1
Executive Summary

Because of continuing uncertainty about the long-term health effects of exposure to herbicides used in Vietnam, Congress passed Public Law 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. 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 (IOM, 1994).

Public Law 102-4 also called for the NAS to conduct subsequent reviews at least every two years for a period of ten years from the date of the first report. The NAS was instructed to conduct a comprehensive review of the evidence that has become available since the previous IOM committee report; and reassess its determinations and estimates of statistical association, risk, and biological plausibility.

This IOM report presents the first updated review and evaluation of the newly published scientific evidence regarding associations between diseases and exposure to dioxin and other chemical compounds in herbicides used in Vietnam. For each disease, the IOM 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 epidemiological methods used to detect the association; 2) the increased risk of the disease among those



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--> 1 Executive Summary Because of continuing uncertainty about the long-term health effects of exposure to herbicides used in Vietnam, Congress passed Public Law 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. 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 (IOM, 1994). Public Law 102-4 also called for the NAS to conduct subsequent reviews at least every two years for a period of ten years from the date of the first report. The NAS was instructed to conduct a comprehensive review of the evidence that has become available since the previous IOM committee report; and reassess its determinations and estimates of statistical association, risk, and biological plausibility. This IOM report presents the first updated review and evaluation of the newly published scientific evidence regarding associations between diseases and exposure to dioxin and other chemical compounds in herbicides used in Vietnam. For each disease, the IOM 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 epidemiological methods used to detect the association; 2) the increased risk of the disease among those

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--> exposed to herbicides during Vietnam service; and 3) whether there is a plausible biological mechanism or other evidence of a causal relationship between herbicide exposure and the disease. In addition to bringing the earlier scientific evidence up to date, the committee has addressed several specific areas of concern, as requested by the Department of Veterans Affairs (DVA). These are: 1) the relationship between exposure to herbicides and the development of acute and subacute peripheral neuropathy; 2) the relationship between exposure to herbicides and the development of prostate cancer, hepatobiliary cancer, and nasopharyngeal cancer; and 3) the relationship between the length of time since first exposure and the possible risk of cancer development. 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 The conclusions in this updated report are based on cumulative evidence from the scientific literature reviewed in Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, which will be abbreviated here as VAO. This update is intended to supplement rather than replace VAO; therefore, most of the background information has not been repeated. Most chapter sections begin with brief summaries of the scientific data in VAO, followed by a more thorough discussion of the newly published data and their interpretation. The reader is referred to relevant sections of VAO for additional detail and explanation. Chapter 2 provides an overview of the methods and conclusions of VAO. In addition, it provides a summary of the recent activities of several federal government agencies that are relevant to the health effects of Agent Orange and other herbicides used in Vietnam. Chapter 3 provides an update of the recent experimental toxicology data on the effects of the herbicides and of TCDD, a compound found as a contaminant in the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). These data serve as the basis for the biological plausibility of potential health effects in human populations. Chapter 4 describes the methodological considerations that guided the committee's review and its evaluation. Chapter 5 updates the exposure assessment issues in VAO. Chapter 8 reviews the methods used to study latency, or time-related effects—a topic of special interest to the DVA—and evaluates the evidence on latency for the cancers under study. The committee focused most of its efforts on reviewing and interpreting epidemiologic studies, in order to judge whether each of the human health effects is associated with exposure to herbicides or dioxin. The committee weighed the

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--> strengths and limitations of the scientific data in VAO as well as the newly published scientific data, and reached its conclusions by interpreting the new evidence in the context of the original report. In particular, each disease has been placed into one of four categories, depending on the strength of evidence for an association (see Conclusions about Health Outcomes, below). The committee used the same criteria to categorize diseases as were used in VAO. In the chapters on the various health outcomes (7, 9, 10, and 11), the committee relied on many of the same epidemiologic studies when assessing the potential associations with herbicides. Therefore, Chapter 6 provides a framework for the methods used in the epidemiologic studies. 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. Toxicology Summary Chapter 3 reviews the results of animal studies published during the past three years that investigated the toxicokinetics, mechanism of action, and disease outcomes of TCDD, plus the herbicides themselves. TCDD elicits a diverse spectrum of biological sex-, strain-, age-, and species-specific effects, including carcinogenicity, immunotoxicity, reproductive/developmental toxicity, hepatotoxicity, neurotoxicity, chloracne, and loss of body weight. These effects vary according to the age, sex, species, and strain of the animals involved. To date, the scientific consensus is that TCDD is not genotoxic and that its ability to influence the carcinogenic process is mediated via epigenetic events such as enzyme induction, cell proliferation, apoptosis, and intracellular communication. Recent studies on the effects of TCDD and related substances on the immune system amplify earlier findings and suggest that these compounds affect primarily the T-cell arm of the immune response. Direct effects of TCDD on T cells in vitro, however, have not been demonstrated suggesting that the action of TCDD may be indirect. In contrast, a number of animal studies of the reproductive and developmental toxicity of TCDD suggests that developing animals may be particularly sensitive to the effects of TCDD. Specifically, male reproductive function has been reported to be altered following perinatal exposure to TCDD. In addition, experimental studies of the effects of TCDD in the peripheral nervous system suggest that TCDD can cause a toxic polyneuropathy in rats after a single, low dose. Other recent studies provide evidence that hepatotoxicity of TCDD involves AhR-dependent mechanisms. The most recent studies have focused on the elucidation of the molecular mechanism of TCDD toxicity. The evidence further supports the concept that the toxic effects of TCDD involve AhR-dependent mechanisms. A better appreciation of the complexity of TCDD effects in target cells has led to the development

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--> of refined, physiologically based pharmacokinetic models. These models take into account intracellular diffusion, receptor and protein binding, and liver induction to establish the fractional distribution of the total body burden as a function of the overall body concentration. The association of TCDD with the cytosolic AhR has been shown to require a second protein, known as ARNT, for DNA binding capability and transcriptional activation of target genes. There is also increasing evidence suggesting that events other than receptor binding influence biological response to TCDD. It is now clear that AhR-related signaling influences, and is itself influenced by, other signal transduction mechanisms at low concentrations. Signaling interactions explaining the toxic effects of TCDD may involve growth factors, free radicals, the interaction of TCDD with the estrogen transduction pathway, and protein kinases. The toxicity of the herbicides used in Vietnam remains poorly studied. In general, the herbicides 2,4-D, 2,4,5-T, cacodylic acid, and picloram have not been identified as particularly toxic substances since high concentrations are often required to modulate cellular and biochemical processes. Impairment of motor function has been reported in rats administered high single oral doses of 2,4-D. The ability of 2,4,5-T to interfere with calcium homeostasis in vitro has been documented and linked to the teratogenic effects of 2,4,5-T on the early development of sea urchin eggs. There is evidence suggesting that both 2,4-D and 2,4,5-T are capable of inducing renal lesions in rats. A series of studies indicates that high concentrations of cacodylic acid results in the formation of a toxic intermediate, the dimethylarsenic radical. No recent studies pertaining to the toxicity of picloram have been published. The half-life in the body of 2,4-D and 2,4,5-T is relatively short and does not appear to extend beyond two weeks. 2,4-D binds covalently to hepatic proteins and lipids, but the molecular basis of this interaction and its biologic consequences are unknown. Exposure Assessment Assessment of individual exposure to herbicides and dioxin is a key element in determining whether specific health outcomes are linked to these compounds. The committee has found, however, 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 and among various occupationally and environmentally exposed groups, each approach is limited in its ability to determine precisely the intensity and duration of individual exposure. Since the publication of VAO, there has been considerable progress in the use of serum TCDD levels and/or quantitative exposure indices, as summarized in Chapter 5. There also has been progress in characterizing the TCDD body burdens in several groups, including the Ranch Hand cohort, Seveso residents, German herbicide production employees, and Vietnamese civilians (Michalek et

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--> al, 1996; Needham et al., 1994; Flesch-Janys et al., 1994; Ott et al., 1993; and Verger et al., 1994). The mean half-life of TCDD in humans has been calculated to be about 8.7 years in the Ranch Hand cohort (Michalek et al., 1996). Serum TCDD measurements may provide valuable information about past herbicide exposure under some conditions, and they are best used to detect differences in exposure levels among large groups in epidemiologic studies. This additional information on TCDD body burdens in specific groups and information on half-lives allow more accurate comparisons of relative levels of exposure to TCDD among cohorts. Although definitive data are lacking, the available evidence suggests that Vietnam veterans as a group had substantially lower exposure to herbicides and dioxin than did the subjects in many occupational studies. The participants in Operation Ranch Hand and the Army Chemical Corps are exceptions to this pattern, and it is likely that there are others who served in Vietnam who had exposures comparable in intensity to members of the occupationally exposed cohorts. It is currently not possible to identify this heavily exposed fraction of Vietnam veterans, although exposure reconstruction methods with this capability could perhaps be developed and validated. Conclusions About Health Outcomes Chapters 7, 9, 10, and 11 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 is detailed in Chapter 4, the committee used the epidemiologic evidence it reviewed to assign each of the health outcomes being studied into 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 Chapters 7, 9, 10 and 11. Consistent with the mandate of Public Law 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 Table 1-1 is not intended to imply or suggest any policy decisions; these must rest with the Secretary of Veterans Affairs. Health Outcomes with Sufficient Evidence of an Association In VAO, the committee found sufficient evidence of an association with herbicides and/or TCDD for five diseases: soft-tissue sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, chloracne, and porphyria cutanea tarda (in genetically susceptible individuals). The recent scientific literature continues to support

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--> TABLE 1-1 Updated Summary of Findings in Occupational, Environmental, and Veterans Studies Regarding the Association Between Specific Health Problems 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, larynx, trachea) Prostate cancer Multiple myeloma Acute and subacute peripheral neuropathy (new disease category) Spina bifida (new disease category) Porphyria cutanea tarda (category change in 1996) 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 Female reproductive cancers (cervical, uterine, ovarian) Breast cancer

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--> Inadequate/Insufficient Evidence to Determine Whether an Association Exists (continued) Renal cancer Testicular cancer Leukemia Spontaneous abortion Birth defects (other than spina bifida) Neonatal/infant death and stillbirths Low birthweight Childhood cancer in offspring Abnormal sperm parameters and infertility Cognitive and neuropsychiatric disorders Motor/coordination dysfunction Chronic peripheral nervous system disorders Metabolic and digestive disorders (diabetes, changes in liver enzymes, lipid abnormalities, ulcers) Immune system disorders (immune suppression and autoimmunity) Circulatory disorders Respiratory disorders Skin cancer (category change in 1996) 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) Bladder 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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--> the classification of the first four of these diseases in the category of sufficient evidence. Based on the recent literature, the committee has reclassified porphyria cutanea tarda into the category of limited/suggestive evidence, as described below. Based on the recent literature, there are no additional diseases that satisfy this category's criteria—that 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 regards evidence from several small studies that are free from bias and confounding, and that show an association that is consistent in magnitude and direction, as sufficient evidence for an association. The evidence that supports the committee's conclusions for the three cancers is detailed in Chapter 7; for chloracne in Chapter 11. Health Outcomes with Limited/Suggestive Evidence of Association In VAO, the committee found limited/suggestive evidence of an association for three cancers: respiratory cancer, prostate cancer, and multiple myeloma. The recent scientific literature continues to support the classification of these diseases in the category of limited/suggestive evidence. The literature also indicates that three additional conditions satisfy the criteria necessary for this category: spina bifida, acute and subacute (transient) peripheral neuropathy, and porphyria cutanea tarda (PCT). For outcomes in this category, the evidence must be suggestive of an association with herbicides, 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. The evidence that supports the committee's conclusions for respiratory cancer and multiple myeloma is detailed in Chapter 7 and is not substantially changed from VAO. Because prostate cancer is one of the three cancer types of special interest to the DVA, a brief summary of the relevant scientific evidence is provided here. Because spina bifida, acute and subacute (transient) peripheral neuropathy, and porphyria cutanea tarda have been classified in the category of limited/suggestive since VAO, evidence for these associations is also provided. Several studies have shown an elevated risk for prostate cancer in agricultural or forestry workers. In a large cohort study of Canadian farmers (Morrison et al., 1993), an elevated risk of prostate cancer was associated with herbicide spraying, and the risk increased with increasing number of acres sprayed. The proportionate mortality from prostate cancer was elevated in a study of USDA forest conservationists (PMR = 1.6, CI 0.9-3.0) (Alavanja et al., 1989), and a case-control study of white male Iowans who died of prostate cancer (Burmeister et al., 1983) found a significant association with farming (OR = 1.2) that was not associated with any particular agricultural practice. These results are strengthened by a consistent pattern of nonsignificant elevated risks in studies of chemical

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--> production workers, agricultural workers, pesticide applicators, paper and pulp workers, and the population of Seveso, Italy. The largest recent study demonstrated a significantly increased risk of death from prostate cancer in both white and nonwhite farmers in 22 of the 23 states that were studied (Blair et al., 1993). Studies of prostate cancer among Vietnam veterans or among people who have been exposed environmentally, have not consistently shown an association. However, prostate cancer is generally a disease of older men, and the risk among Vietnam veterans would not be detectable in today's epidemiologic studies. Because there was a strong indication of a dose-response relationship in one study (Morrison et al., 1993) and a consistent positive association in a number of others, the committee felt that the evidence for association with herbicide exposure was limited/suggestive for prostate cancer. There have been three epidemiologic studies that suggest an association between paternal herbicide exposure and an increased risk of spina bifida. In the Ranch Hand study (Wolfe et al., 1995), neural tube defects (spina bifida, anencephaly) were increased among offspring of Ranch Hands with four total (rate of 5 per 1,000), in contrast to none among the comparison infants (exact p = .04). The Centers for Disease Control and Prevention (CDC) VES cohort study (Centers for Disease Control, 1989) found that more Vietnam veterans reported that their children had a central nervous system anomaly (OR = 2.3; 95% CI 1.2-4.5) than did non-Vietnam veterans. The odds ratio for spina bifida was 1.7 (CI 0.6-5.0). In a substudy, hospital records were examined in an attempt to validate the reported cerebrospinal defects (spina bifida, anencephaly, hydrocephalus). While a difference was detected, its interpretation is limited by differential participation between the veteran groups and failure to validate negatives reported; that is, the veterans not reporting their children having a birth defect. Thus, the issue of a recall bias is of major concern with this study. In the CDC Birth Defects Study which utilized the population-based birth defects registry system in the metropolitan Atlanta area (Erickson et al., 1984), there was no association between Vietnam veteran status and the risk of spina bifida (OR = 1.1, CI 0.6-1.7) or anencephaly (OR = 0.9, CI 0.5-1.7). However, the exposure opportunity index (EOI) based upon interview data was associated with an increased risk of spina bifida; for the highest estimated level of exposure (EOI-5) the OR was 2.7 (CI 1.2-6.2). There was no similar pattern of association for anencephaly. Thus, all three epidemiologic studies (Ranch Hand, VES, CDC Birth Defects Study) suggest an association between herbicide exposure and an increased risk of spina bifida in offspring. In contrast to most other diseases, for which the strongest data have been from occupationally exposed workers, these studies focused on Vietnam veterans. Although the studies were judged to be of relatively high-quality, they suffer from methodologic limitations, including possible recall bias, nonresponse bias, small sample size, and misclassification of exposure. For these reasons, the

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--> committee concludes that there is limited/suggestive evidence for an association between exposure to herbicides used in Vietnam and spina bifida in offspring. There is also limited/suggestive evidence of an association between exposure to herbicides and acute and subacute (transient) peripheral neuropathy. There are several published studies relevant to this health outcome, but they are primarily case histories from occupational studies and chemical reports following the Seveso accident, which describe transient symptoms of peripheral neuropathies in highly exposed intervals (Todd, 1962; Berkley and Magee, 1963; Goldstein et al., 1959; Boeri et al., 1978; Pocchiari et al., 1979; Filippini et al., 1981). Todd (1962) reported a sprayer of 2,4-D weedkiller who developed a gastrointestinal disturbance and, within days, after contact with the chemical, a severe sensory/motor polyneuropathy. Recovery occurred over a period of months. Berkley and Magee (1963) reported another patient who developed a polyneuropathy four days after exposure to a liquid solution of 2,4-D, which was being sprayed in a cornfield. The neuropathy was purely sensory in type. The patient's symptoms gradually resolved over months. Goldstein et al. described three patients with sensory/motor polyneuropathies that developed over several days and progressed over several weeks after exposure to 2,4-D. All had incomplete recovery after several years. Although these patients were not examined neurologically before their exposure, the temporal relationship between the development of their clinical deficit and the herbicide exposure was clearly documented in the study (1959). Nonetheless, the possibility that their occurrence was unrelated to the herbicide exposure and was due to other disorders such as idiopathic Guillain-Barre syndrome cannot be entirely excluded. The trend to recovery in the individual cases reported and the negative findings of many long-term follow-up studies of peripheral neuropathy suggest that if a peripheral neuropathy indeed develops, it resolves with time. Case reports and animal studies led to the conclusion in VAO that porphyria cutanea tarda (PCT) was associated with TCDD or herbicide exposure in genetically predisposed individuals. However, three recent reports (Jung et al., 1994; Calvert et al., 1994; and Von Benner et al., 1994) failed to support this association. Two studies (Calvert et al., 1994, and Jung et al., 1994) included extensive analysis of porphyrin levels on 451 workers with demonstrated or potential exposure to herbicides and TCDD. The studies found no relationship between porphyrin levels and TCDD levels, and no excess of PCT in these cohorts. However, some workers had evidence of increased porphyrins in urine, suggesting that further investigation is warranted. These new reports, combined with the literature reviewed in VAO, led the committee to conclude that there is limited/suggestive evidence of an association between PCT and exposure to herbicides and/or TCDD.

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--> Health Outcomes with Inadequate/Insufficient Evidence to Determine Whether an Association Exists The scientific data for the remainder of the cancers and other diseases reviewed by the committee were inadequate or insufficient to determine whether an association exists. For cancers 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 fail to control for confounding or have inadequate exposure assessment. This group includes hepatobiliary cancers, nasal/nasopharyngeal cancer, bone cancer, female reproductive cancers (cervical, uterine, ovarian), breast cancer, renal cancer, testicular cancer, leukemia, and skin cancer. The scientific evidence for each of these cancers is detailed in Chapter 7. Recent published studies contained enough evidence to warrant moving skin cancer from the limited/suggestive evidence of no association category to this category. The scientific evidence for two cancers that are of special interest to the DVA—hepatobiliary cancer and nasopharyngeal cancer—will also be summarized here. Because of its public health importance, breast cancer also receives attention. Several reproductive effects are classified in this category, including spontaneous abortion, birth defects other than spina bifida, neonatal/infant death and stillbirths, low birthweight, childhood cancer in offspring, and abnormal sperm parameters and infertility. The scientific evidence for reproductive effects is detailed in Chapter 9. Neurobehavioral effects that are classified in this category include cognitive and neuropsychiatric disorders, motor/coordination dysfunction, and chronic peripheral nervous system disorders. The scientific evidence for these effects is detailed in Chapter 10. Other health effects that are classified in this category include metabolic and digestive disorders, immune system disorders, circulatory disorders, and respiratory disorders. The scientific evidence for these effects is detailed in Chapter 11. On the whole, the estimated relative risks for skin cancer are fairly evenly distributed around the null, and in a number of studies the confidence intervals were relatively narrow. This conclusion led the committee responsible for VAO to conclude that there was limited/suggestive evidence of no association between skin cancer and exposure to herbicides used in Vietnam. One other recent study (Lynge, 1993), however, found an excess risk of skin cancer. Based on four cases, a statistically significant increase in the risk of melanoma was observed in the subgroup of men who had been employed for at least one year, using a ten year latency period (SIR = 4.3, CI 1.2-10.9). However, no information is given about the risk in men with less than 10 years of latency and expected numbers for women are not reported so observed elevated risk in the men with 10+ years of latency cannot be put into context. Another study found a significant excess risk in men from the Seveso area (SMR = 3.3), based on only three cases (Bertazzi et al., 1989a,b). The committee felt that these results, while not even suggestive

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--> evidence about an association, undermined the evidence of no association in VAO, and thus warranted changing skin cancer to the ''inadequate/insufficient evidence to determine whether an association exists" category. There are relatively few occupational, environmental, and veterans studies of hepatobiliary cancer, and most of these are small in size and have not controlled for lifestyle-related factors. The estimated relative risk in the various studies range from 0.3 to 3.3, usually with broad confidence intervals. Given the methodological difficulties associated with most of these studies, the evidence regarding hepatobiliary cancer is not convincing with regard to either an association or lack of association with herbicides or TCDD. The few studies that have been published since VAO (Asp et al., 1994; Bertazzi et al., 1993; Blair et al., 1993; Collins et al., 1993; and Cordier et al., 1993) do not change the conclusion that there is inadequate evidence to determine whether an association exists between exposure to herbicides and hepatobiliary cancer. There are only a few occupational studies, one environmental study, and one veterans study of nasal and/or nasopharyngeal cancer, including two recently published studies (Asp et al., 1994, and Bertazzi et al., 1993). The estimated relative risks in the various studies range from 0.6 to 6.7, usually with broad confidence intervals. Thus, there is inadequate/insufficient evidence to determine whether an association exists between exposure to herbicides and nasal/nasopharyngeal cancer. There have been a few occupational studies, two environmental studies, and two veterans studies of breast cancer among women exposed to herbicides and/or TCDD. These include four recently published studies (Bertazzi et al., 1993; Blair et al., 1993; Dalager et al., 1995; and Kogevinas et al., 1993). Most of these studies reported a relative risk of approximately 1.0 or less, but it is uncertain whether or not the female members of these cohorts had substantial chemical exposure. TCDD appears to exert a protective effect on the incidence of mammary tumors in experimental animals (see Chapter 3), which is consistent with the tendency for the relative risks to be less than 1.0. In summary, however, the committee believes that there is insufficient evidence to determine whether an association exists between exposure to herbicides and breast cancer. 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), brain tumors, and bladder cancer. The recent scientific evidence continues to support the classification of these cancers in this category, and it is detailed in Chapter 7. Based on the recent literature, there are no additional diseases that satisfy the criteria necessary for this category.

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--> For outcomes in this category, several adequate studies covering the full range of levels of herbicide exposure that human beings are known to encounter are mutually consistent in not showing a positive association between exposure and health risk at any level of exposure. These studies have relatively narrow confidence intervals. 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. The Relationship Between the Length of Time Since Exposure and the Possible Risk of Cancer Development The importance of latency effects and other time-related factors in determining cancer risk has long been recognized, and statistical methodologies have been developed to study this issue. A variety of practical difficulties relating to exposure assessment and other data requirements, however, have limited the use of these methods in epidemiological studies of environmental carcinogens. In response to the request from the DVA to explore latency issues related to herbicides used in Vietnam, the committee attempts in Chapter 8 to establish a methodology to address the timing of herbicide exposure and the risk of cancer. This chapter also reviews the literature on herbicide exposure and cancers classified in the "Sufficient Evidence of an Association" and "Limited/Suggestive Evidence of an Association" categories for results that describe how timing of exposure affects the relative risk due to exposure. For four of the cancers studied—soft-tissue sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, and multiple myeloma—the committee concluded that there was not enough information in the literature about the timing of exposure and subsequent risk to further discuss latency issues. The committee did find that there was enough information about the timing of exposure and respiratory and prostate cancers, with considerably more information about the former than the latter, to warrant analysis of results. Both of these cancers are in the "Limited/Suggestive Evidence of an Association" category, and this conclusion has not changed after this investigation of time-related factors. The evidence in the literature suggests that the time from exposure to TCDD to increased risk of respiratory cancer is less than ten years, and that the increase in relative risk continues for somewhat more than 20 years. The available literature does not indicate how long it takes for relative risks to return to one. These conclusions are based primarily on the study conducted by the National Institute for Occupational Safety and Health (Fingerhut, 1991), since this study is the most informative about the changes in risk of respiratory cancer with time since first exposure to TCDD, but the calculations are supported by other studies that have investigated time-related effects. The epidemiological literature was not informative

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--> on the effect of the age at which the exposure was received, or whether the carcinogen appeared to act at an early or late stage of the carcinogenic process. The limited data do not indicate any increase in the relative risk of prostate cancer with time since exposure to TCDD. For prostate cancer, the epidemiological literature was not informative on how long the effects of exposure last, the effect of the age at which the exposure was received, or whether the carcinogen acts at an early or late stage of the carcinogenic process. Increased Risk of Disease in 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 in Table 1-1 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 summarized in Table 1-1; however, the lack of adequate data on Vietnam veterans per se complicates the second part of the committee's charge, which is to determine the 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 that have been reviewed (Chapters 7, 9, 10, and 11), the inadequate control for important confounders, and the 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, in general, it is not possible for the committee to quantify the degree of risk likely to be experienced by veterans because of their exposure to herbicides in Vietnam. The quantitative and qualitative evidence about herbicide exposure among various groups studied suggests that most Vietnam veterans (except for selected groups with documented high exposures, such as participants in Operation Ranch Hand) had lower exposure to herbicides and TCDD than the subjects in many occupational and environmental studies. However, individual veterans who had very high exposures to herbicides could have risks approaching those in the occupational and environmental studies. References Alavanja MC, Merkle S, Teske J, Eaton B, Reed B. 1989. Mortality among forest and soil conservationists. Archives of Environmental Health 44:94-101. Asp S, Riihimaki V, Hernberg S, Pukkala E. 1994. Mortality and cancer morbidity of Finnish chlorophenoxy herbicide applicators: an 18-year prospective follow-up. American Journal of Industrial Medicine 26:243-253.

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