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Veterans and Agent Orange: Update 1998 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, 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 (henceforth called VAO) (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 to reassess its determinations and estimates of statistical association, risk, and biological plausibility. On completion of VAO, a successor committee was formed that produced Veterans and Agent Orange: Update 1996 (henceforth called Update 1996) (IOM, 1996). The present IOM report is the second 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
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Veterans and Agent Orange: Update 1998 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 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 five specific areas of interest identified by the Department of Veterans Affairs (DVA). These are: (1) the relationship between exposure to herbicides and the subsequent development of diabetes; (2) the issue of the latency between exposure to herbicides and development of adverse health outcomes; (3) the classification of chondrosarcomas of the skull; (4) herbicide exposure assessment for Vietnam veterans; and (5) the potential for using data combination methodologies to informatively reexamine existing data on the health effects of herbicide or dioxin exposure. 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 VAO and Update 1996. This present update is intended to supplement rather than replace the two previous reports; therefore, much of the information on studies reviewed in those reports has not been repeated. Most chapters begin with brief summaries of the scientific data in VAO and Update 1996 , followed by a more thorough discussion of the newly published data and their interpretation. The reader is referred to relevant sections of the previous reports for additional detail and explanation. Chapter 2 provides an overview of the methods and conclusions of VAO and Update 1996. 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 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-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 of evaluation. Chapter 5 addresses exposure assessment issues. Chapter 6
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Veterans and Agent Orange: Update 1998 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. 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. Health outcomes are addressed in the remaining chapters: Chapter 7 focuses on cancer outcomes; Chapter 9, on reproductive effects; Chapter 10, on neurobehavioral disorders; and Chapter 11, on other (noncancer) health effects including respiratory, immune system, metabolic, digestive, and circulatory disorders. Many of the same epidemiologic studies were used to assess different types of health outcomes (see Chapter 6). The committee focused most of its efforts on reviewing and interpreting epidemiologic studies, in order to evaluate the extent to which the scientific literature does or does not suggest that particular human health effects are associated with exposure to herbicides or dioxin. The committee weighed the strengths and limitations of the scientific data in VAO and Update 1996, as well as the newly published scientific data, and reached its conclusions by interpreting the new evidence in the context of the whole of the literature. 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 health outcomes as used in the two previous reports. TOXICOLOGY SUMMARY The results of cellular and animal studies published since the release of Update 1996 that investigated the toxicokinetics, mechanism of action, and disease outcomes of TCDD, plus the herbicides themselves are reviewed in Chapter 3. TCDD elicits a diverse spectrum of biological sex-, strain-, age-, and species-specific effects, including carcinogenicity, immunotoxicity, reproductive or developmental toxicity, hepatotoxicity, neurotoxicity, chloracne, and loss of body weight. 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. There is evidence that the mechanism by which TCDD induces tumor promotion may involve oxygen radicals. In support of this, other studies have shown that TCDD induction of cancer-causing processes appears to result in a release of oxygen radicals and subsequent oxidative DNA damage that could lead to muta-
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Veterans and Agent Orange: Update 1998 tion and cancer. This is also evidence that TCDD tumor promotion may be due to its ability to interfere with intercellular communications. Low doses of TCDD administered to experimental animals alter the reproductive development and fertility of the progeny. Studies in male rats and hamsters have shown that decreased daily sperm production and cauda epididymal sperm number are some of the most sensitive effects of in utero and lactational TCDD exposure. However, in utero and lactational TCDD exposure does not appear to alter sperm transit time through the whole epididymis. Studies have been conducted to determine whether in utero and lactational TCDD exposure decreases male rat accessory sex organ weights during postnatal development and whether this effect involved decreases in hormone production or metabolism. Results suggest that in utero and lactational TCDD exposure selectively impairs rat prostate growth and development. TCDD exposure in gestating animals results in malformations of the external genitalia, including complete to partial clefting of the phallus. Additionally, functional reproductive alterations in female progeny are observed after TCDD exposure. Moreover, TCDD-mediated inhibition of angiogenesis has been suggested as an important contributor to the embryo-toxicity of TCDD. Animal studies and test-tube studies continue to emphasize the importance of alterations in neurotransmitter systems as underlying mechanisms of TCDD-induced behavioral dysfunction. TCDD can affect the metabolism of serotonin, a neurotransmitter in the brain able to modulate food intake. This biochemical change is consistent with observations of progressive weight loss and anorexia in experimental animals exposed to TCDD. In certain brain cells, there is evidence that TCDD may increase the uptake of calcium. TCDD exposure causes a broad range of immunologic effects in experimental animals. Recent studies support earlier data that TCDD decreases innate immunity and host resistance to pathogenic microorganisms; impairs cell-mediated immune responses, such as the generation and lytic activity of cytotoxic T cells; and suppresses humoral immunity by inhibiting B-lymphocyte differentiation into antibody-producing cells. Despite considerable laboratory research, the mechanisms underlying the immunotoxic effects of TCDD are still unclear. TCDD immunotoxicity appears to be mediated primarily through aryl hydrocarbon receptor (AhR) dependent processes, but some components of immunosuppression have been shown to act independently of the Ah receptor. Several recent studies have examined the effects of TCDD on specific disease outcomes in animals. Liver enlargement has, for example, been shown to occur following high subchronic doses. The mechanism by which TCDD affects the liver is still under investigation. Recently, TCDD has been shown to inhibit DNA synthesis of liver cells, decrease certain receptors in liver cell membranes, and inhibit liver enzymatic activity. TCDD has also been shown to affect blood serum hormone levels, an outcome thought to be partially due to the action of TCDD on the pituitary gland. TCDD has also been shown to affect the develop-
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Veterans and Agent Orange: Update 1998 ment of skin cells by binding to the AhR. This effect is antagonized by retinoids. Several reports published during the reference period describe developmental deficits in the cardiovascular system of TCDD-treated animals. Evidence suggests that the endothelial lining of blood vessels is a primary target site of TCDD-induced cardiovascular toxicity. Much research over the past two years has focused on the elucidation of the molecular mechanism of TCDD toxicity. Recent studies confirm earlier findings that the toxic effects of TCDD are caused by the binding of TCDD to the aryl hydrocarbon receptor. TCDD binding to this receptor triggers other effects that result in a toxic sequelae. Structural and functional studies of AhR and its partner protein Arnt indicate that similar protein receptors exist in a number of different species and interact with a number of other proteins to influence receptor function. TCDD may influence the ways in which genes are expressed by binding to the AhR. Researchers have recently bred mice that lack the AhR protein, and it is anticipated that these mice will allow more informative studies of TCDD effects in the future. The toxicity of the herbicides used in Vietnam remains poorly studied. In general, the herbicides 2,4-D (2,4-dichlorophenoxyacetic acid), 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. New reports suggest that 2,4-D may affect the membrane sheath around nerve cells. Other studies support the view that 2,4-D may disrupt cellular processes in the liver, and reports of kidney and muscle damage have been published. A case-control study of dogs exposed to 2,4-D, in addition to other pesticides used in yard work, reported an increase in lymphomas associated with exposure. Some animal studies suggest that 2,4,5-T may alter nerve and muscle function. 2,4,5-T may also induce mutations at different stages of cell development and hinder a cellular process that is involved in the elimination of harmful carcinogens. Limited evidence from bioassays published during the past two years suggests that cacodylic acid may promote urinary, bladder, kidney, liver, and thyroid gland cancer in some species of animals. 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 responsible for producing VAO 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, each approach is limited in its ability to determine precisely the intensity and duration of individual exposure. A separate effort by another Institute of Medicine committee is facilitating
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Veterans and Agent Orange: Update 1998 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 for exposure assessment research in 1997 (IOM, 1997) and has begun to carry out scientific oversight of the research. Although definitive data are presently 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. Participants in Operation Ranch Hand and members of 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. Although it is currently not possible to identify this heavily exposed fraction of Vietnam veterans, the exposure assessment research effort presently under way may allow progress to be made on this important question. 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 detailed in Chapter 4, the committee used the epidemiologic evidence it reviewed to assign each of the health outcomes being studied 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 health outcomes chapter (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 Update 1996, the committee found sufficient evidence of an association between exposure to herbicides and/or TCDD and four diseases: soft-tissue sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, and chloracne. The recent scientific literature continues to support the classification of these diseases in the category of sufficient evidence. 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 commit-
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Veterans and Agent Orange: Update 1998 TABLE 1-1 Updated (1998) 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 Spina bifida in the children of veterans Porphyria cutanea tarda 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 Breast cancer Female reproductive cancers (cervical, uterine, ovarian) Urinary bladder cancer (category change in 1998) Renal cancer Testicular cancer Leukemia Spontaneous abortion Birth defects (other than spina bifida) Neonatal/infant death and stillbirths
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Veterans and Agent Orange: Update 1998 Low birthweight Childhood cancer in offspring Abnormal sperm parameters and infertility 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 cancers 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. tee 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 and for chloracne in Chapter 11. Health Outcomes with Limited/Suggestive Evidence of Association In Update 1996, the committee found limited/suggestive evidence of an association for six classes of diseases, three cancers—respiratory (larynx, lung/ bronchus, and trachea) cancer, prostate cancer, and multiple myeloma—and three other health outcomes—spina bifida in the children of veterans, acute and sub-acute (transient) peripheral neuropathy, and porphyria cutanea tarda. The recent
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Veterans and Agent Orange: Update 1998 scientific literature continues to support the classification of these diseases in the limited/suggestive category of sufficient evidence. Based on the recent literature, there are no additional diseases that satisfy this category's criteria. 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. Since the last update, there have been several studies of respiratory cancer among occupationally exposed groups and Vietnam veterans. Newly published studies of phenoxy herbicide production workers (Kogevinas et al., 1997) and workers exposed as a result of an industrial accident (Ott and Zober, 1996) show small but statistically significant excesses of lung cancer mortality. Results in both studies indicate higher estimated risk for individuals with higher estimated exposure. One other occupational study (Ramlow et al., 1996) reports a relative risk indistinguishable from 1. A study of rice farmers in Italy (Gambini et al., 1997) found lower lung cancer incidence than observed in the general population, a result similar to that found in studies of U.S. farmers, which may reflect lower incidence of smoking in this occupational group. New data from the Seveso accident (Bertazzi et al., 1997) do not indicate any increase in lung cancer mortality in this environmentally exposed group, but an insufficient number of years have passed since exposure to draw conclusions about any effect that the accidental exposure may have had. Increases in respiratory cancers were seen in new studies of U.S. and Australian Vietnam veterans, although there is evidence that cigarette smoking was more prevalent among Vietnam veterans than among non-Vietnam veterans or the general public. In summary, the most recently published studies continue to support placing respiratory cancers in the category of limited/ suggestive evidence. Although smoking undoubtedly plays a role in these cancers, the consistency of the finding across several studies argues against the notion that it is the sole explanatory factor. New studies of production workers continue to show weak but consistent evidence of effects on prostate cancer mortality, whereas new research on agricultural workers shows no indication of increased risk. A detailed and well-conducted analysis of Australian male Vietnam veterans' mortality (Crane et al., 1997) found a statistically significant relationship between Vietnam service and prostate cancer. The committee's summary evaluation, based on all of the epidemiologic evidence, was that the data continue to support the classification of prostate cancer in the limited/suggestive category. The evidence that supports the committee's conclusions for multiple myeloma is detailed in Chapter 7 and is not substantially changed from Update 1996. In Update 1996 the committee identified three studies of the offspring of Vietnam veterans that were suggestive of an association between exposure to the
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Veterans and Agent Orange: Update 1998 herbicides considered in this report and spina bifida, although a number of methodologic issues limited the interpretation of these results. Since the publication of that report, occupational studies of the offspring of fathers employed in British Columbia sawmills (Dimich-Ward et al., 1996) and the offspring of Norwegian farmers (Kristensen et al., 1997), and a multicenter case-control study of paternal occupation and risk of spina bifida conducted in the Netherlands (Blatter et al., 1997), have provided some additional support for the association with this specific birth defect, although concerns remain including control of confounding, exposure determination, and isolation of exposure to specific herbicides and TCDD. No additional evidence has been published since Update 1996 regarding acute and subacute transient peripheral neuropathy or porphyria cutanea tarda. 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. 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 fail to control for confounding or have inadequate exposure assessment. This group includes hepatobiliary cancers (cancers of the liver and intrahepatic bile duct), nasal and nasopharyngeal cancer, bone cancer, skin cancers (including basal cell carcinoma, squamous cell carcinoma, and non-melanocytic 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. Based on an evaluation of all the epidemiologic evidence, including studies published since the release of Update 1996, the committee felt that urinary bladder cancer should be added to this category. Although there is no evidence that exposure to herbicides or dioxin is related to this cancer, relative risks in some of the largest cohorts tended to be greater than 1, weakening the committee's prior conclusion that there was positive evidence of no relationship. The co-exposure to TCDD and a variety of known bladder carcinogens makes it very difficult to isolate any possible additional effect of herbicides, although little total effect was seen. A recent community based case-control study examining herbicide exposure and skin cancers drew the attention of the committee (Gallagher et al., 1996). This study, which controlled for a number of factors known to influence skin cancer rates, found increasing risk of squamous cell carcinoma with increasing lifetime exposure to herbicides. Although there are concerns regarding the study's
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Veterans and Agent Orange: Update 1998 control of confounding and the adequacy of the exposure assessment, the committee concluded that the study was the best of its kind to date. The available evidence is insufficient to determine whether an association exists between herbicide exposure and any of the forms of skin cancer. However, the committee encourages further study of basal and squamous cell skin cancer incidence among working and Vietnam veteran populations. In any future studies, careful attention should be paid to exposure assessment, as well as to controlling for confounding from UV exposures. Efforts to examine the carcinogenicity of organic arsenicals are also encouraged. 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, 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 or 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. Diabetes is a health outcome of special interest to the DVA. When viewed in the context of the total literature the committee concludes that, at this time, there is inadequate/insufficient evidence to determine whether an association exists between herbicide or dioxin exposure and increased risk of diabetes. Further analyses and full publication of existing studies may justify a reevaluation of this conclusion. Many animal studies provide potential biological mechanisms for an association between herbicide exposure and diabetes risk. Although the majority of earlier reports on humans suggest little association, the potentially more definitive 1997 report from the Ranch Hand study (Henriksen et al., 1997) raises the possibility that the highest-exposure group (highest TCDD level) may have an increased risk. Such a conclusion may be supported by a currently unpublished NIOSH study of exposed workers. It is important to note that both these studies used serum TCDD levels as the measure of exposure. At this time, questions concerning case definition and full control for obesity, or other confounders (in the Ranch Hand study) preclude determining whether or not an association exists between herbicide exposure and diabetes in these studies. The committee strongly urges that the NIOSH study be documented more completely and published in the peer-reviewed literature, so that its potentially important findings can be evaluated fully. It strongly recommends that the Ranch Hand study develop a fully adjusted multivariate model (e.g., Cox Proportional Hazard with time to diabetes as the outcome), fully controlling for baseline age and obesity (BMI) and, if possible, for family history of diabetes, central fat distribution, diabetogenic drug
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Veterans and Agent Orange: Update 1998 exposure, and a measure of obesity at the time of Vietnam service. The committee recommends consideration be given to a combined analysis of the Ranch Hand and NIOSH studies to further examine the possibility that herbicide exposure leads to an increased risk of diabetes. 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 classification 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. 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 epidemiologic 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 some cancers for results that describe how the timing of exposure affects the relative risk due to exposure. One of the committee's tasks was to assess the likelihood that exposure to herbicides used in Vietnam resulted in or will result in increased risk of disease in Vietnam veterans. Currently, any such inference would have to be based on extrapolation from the findings about disease experience of other groups exposed to TCDD or herbicides generally. Given that we know when the potential exposure to TCDD and other herbicides used in Vietnam began and ended, it would
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Veterans and Agent Orange: Update 1998 appear reasonable to examine time-related factors for those who served in Vietnam, but to date, no adequate analysis of time-related factors for cancer occurrence in Vietnam veterans has been published. Extrapolation from other types of studies is problematic for several reasons. Brief exposures, such as occurred in Seveso, and chronic occupational exposures may not apply to Vietnam veterans because of the different exposure situation. For example, there is evidence in the literature (e.g., for respiratory cancer) that latency can vary not only among individuals, but also according to other aspects of the exposure scenario, such as the magnitude of exposure. Thus, if high exposures in an occupational setting result in a certain pattern of relative risks for a given time since first exposure, this pattern may not hold for lower level exposures such as occurred in Vietnam. Similarly, direct evidence was not presented to evaluate the impact of age at exposure to herbicides. It is possible that the age at which exposure was received could influence the pattern of latency that would be observed (e.g., exposures incurred at younger ages could be more potent, but the impact might not be seen for a longer time period; conversely, exposures at older ages might be more harmful, particularly in the short run). Unfortunately, the data are not available to evaluate the hypothesis that age at exposure is important. A major limitation of the analyses discussed in this chapter is the failure of most studies to conduct analyses of latency that also controlled for factors such as duration of exposure, age, and calendar time of exposure (or analyses of age at exposure that controlled for time since exposure), particularly for occupational cohorts with protracted exposure periods. Another consideration is the long retention time of TCDD and other highly chlorinated herbicides. Since body burdens from any exposure, no matter how brief, result in continuing exposures to internal organs, the concept of time since exposure ended has a different meaning than for chemical agents that are eliminated quickly. A third issue concerns the distinction between morbidity and mortality. As discussed in Chapter 8, the latency between exposure and death is composed of two parts: (1) latency until disease appears and (2) time between disease occurrence and death. For diseases with low survival rates, such as respiratory cancer, the time between disease occurrence and death is generally short; therefore, a study focusing on mortality will give a good approximation of the latency period. However, for diseases that are not always fatal or that have a long survival time such as prostate cancer, it is preferable to examine incidence rather than mortality. Thus, further data on prostate cancer incidence would be of great help, since relatively few men with prostate cancer die from it. Overall, the data on latency do not alter the committee's conclusions with regard to the categories of evidence for individual cancer sites, but they do provide some information on how long the effects of herbicide exposures last. The evidence suggests that if respiratory cancer does result from exposure to herbicides used in Vietnam, the greatest relative risk for lung cancer may be in
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Veterans and Agent Orange: Update 1998 the first decade after exposure, but until further follow-up has been carried out for some of the cohorts, it will not be possible to put an upper limit on the length of time these herbicides could exert their effect. For prostate cancer, the published data are largely uninformative, and conclusions must await more definitive studies, preferably using incidence rather than mortality. For non-Hodgkin's lymphoma, effects are seen in the second decade after exposure begins and continue to be observed more than 20 years after external exposure ends. Because of the long retention times of TCDD, internal exposures can continue long after external exposures cease. Increased Risk of Disease Among Vietnam Veterans One of the three primary charges contained in the Agent Orange Act of 1991 (Public Law 102-4, subsequently codified as 38 USC Sec. 1116) states: For each disease reviewed, the Academy shall determine (to the extent that available scientific data permit meaningful determinations) . . . the increased risk of the disease among those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era. . . . 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 that have been reviewed (Chapters 7, 9, 10, and 11), the inadequate control for other important risk factors, 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, 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. As discussed above, the epidemiologic analyses to date have many limitations which prevent a more quantitative exposure-response analysis. Where there is inadequate/insuffi-
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Veterans and Agent Orange: Update 1998 cient 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 where the committee can draw more specific conclusions, and this information is related in the discussion of those diseases. REFERENCES Blatter BM, Hermens R, Bakker M, Roeleveld N, Verbeek AL, Zielhuis GA. 1997. Paternal occupational exposure around conception and spina bifida in offspring. American Journal of Industrial Medicine 32(3):283-291. Bertazzi PA, Zochetti C, Guercilena S, Consonni D, Tironi A, Landi MT, Pesatori AC. 1997. Dioxin exposure and cancer risk: A 15-year mortality study after the "Seveso Accident." Epidemiology 8(6):646-652. Crane PJ, Barnard DL, Horsley KW, Adena MA. 1997. Mortality of Vietnam veterans: the veteran cohort study. A report of the 1996 retrospective cohort study of Australian Vietnam veterans. Canberra: Department of Veterans' Affairs. Dimich-Ward H, Hertzman C, Teschke K, Hershler R, Marion SA, Ostry A, Kelly S. 1996. Reproductive effects of paternal exposure to chlorophenate wood preservatives in the sawmill industry. Scandinavian Journal of Work, Environment and Health 22:267-273. Gallagher RP, Bajdik CD, Fincham S, Hill GB, Keefe AR, Coldman A, McLean DI. 1996. Chemical exposures, medical history, and risk of squamous and basal cell carcinoma of the skin. Cancer Epidemiology, Biomarkers and Prevention 5(6):419-424. Gambini GF, Mantovani C, Pira E, Piolatto PG, Negri E. 1997. Cancer mortality among rice growers in Novara Province, Northern Italy. American Journal of Industrial Medicine 31:435-441. Henriksen GL, Ketchum NS, Michalek JE, Swaby JA. 1997. Serum dioxin and diabetes mellitus in veterans of Operation Ranch Hand. Epidemiology 8:252-258. Hill, AB. 1971. Principles of Medical Statistics, 9th ed. New York: Oxford University Press. Institute of Medicine (IOM). 1994. Veterans and Agent Orange Health: Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press. Institute of Medicine. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. Institute of Medicine. 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. Kogevinas M, Becher H, Benn T, Bertazzi PA, Boffetta P, Bueno-de-Mesquita HB, Coggon D, Colin D, Flesch-Janys D, Fingerhut M, Green L, Kauppinen T, Littorin M, Lynge E, Mathews JD, Neuberger M, Pearce N, Saracci R. 1997. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins. An expanded and updated international cohort study. American Journal of Epidemiology 145(12):1061-1075. Kristensen P, Irgens LM, Andersen A, Bye AS, Sundheim L. 1997. Birth defects among offspring of Norwegian farmers, 1967-1991. Epidemiology 8(5):537-544.
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Veterans and Agent Orange: Update 1998 Ott MG, and Zober A. 1996. Cause specific mortality and cancer incidence among employees exposed to 2,3,7,8-TCDD after a 1953 reactor accident. Occuptional and Environmental Medicine 53:606-612. Ramlow JM, Spadacene NW. Hoag SR, Stafford BA, Cartmill JB, Lerner PJ. 1996. Mortality in a cohort of pentachlorophenol manufacturing workers, 1940-1989. American Journal of Industrial Medicine 30:180-194.
Representative terms from entire chapter: