produces its biological and toxic effects by binding to a protein that regulates gene expression, the aryl hydrocarbon receptor (AhR). The binding of TCDD to the AhR triggers a sequence of cellular events that involve interactions with numerous other cellular components. The actual biochemical and cellular events that follow the initial binding of these chemicals to the AhR and lead to particular toxic end points, however, have yet to be defined. Thus, although the presence of the AhR appears to be necessary for toxicity to occur, it alone is not sufficient. The findings that many AhR-modulated genes and responses are regulated in a cell-, tissue-, developmental stage-, and species-specific pattern suggest that the molecular and cellular pathways leading to any particular toxic event are extremely complex and probably involve multiple events, genes, and signal transduction pathways. Further definition of the pathways regulated by the AhR in a tissue-specific fashion will help to clarify the understanding of the relationships between the dose of TCDD that reaches the tissue and the events leading to specific toxic end points. Several publications have documented the presence of the AhR and associated proteins in a variety of tissues from different animal species and strains. Detailed analysis of variant forms has associated structure and levels of expression with function. Experiments in species and strains expressing different forms of the AhR suggest that differences in specific regions of the receptor also may be responsible in part for differential sensitivity to TCDD. Humans express the AhR, but differences in the levels of AhR among species and cell types preclude direct extrapolation of effects from one animal to another. Evidence continues to indicate that the sequence of the AhR in humans is highly conserved across individuals; therefore, expression of different forms of the AhR is not likely to explain differential responses to TCDD among individuals. Although structural differences in the AhR have been identified, it operates in a similar manner in animals and humans, and a connection between TCDD exposure and human health effects is, in general, considered biologically plausible. However, as mentioned previously, animals differ greatly in their susceptibility to TCDD-induced effects. Controversy still exists over whether the effects of TCDD are threshold dependent, that is, whether some exposure levels may be too low to induce any effect. Investigations into the endogenous ligand for the AhR (i.e., the compound in the body that normally binds to the receptor) continue. Although several endogenous compounds that bind to the AhR have been described, it is not yet clear whether these have any physiological significance. Recent experiments demonstrate that 2,4-dichlorophenoxyacetic acid (2,4-D) can cause behavioral effects, muscle weakness, and incoordination in animals, but these effects are seen only at high doses. 2,4-D affects neuron function and some hormones, including reproductive hormones. Reproductive and developmental effects have been seen in animals following 2,4-D exposure, but also only

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Veterans and Agent Orange: Update 2000 at high doses. A precursor of 2,4-D,2,4-dichlorophenoxybutyric acid (2,4-DB), did not cause an immunotoxic or carcinogenic response in rodents or dogs. 2,4-D does not appear to be genotoxic except at very high concentrations, and it has very low oncogenic (i.e., tumor-forming) activity. Little recent work has been conducted on 2,4,5-T. One study, which investigated its myelotoxicity, found that it had relatively weak potency to produce toxic effects on blood components. No new studies were identified that investigate disease outcomes associated with 2,4,5-T exposure in animals. Cacodylic acid (dimethylarsinic acid, DMA) has been shown to cause bladder tumors in rats and lung cancer in mice, and to promote skin cancer in mice sensitized by genetic manipulation or by exposure to ultraviolet B radiation. One recent report was found in which the toxic effects of picloram were investigated. In that study, a herbicide mixture was used and the observed effects were attributed to ingredients other than picloram. Researchers continue to investigate the actions of 2,4-D,2,4,5-T, and cacodylic acid at the molecular and cellular levels to determine the mechanisms that underlie the toxicity of these compounds. No one mechanism has been established that explains their toxicity. EXPOSURE ASSESSMENT Assessment of individual exposures to herbicides and dioxin is a key element in determining whether specific health effects are linked to these compounds. The committee that produced VAO found that the definition and quantification of exposure are the weakest methodologic aspects of the epidemiologic studies. Although different approaches have been used to estimate exposure among Vietnam veterans, each approach is limited in its ability to determine precisely the intensity and duration of individual exposure. Another IOM committee is facilitating the development and evaluation of models of herbicide exposure for use in studies of Vietnam veterans. That committee authored and disseminated a Request for Proposals (RFP) for exposure assessment research in 1997 (IOM, 1997) and is performing scientific oversight of the research. Work funded under this RFP began in 1998 and was still under way at the end of 2000. CONCLUSIONS ABOUT HEALTH OUTCOMES Chapters 7, 8, 9, and 10 provide a detailed evaluation of the epidemiologic studies reviewed by the committee and their implications for cancer, reproductive effects, neurobehavioral effects, and other health effects. As detailed in Chapter 4, the committee weighed the strengths and limitations of the epidemiologic evidence in previous Veterans and Agent Orange reports as well as the newly published scientific data and reached its conclusions by interpreting the new

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Veterans and Agent Orange: Update 2000 evidence in the context of the whole of the literature. It assigned each health outcome being considered to one of the four categories listed in Table 1–1. The definitions of the categories and the criteria for assigning a particular health outcome to them are described in the table, and the specific rationale for each of the findings is detailed in the appropriate chapter. Since this update is intended to supplement rather than replace earlier reports, much of the information on studies reviewed in those reports has not been repeated. The reader is referred to relevant sections of the previous reports for additional detail and explanation. Consistent with the mandate of P.L. 102–4, the distinctions between categories are based on “statistical association,” not on causality, as is common in scientific reviews. Thus, standard criteria used in epidemiology for assessing causality (Hill, 1971) do not strictly apply. The committee was charged with reviewing the scientific evidence, rather than making recommendations regarding DVA policy, and the findings reported in Table 1–1 are not intended to imply or suggest any policy decisions; these must rest with the Secretary of Veterans Affairs. TABLE 1–1 Updated (2000) Summary of Findings in Occupational, Environmental, and Veterans Studies Regarding the Association Between Specific Health Outcomes and Exposure to Herbicides 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 for an association. There is sufficient evidence of an association between exposure to herbicides and the following health outcomes: Soft-tissue sarcoma Non-Hodgkin’s lymphoma Hodgkin’s disease Chloracne Limited/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/suggestive evidence of an association between exposure to herbicides and the following health outcomes: Respiratory cancers (lung/bronchus, larynx, trachea) Prostate cancer Multiple myeloma Acute and subacute transient peripheral neuropathy Porphyria cutanea tarda Type 2 diabetes (category change from Update 1998)

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Veterans and Agent Orange: Update 2000 Spina bifida in the children of veterans Acute myelogenous leukemia (AML) in the children of veterans (category change from Update 1998) Inadequate/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 cancers Nasal/nasopharyngeal cancer Bone cancer Skin cancers (melanoma, basal, and squamous cell) Breast cancer Female reproductive cancers (cervical, uterine, ovarian) Testicular cancer Urinary bladder cancer Renal cancer Leukemia Spontaneous abortion Birth defects (other than spina bifida) Neonatal/infant death and stillbirths Low birthweight Childhood cancer in offspring, other than acute myelogenous leukemia Abnormal sperm parameters and infertility Cognitive and neuropsychiatric disorders Motor/coordination dysfunction Chronic peripheral nervous system disorders Gastrointestinal, metabolic, and digestive disorders (changes in liver enzymes, lipid abnormalities, ulcers) Immune system disorders (immune suppression and autoimmunity) Circulatory disorders Respiratory disorders AL-type primary amyloidosis (new health outcome) Limited/Suggestive Evidence of No Association 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. A conclusion of “no association” is inevitably limited to the conditions, level 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. There is limited/suggestive evidence of no association between exposure to herbicides and the following health outcomes: Gastrointestinal tumors (stomach cancer, pancreatic cancer, colon cancer, rectal cancer) Brain tumors NOTE: “Herbicides” refers to the major herbicides used in Vietnam: 2,4-D (2,4-dichlorophenoxyacetic acid), 2,4,5-T (2,4,5-trichlorophenoxyacetic acid) and its contaminant TCDD (2,3,7,8-tetrachlorodibenzo-p-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 2000 Health Outcomes with Sufficient Evidence of an Association In Update 1998, the committee found sufficient evidence of an association between exposure to herbicides and/or TCDD and soft-tissue sarcoma, non-Hodgkin’s lymphoma, Hodgkin’s disease (HD), and chloracne. Recent scientific literature continues to support the classification of these diseases in this category. Based on the recent literature, there are no additional diseases that satisfy this category’s criteria. The evidence that supports the committee’s conclusions for the three cancers is detailed in Chapter 7 and for chloracne in Chapter 10. The studies reviewed for this report continue a pattern of mixed findings regarding the evidence of an association between soft-tissue sarcoma (STS) and herbicide or dioxin exposure. No new cases were observed in the latest update of ongoing studies of U.S. and Dutch chemical workers. A study of Danish paper mill workers found some excess of STS, but the possible link with dioxin exposure was not well established. Updates of the Air Force Health Study and Seveso populations did not add any new information on STS. An investigation of cancers in the vicinity of a solid waste incinerator in France found a statistically significant spatial cluster, although methodologic concerns lessen confidence in these findings. Several new studies of non-Hodgkin’s lymphoma incidence and mortality have been published since Update 1998. Of the three with the largest sample populations, two—studies of a population living near a solid waste incinerator and of male Vietnam veterans from Australia—reported elevated incidence rates. The third—a mortality study in areas where chlorophenoxy herbicides may have been used—observed rates similar to those expected in the general population. Three new reports of males occupationally exposed to chlorinated organic compounds indicated either elevated HD incidence or mortality. Elevated rates for men and women were also observed in the “medium-exposure” zone for the environmentally exposed Seveso cohort. A new study found that despite the high frequency of skin disorders reported during service in Vietnam, there were no cases of chloracne and no evidence for an increased risk of acne among Ranch Hand participants compared to other theater veterans either during the Vietnam conflict or subsequently. Nonetheless, there is abundant evidence that TCDD exposure causes chloracne. Health Outcomes with Limited/Suggestive Evidence of an Association In Update 1998, the committee found limited/suggestive evidence of an association for three cancers—respiratory (larynx, lung or bronchus, and trachea) cancer, prostate cancer, and multiple myeloma—and three other health outcomes—spina bifida in the children of veterans, acute and subacute (transient) peripheral neuropathy, and porphyria cutanea tarda. The recent scientific literature continues to support the classification of these diseases in the limited/suggestive category of evidence.

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Veterans and Agent Orange: Update 2000 In 2000, the committee responsible for Type 2 Diabetes found that 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. The committee also found that one additional condition satisfies the criteria necessary for inclusion in this category: acute myelogenous leukemia (AML)1 in the children of veterans. Two studies, in particular, support this conclusion. One is a case-control study of AML (Wen et al., 2000) in which self-reported service in Vietnam or Cambodia was associated with an elevated risk after adjustment for numerous potentially confounding life-style and sociodemographic factors. The second, a study of the children of Australian Vietnam veterans (AIHW, 2000), found a greater than fourfold risk although confounding factors other than age and gender were not controlled. While direct measures of exposure are lacking, the committee found the following characteristics of these studies to be particularly persuasive: (1) both were conducted in Vietnam veteran populations; (2) the association was specific for AML, with no excess risk found for other forms of leukemia; (3) one study adjusted for numerous confounders, while the other had an association of sufficiently large magnitude to reduce the likelihood of being completely due to confounding; and (4) the strongest association was seen in children diagnosed at the youngest ages—cases that are considered the strongest candidates for an etiology of parental origin. These characteristics diminish the likelihood that the outcomes were unrelated to service in Vietnam. A third study (Buckley et al., 1989), which reported a 2.7-fold increased risk of AML in the children of fathers with self-reported exposure of more than 1,000 days to pesticides or weed killers, adds to the plausibility that herbicide exposure could be related to the higher risk observed among those who served in Vietnam. Recently published research on lung and bronchus cancer in U.S. chemical production workers and Ranch Hand veterans continues to support the finding that there is limited/suggestive evidence for an association between the herbicides of concern in this report and the risk of these outcomes. Evidence for an exposure-response relationship has been slightly strengthened since Update 1998 but still does not support a conclusion of sufficient evidence. Although the latest data on the Seveso cohort do not show an excess, it remains early in the followup of this cohort for the characterization of cancers with latencies of decades. Studies also continue to support the conclusion that there is limited/suggestive evidence of an association between laryngeal cancer and exposure to the herbicides of concern in this report. The conclusion that there is sufficient evidence cannot be reached at this time because the most important risk factors for cancer of the larynx are not controlled in any of these studies and may confound the 1   Acute myelogenous leukemia (ICD•9 205) is referred to by other names as well, including acute myeloid leukemia and acute nonlymphocytic leukemia. There are also numerous subtypes of the disease.

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Veterans and Agent Orange: Update 2000 relationship to the extent that they could produce the slight elevation observed in most positive studies. The new data on prostate cancer are not entirely consistent. Excess incidence was reported in studies of pesticide appliers in Sweden and Florida, but the exposure of both cohorts is not well defined and the studies do not provide direct evidence that dioxin is carcinogenic to the prostate. The clear excess observed in Australia’s Vietnam veterans supports an association between prostate cancer and service in Vietnam, under the assumption that the veterans are not receiving better health surveillance than the general population of the same age in that country. The null findings among Ranch Hand personnel run counter to this conclusion. Among the three newly reviewed mortality studies of prostate cancer, the two cohorts showing nonsignificant excesses of about 20 percent had the highest-quality exposure information. Although the results for this outcome are mixed, it should be kept in mind that most Vietnam veterans have not yet reached the age at which prostate cancer tends to appear. Among the newly reviewed studies of multiple myeloma (MM), only the National Institute of Occupational Safety and Health cohort of chemical production workers has both a relatively large number of subjects and data that clearly point to exposure to the herbicides and contaminants most relevant to Vietnam veterans. This study found a twofold increased mortality risk. The committee is aware of no new publications that investigate the association between exposure to the compounds of interest and acute or subacute transient peripheral neuropathy, and knows of no evidence that new cases of these conditions that develop long after service in Vietnam would be associated with wartime herbicide exposure. Since Update 1998 was published, a validation study found a significant excess of spina bifida cases in the children born to Australian Vietnam veterans. A study of occupational exposure to pesticides and selected congenital malformations in Spain did not find an increased risk where there had been paternal exposure to organophosphates or organochlorines pesticides, although there were a small number of exposed cases and the statistical power and precision of the study were poor. A new study of a group of Austrian chemical workers exposed to TCDD in herbicide production in the 1970s reported that urinary porphyrins remained abnormal, although not clinically characteristic of porphyria cutanea tarda (PCT). Coproporphyrinogen levels were within the normal range, but there was a reversal in the normal ratio of isomer I to isomer III in almost half of the subjects. The authors inferred that this indicated persistent liver injury and abnormal porphyrin metabolism due to TCDD, and implied that exposed workers may be at risk for related conditions including PCT. Several new studies of herbicide or dioxin exposure and Type 2 diabetes were published after the completion of Update 1998. As detailed in Type 2

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Veterans and Agent Orange: Update 2000 Diabetes, no one paper or study was determinative in reaching the finding that there was limited/suggestive evidence of an association. Instead, the committee found that the information accumulated over years of research met the definition established for this category. Positive associations were reported in many mortality studies, which may underestimate the incidence of diabetes, and in most of the morbidity studies identified by the committee. Since the completion of Type 2 Diabetes, an updated review of the Seveso cohort has been published that found an excess incidence of this condition among women but not men in the high- and medium-exposure zones. Health Outcomes with Inadequate/Insufficient Evidence to Determine Whether an Association Exists The scientific data for many of the cancers and other diseases reviewed by the committee were inadequate or insufficient to determine whether an association exists. This group includes hepatobiliary cancers (cancers of the liver and intrahepatic bile duct), nasal and nasopharyngeal cancer, bone cancer, skin cancers (including melanoma, basal or squamous cell carcinoma and nonmelanocytic skin cancers), breast cancer, cancers of the female reproductive system (including cervix, endometrium, and ovaries), testicular cancer, urinary bladder cancer, renal cancer (cancers of the kidney and renal pelvis), and leukemias. The scientific evidence regarding each of these cancers is detailed in Chapter 7. Several reproductive effects are classified in this category, including spontaneous abortion, birth defects other than spina bifida, neonatal or infant death and stillbirths, low birthweight, childhood cancer in offspring (other than acute myelogenous leukemia), and abnormal sperm parameters and infertility. The scientific evidence for reproductive effects is detailed in Chapter 8. Evidence for the neurobehavioral effects classified in this category—cognitive and neuropsychiatric disorders, motor or coordination dysfunction, and chronic peripheral nervous system disorders—is detailed in Chapter 9. Other health effects that are classified in the inadequate/insufficient category include metabolic and digestive disorders, immune system disorders, circulatory disorders, respiratory disorders, and AL-type primary amyloidosis. The scientific evidence underlying these findings is detailed in Chapter 10. Health Outcomes with Limited/Suggestive Evidence of No Association In VAO, the committee found a sufficient number and variety of well-designed studies to conclude that there is limited/suggestive evidence of no association between a small group of cancers and exposure to TCDD or herbicides. This group includes gastrointestinal tumors (colon, rectal, stomach, and pancreatic) and brain tumors. Recent scientific evidence continues to support the classifica-

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Veterans and Agent Orange: Update 2000 tion of such cancers in this category and is detailed in Chapter 7. Based on the recent literature, there are no additional diseases that satisfy the criteria necessary for this category. A conclusion of “no association” is inevitably limited to the conditions, level 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 Although there have been numerous health studies of Vietnam veterans, most 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 disease association 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 committee found this body of evidence sufficient for reaching the conclusions about statistical associations between herbicides and the health outcomes. However, the lack of adequate data on Vietnam veterans per se complicates the quantification of any increased risk of disease among individuals exposed to herbicides during service in Vietnam. Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the epidemiologic studies reviewed (Chapters 7–10), the inadequate control for other important risk factors in many studies, and uncertainty about the nature and magnitude of exposure to herbicides in Vietnam (Chapter 5), the necessary information to undertake a quantitative risk assessment is lacking. Thus, the committee cannot quantify the degree of risk likely to be experienced by those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era. For those outcomes in the “sufficient” and “limited/ suggestive” categories, what can be said is that too little is known about the herbicide exposure of veterans to make a meaningful determination of the increased risk, if any, of these outcomes among Vietnam veterans. Where there is inadequate/insufficient evidence to determine whether an association exists between herbicide exposure and a particular health outcome, there is also inadequate/insufficient information to assess the increased risk, if any, of that outcome. Finally, a finding of “limited/suggestive evidence of no association” between herbicide exposure and a health outcome means that the evidence suggests there is no increased risk of that outcome among Vietnam veterans. These conclusions are inevitably limited to the conditions, level of exposure, and length of observation covered by the studies reviewed by the committee. There are certain diseases about which the committee can draw more specific conclusions, and this information is related in the discussion of those diseases.

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Veterans and Agent Orange: Update 2000 OBSERVATIONS AND RESEARCH RECOMMENDATIONS Although great strides have been made over the past several years in understanding the health effects of exposure to the herbicides used in Vietnam and dioxin, and in elucidating the mechanisms underlying these effects, there are still important gaps in our knowledge. Subsequent chapters of this report contain recommendations for further work addressing some specific research needs identified in the course of this study. Additional observations on one major research effort are offered below. The Air Force Health Study (AFHS) is an epidemiologic study whose purpose is to determine whether exposure to the herbicides used in Vietnam may be responsible for any adverse health conditions observed in a cohort of Air Force personnel responsible for conducting aerial spray missions (the Ranch Hands). A baseline morbidity study of the Ranch Hands and a matched comparison cohort was conducted in 1982, with follow-up assessments in 1985, 1987, 1992, and 1997. In accordance with the study protocol, one additional assessment is planned for 2002, after which a final report will be issued. Because this study represents one of the few primary sources of information on the health of Vietnam veterans and is coming close to its scheduled end, the committee believes it is timely to offer some observations and recommendations about it. The AFHS cohorts represent an unusually thoroughly studied population. Some of the data generated in the course of the study are already or soon will be available to the public. However, there are also medical records and biological specimens that are not amenable to such public disclosure. The committee believes there is scientific merit in retaining and maintaining these medical records and samples, so that—with proper respect for the privacy of the study participants—they could be available for future research. It therefore recommends that the federal government examine whether and how the various forms of data and specimens collected in the course of the Air Force Health Study could be retained and maintained, and what form of oversight should be established for their future use. The committee further recommends that consideration be given to whether it is appropriate to continue the study past its planned completion date. It notes that the AFHS cohorts are only now reaching the age where several health outcomes of interest may be expected to manifest. The committee cannot draw a conclusion on whether or not a continuation of research on the AFHS cohorts will inform specific questions regarding the health effects of exposure to the herbicides used in Vietnam. However, the committee’s judgment is that continued research on the health of the Ranch Hand and comparison veterans is likely to yield important information on the determinants of health and disease in males who served in the military during the Vietnam era and perhaps their offspring. If the records were to be retained and maintained and/or the research continued, this would have to be done with the full knowledge and consent of the AFHS population and be subject to controls that would respect the privacy of the participants.

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Veterans and Agent Orange: Update 2000 REFERENCES AIHW (Australian Institute of Health and Welfare). 2000. Morbidity of Vietnam veterans. Adrenal gland cancer, leukaemia and non-Hodgkin’s lymphoma: Supplementary report No. 2. (AIHW cat. No. PHE 28). Canberra: AIHW. Buckley JD, Robison LL, Swotinsky R, Garabrant DH, LeBeau M, Manchester P, Nesbit ME, Odom L, Peters JM, Woods WG, Hammond GD. 1989. Occupational exposures of parents of children with acute nonlymphocytic leukemia: a report from the Children’s Cancer Study Group. Cancer Research 49:4030–4037. Hill, AB. 1971. Principles of Medical Statistics, 9th Ed. New York: Oxford University Press. 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. 1997. Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research. 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. Wen WQ, Shu XO, Steinbuch M, Severson RK, Reaman GH, Buckley JD, Robison LL. 2000. Paternal military service and risk for childhood leukemia in offspring. American Journal of Epidemiology 151(3):231–240.