11
Other Health Effects

INTRODUCTION

A variety of health outcomes are evaluated in this chapter, including chloracne, porphyria cutanea tarda, respiratory disorders, immune system disorders (immune suppression, autoimmunity), diabetes mellitus, lipid abnormalities, gastrointestinal and digestive disease (including liver toxicity), and circulatory disorders. Many of these outcomes have not been addressed as thoroughly in the epidemiologic literature as the health outcomes described in Chapters 7, 9, and 10.

For most of the health outcomes discussed in this chapter, a brief summary of the scientific evidence described in Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (henceforth called VAO) (IOM, 1994) and Veterans and Agent Orange: Update 1996 (henceforth called Update 1996) (IOM, 1996) is presented, followed by an update of the recent scientific literature. Because of special interest expressed by the Department of Veterans Affairs, a complete discussion of the evidence, including the studies cited in VAO and Update 1996, is presented for diabetes and for lipid and lipoprotein disorders.

CHLORACNE

Background

Skin disorders are among the most common health problems encountered in combat, aside from traumatic injuries. Because of the tropical environment and



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Veterans and Agent Orange: Update 1998 11 Other Health Effects INTRODUCTION A variety of health outcomes are evaluated in this chapter, including chloracne, porphyria cutanea tarda, respiratory disorders, immune system disorders (immune suppression, autoimmunity), diabetes mellitus, lipid abnormalities, gastrointestinal and digestive disease (including liver toxicity), and circulatory disorders. Many of these outcomes have not been addressed as thoroughly in the epidemiologic literature as the health outcomes described in Chapters 7, 9, and 10. For most of the health outcomes discussed in this chapter, a brief summary of the scientific evidence described in Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (henceforth called VAO) (IOM, 1994) and Veterans and Agent Orange: Update 1996 (henceforth called Update 1996) (IOM, 1996) is presented, followed by an update of the recent scientific literature. Because of special interest expressed by the Department of Veterans Affairs, a complete discussion of the evidence, including the studies cited in VAO and Update 1996, is presented for diabetes and for lipid and lipoprotein disorders. CHLORACNE Background Skin disorders are among the most common health problems encountered in combat, aside from traumatic injuries. Because of the tropical environment and

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Veterans and Agent Orange: Update 1998 living conditions in Vietnam, veterans developed a variety of skin conditions ranging from bacterial and fungal infections to a condition known as ''tropical acne" (Odom, 1993). However, the only dermatologic disorder consistently reported to be associated with Agent Orange and other herbicides, including the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD, TCDD, or dioxin), is chloracne. Therefore, this discussion focuses on chloracne and its link to TCDD. Among the numerous industrial chemicals known to cause chloracne, the most potent appears to be TCDD. However, as noted later in this discussion, individual host factors appear to play an important role in determining disease expression. Even at relatively high doses, not all exposed individuals develop chloracne, whereas others with similar or lower exposure manifest the condition. Chloracne has a variable natural history. Longitudinal studies of exposed cohorts suggest that the lesions typically regress and heal over time. However, historical reports indicate that a chronic form of the disease can persist up to 30 years after an exposure (Suskind and Hertzberg, 1984). Like many dermatologic conditions, chloracne can reasonably be suspected on the basis of a careful medical history or appropriate questionnaire information. A key element in diagnosis is the characteristic anatomic distribution. Because acne is such a common dermatologic condition, a number of precautionary steps should be taken in any analysis attempting to link acne or chloracne with an environmental or occupational exposure; it is critical that adequate attention be paid to the clinical characteristics, time of onset, and distribution of lesions and that there be careful comparison with an appropriate control group. Definitive diagnosis may require histologic confirmation from a biopsy specimen. Chloracne can be viewed as both a toxic outcome of exposure to TCDD and a potential clinical marker of TCDD exposure. It is the latter that has generated the most controversy. In this section, the primary focus is on the linkage of chloracne to TCDD exposure. Dose-response relationships between TCDD exposure and chloracne are addressed briefly. The inadequacies of chloracne as a human biomarker of dioxin exposure are discussed in more detail in Chapter 5. A major unresolved issue is whether TCDD exposure below the level required to cause chloracne may have other adverse health consequences such as cancer. Summary of VAO and Update 1996 Chloracne has been linked to TCDD exposure in numerous epidemiologic studies of occupationally and environmentally exposed populations. The data on Vietnam veterans potentially exposed to Agent Orange and other herbicides are less convincing. From the studies reviewed in VAO and Update 1996, it is apparent that higher levels of exposure to TCDD, as reflected by increased serum levels, are

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Veterans and Agent Orange: Update 1998 associated in a general way with increased risk of developing chloracne. However, the great degree of variability in TCDD levels among subjects with a history of chloracne and among those with no evidence of the condition suggests a complex dose-response relationship, with highly variable individual susceptibility. In addition, in many subjects the serum TCDD levels were measured many years after first exposure or onset of chloracne. Based on current data, it is not possible to assign a "threshold" TCDD level associated with chloracne. Update of the Scientific Literature No new informative publications were identified that related chloracne to exposure to herbicides or dioxin in humans. Because TCDD-associated chloracne becomes evident shortly after exposure, there is no risk that new cases will occur in veterans due to Vietnam service-related exposures. Conclusions Strength of Evidence in Epidemiologic Studies Evidence is sufficient to conclude that there is a positive association between exposure to the herbicides considered in this report and chloracne. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Biologic Plausibility The formation of chloracne lesions after administration of TCDD is observed in some species of laboratory animals. Similar observations have not been reported for the herbicides. A more thorough discussion of biologic plausibility with respect to exposure to TCDD or herbicides and chloracne is contained in Chapter 3; a summary is presented in the conclusion to this chapter. PORPHYRIA CUTANEA TARDA Background Porphyria cutanea tarda (PCT) is an uncommon disorder of porphyrin metabolism manifest in patients by thinning and blistering of the skin in sun-exposed areas, as well as by hyperpigmentation (excess pigment in skin) and hypertrichosis (excess hair growth) (Muhlbauer and Pathak, 1979; Grossman and Poh-Fitzpatrick, 1986). The disease is caused by a hereditary or acquired deficiency of uroporphyrinogen decarboxylase (UROD), a cytoplasmic enzyme in the pathway of hemoglobin synthesis (Sweeney, 1986). In the hereditary form, no precipitat-

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Veterans and Agent Orange: Update 1998 ing exposure is necessary for the appearance of excess uroporphyrin and coproporphyrin in the urine and the development of clinical symptoms. In cell culture and in rodents (mice and rats), TCDD causes a toxic porphyria resembling PCT in humans (De Verneuil et al., 1983; Cantoni et al., 1984; Smith and De Matteis, 1990). Summary of VAO and Update 1996 The occurrence of clinical PCT is rare and may be influenced by genetic predisposition of individuals with low enzyme levels of UROD. The cases reported have occurred relatively shortly after exposure to specific chemicals, including TCDD, and have improved after removal of the agent. Simultaneous exposure to alcohol and other chemicals, such as hexachlorobenzene, probably increases the risk and severity of PCT. Abnormal porphyrin excretion without clinical illness may occur more commonly than clinical evidence of PCT and may represent a preclinical stage of PCT. There is no suggestion of an increase in PCT in studies of Vietnam veterans or Ranch Hands, possibly because of comparatively low dioxin exposure even for Ranch Hand veterans or a fortuitous absence of genetically predisposed individuals who could develop PCT after exposure to TCDD. Further studies of PCT incidence in Vietnam veterans would not be called for, since the biologic and clinical evidence indicates that the rare appearance of PCT occurs soon after heavy TCDD exposure and improves with time. Moreover, the association of PCT with alcoholism makes it difficult to interpret studies of TCDD exposure and PCT that do not simultaneously assess alcohol consumption. Jung et al. (1994) presented porphyrin data on former workers in a German pesticide plant that had manufactured 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). The study found no difference in porphyrin levels or abnormal liver function tests between subjects with and without chloracne. There was also no relationship between porphyrin levels in urine, red blood cells, or plasma and TCDD levels in adipose tissue. Three cases of chronic hepatic porphyria (none with overt PCT and none with chloracne) were identified, which did not exceed the expected prevalence in this population. Calvert et al. (1994) analyzed porphyrin levels and TCDD serum levels in a cross-sectional medical study of the National Institute for Occupational Safety and Health (NIOSH) cohort of workers who had been previously exposed to TCDD through manufacture of sodium trichlorophenol, 2,4,5-T, or hexachlorophene. There were no cases of overt PCT, and three exposed and three unexposed subjects had subclinical PCT. Porphyrin levels did not differ between exposed and unexposed workers, and there was no significant relationship between urinary porphyrin levels and serum TCDD levels. Taken together, the studies reviewed did not support the hypothesis that TCDD caused disturbances in heme metabolism in humans, even at the relatively

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Veterans and Agent Orange: Update 1998 high exposure levels experienced by these cohorts. Reports that some persons employed in herbicide production have evidence of increased porphyrins in urine warrant further investigation. Update of the Scientific Literature No informative publications were identified relating PCT to exposure to herbicides or dioxin in humans. Because TCDD-associated PCT becomes evident shortly after exposure, there is no risk that new cases will occur in veterans due to Vietnam service-related exposures. Conclusions Strength of Evidence in Epidemiologic Studies There is limited/suggestive evidence of an association between exposure to the herbicides considered in this report and porphyria cutanea tarda. Evidence regarding the association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. Biologic Plausibility There is some evidence that TCDD can be associated with porphyrin abnormalities in laboratory animals, although PCT has not been reported. Porphyria has not been reported in animals exposed to herbicides. A more thorough discussion of biologic plausibility with respect to exposure to TCDD or herbicides and PCT is contained in Chapter 3; a summary is presented in the conclusion to this chapter. RESPIRATORY DISORDERS Background The studies reviewed in this section cover a wide range of respiratory conditions encompassed by International Classification of Diseases, Ninth Edition (ICD·9) codes 460-519, including acute respiratory infections, other diseases of the upper respiratory tract, pneumonia, influenza, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, asthma, pleurisy, and pneumoconiosis. In the morbidity studies, a variety of methods were used to assess the respiratory system, including assessment of symptoms, physical examination of the chest, lung function tests, and chest radiographs. Lung function (also called pulmonary function) tests included tests commonly used to detect airflow obstruction (which can occur in conditions such as asthma, chronic bronchitis, and emphysema) and

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Veterans and Agent Orange: Update 1998 restriction or decrease in lung volume (which can occur because of lung scarring or inflammation). Tests that measure airflow obstruction include FEV1 (forced expirating volume, the amount of air that can be exhaled forcefully in one second); the ratio FEV1/FVC (forced vital capacity, the total amount of air that can be forcefully exhaled); FEF25-75 (forced expiratory flow, the rate of airflow in the middle range of total volume); and FEFmax (rate of airflow at highest lung volume). The test that measures restriction is FVC, which determines the total amount of air that can be exhaled with sustained effort. Chest radiographs, which were used in several studies, can assess whether inhaled agents have damaged the lungs; damage is usually apparent as opacities such as scarring, inflammation, or both. Summary of VAO and Update 1996 Among the morbidity studies, strong rationales for examining respiratory outcomes were not given. However, in the case of occupational exposures or exposures of military personnel involved in herbicide spraying, the respiratory tract could be viewed as a target organ for aerosol or other particulate deposition. In general, the lack of working hypotheses about respiratory disease outcomes associated with herbicides, the nonuniformity in methods and reported results, and the variable ability to adjust for the effects of cigarette smoking make it difficult to interpret much of the morbidity data, especially reports of symptoms and radiographic data. Interpretation of many of the mortality studies was generally limited by the small number of deaths observed. These studies also tended to use the ICD·9 codes for all respiratory diseases. The wide range of diverse conditions and small number of total deaths make it difficult to assess any particular respiratory outcome using mortality studies. In some studies, the specific ICD·9 codes used were not stated, thus making comparisons with other studies difficult. Overall, there was little evidence of any associations with herbicide or dioxin exposure. Update of the Scientific Literature Occupational Studies Becher et al. (1996) examined mortality among workers in four German facilities that produced phenoxy herbicides and chlorophenols. The population included workers who had a least one month of employment, and resulted in a cohort consisting of 2,479 male workers. Standardized mortality ratios (SMRs) and 95 percent confidence intervals (95% CIs) were calculated using West German mortality rates by five-year age and calendar intervals. SMRs for respiratory system disease among the four plants ranged from 0.5 to 0.8. Svensson et al. (1995) studied mortality and disease incidence in two cohorts

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Veterans and Agent Orange: Update 1998 of Swedish fishermen. One group (2,896 men) resided on the east coast of Sweden and consumed fish from the Baltic Sea. These fatty fish (particularly salmon and herring) are reported to contain elevated levels of polychlorinated biphenyls (PCBs), polychlorinated dibenzodioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs). The other group of fishermen (8,477 men) resided on the west coast of Sweden and were presumed to have a higher intake of lean (and less contaminated) fish, including cod and flat fish. Bronchitis and emphysema rates (ICD·9 codes 490-493), were reported, and no significant increase was found among east coast fishermen (SMR 0.5, 95% CI 0.1-1.2). Ott and Zober (1996) updated the experience of workers exposed to TCDD during the cleanup of a trichlorophenol (TCP) reactor that exploded in 1953 at a BASF plant in Ludwigshafen, Germany. They studied disease incidence and mortality up to 1992 for a group of 243 men and developed TCDD dose estimates based on work activity information, blood TCDD determinations on a subset of the population, and estimates of TCDD elimination rates. Expected numbers of incident cases and cause-specific deaths were obtained from German sources by five-year age and calendar intervals. The overall SMR (95% CI) for respiratory system diseases was 0.1 (0.0-0.8); in the highest TCDD dose group, the SMR (95% CI) was 0.4 (0.0-2.0). Ramlow et al. (1996) examined mortality in a cohort of workers exposed to pentachlorophenol (PCP), as part of a larger study of Dow chemical manufacturing workers exposed to the higher chlorinated dioxins. The study cohort was assembled from company records, starting with a cohort of 2,192 workers ever employed in a department with potential PCDD exposure between 1937 and 1980. From this cohort, 770 workers were identified who were considered to have potential PCP exposure based on work history records. Cumulative exposure indices for PCP and dioxin were calculated using scores described by Ott et al. (1987). In the study analysis, the U.S. white male death rates (five-year age and calendar time specific) and the death rates of non-PCP and non-PCDD male Dow Michigan employees for 1940 to 1989 were both used as reference values to calculate expected deaths. The overall SMR (95% CI) for respiratory system disease was 0.9 (0.5-1.5), with no significant effect of latency or estimated exposure level. In an update and expansion of the International Agency for Research on Cancer (IARC) cohort study, Kogevinas et al. (1997) examined mortality in a cohort of 26,615 male and female workers engaged in the production or application of phenoxy herbicides. Exposure information varied between cohorts, but in general exposures were reconstructed from job records. Based on job categories and information on production processes and the composition of the materials used, exposed workers were classified into three categories: exposed to TCDD or higher chlorinated dioxins, unexposed to the same, and unknown exposure to the same. Analysis was performed by calculating SMRs and 95% CI, using the World Health Organization (WHO) mortality data bank to calculate national

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Veterans and Agent Orange: Update 1998 mortality rates by sex, age (five-year intervals), and calendar period (five years). Overall, a decrease in respiratory system disease was observed in exposed workers compared to unexposed workers for males (SMR 0.8, 95% CI 0.7-0.9), with no significant differences observed for women (SMR 1.1, 95% CI 0.4-2.2). Studies of Vietnam Veterans In a study of postservice suicide among Vietnam veterans, Bullman and Kang (1996) reported subsequent cause-specific mortality for 34,534 veterans who had been hospitalized for wounds suffered in Vietnam, compared to U.S. men overall. They observed no significant difference in respiratory system disease deaths (SMR 0.9, 95% CI 0.7-1.2) compared to U.S. men. O'Toole et al. (1996) described the results of a simple random sample of Australian Army Vietnam veterans on self-reported health status. Data were obtained on 641 veterans from the Australian Bureau of Statistics Health Interview Survey 1989-90, and illness rates were compared to the age-and sex-matched Australian population. They observed no significant increase in overall respiratory system disease among veterans; the relative risk (RR) was 2.0 (99% CI 0.0-7.1). Hay fever (RR 1.6, [CI, 1.3-1.9]), bronchitis or emphysema (4.1 [CI 2.8-5.5]), and other respiratory disease (4.0 [CI 2.2-5.9]) were significantly elevated compared to the general population, although none of these conditions were related to an index of combat exposure. The veterans were significantly less likely to have never smoked than the general population (0.7 [CI 0.5-0.8]), a finding similar to data reported by McKinney et al. (1997) on U.S. Vietnam veterans. No information was available on other potential confounding factors such as occupational exposures. Watanabe and Kang (1996) reported on the mortality of 33,833 U.S. Army and Marine Corps Vietnam veterans who died during 1965-1988, compared to mortality among 36,797 deceased non-Vietnam veterans, using proportionate mortality ratios (PMRs). They observed no increase in respiratory system disease mortality among Army Vietnam veterans (PMR 0.9) or among Marine Vietnam veterans (PMR 1.1). Dalager and Kang (1997) reported a study comparing 2,872 Vietnam veterans with 2,737 non-Vietnam veterans (all of whom served in Chemical Corps specialties). All study subjects served at least 18 months' active duty between 1965 and 1973, and vital status ascertainment was complete for both groups. They reported no significant increase in respiratory system disease mortality among Vietnam veterans, with an RR (95% CI) of 2.6 (0.6-12.2). A report on Australian Vietnam veterans (Crane et al., 1997a) compared cause-specific mortality rates of 59,036 male Vietnam veterans with those of other Australian males. They found a significant decrease in respiratory system disease (SMR [95% CI] for deaths in 1964-1979 (0.1 [0.0-0.3]) and no significance from expected rates for 1980-1994:0.9 (0.7-1.1).

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Veterans and Agent Orange: Update 1998 A second cohort study of Australian veterans compared the mortality for 1982-1994 for 18,949 national servicemen who had served in Vietnam (veterans) with 24,646 national servicemen who had not served in Vietnam (nonveterans) (Crane et al., 1997b). They observed an RR (95% CI) for veterans compared to nonveterans of 0.9 (0.3-2.7) for all respiratory diseases and 0.3 (0.0-3.2) for chronic obstructive airways disease. The ongoing study of Ranch Hand veterans (AFHS, 1996) reported cause-specific mortality among 1,261 Ranch Hand personnel compared to 19,080 Air Force veterans from the same era who did not handle herbicides. No increase was observed in respiratory system disease deaths (SMR 0.5). Synthesis Although there were sporadic reports of increased respiratory disease potentially related to exposure to herbicides or TCDD, the results were inconsistent across studies. In addition, interpretation of individual studies was generally limited by a lack of information on cigarette smoking. In the one study that showed the strongest association between potential exposure and respiratory disease (O'Toole et al., 1996), veterans were much more likely to have smoked than nonveterans. Additional research, with adequate information on cigarette smoking and other risk factors for respiratory disease, is required to adequately assess the potential association between respiratory disease and herbicide or TCDD exposure. Conclusions Strength of Evidence in Epidemiologic Studies There is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides and mortality from respiratory diseases; symptoms or history of respiratory illnesses, such as chronic bronchitis, bronchitis, asthma, pleurisy, pneumonia, tuberculosis, and respiratory conditions; abnormalities on lung or thorax physical examination; pulmonary function test results; and chest radiographs. The evidence regarding association is drawn from occupational and veteran studies in which subjects were exposed to a variety of herbicides and herbicide components. Biologic Plausibility A thorough discussion of biologic plausibility with respect to exposure to TCDD or herbicides and respiratory disorders is contained in Chapter 3; a summary is presented in the conclusion to this chapter.

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Veterans and Agent Orange: Update 1998 IMMUNE SYSTEM DISORDERS Background Immunotoxicology is the study of the effects of xenobiotics (chemical compounds that are foreign to the human body) on the immune system. The compounds may produce an impaired immune response (immunosuppression) or an enhanced immune response (immune-mediated disease). Although alterations in the immune system can be related to increases in the incidence of infection and neoplasm (immune suppression) and immune-mediated diseases (allergy and autoimmunity), there has been no observed increase in infectious or immune-mediated disease in the populations examined after exposure to herbicides. However, alterations have been observed in measures of immune function or populations of immune cells. The question of possible increases in neoplastic diseases is dealt with in Chapter 7. Immune Suppression The immune system helps defend the host against foreign invaders. It confers resistance to infection by bacteria, viruses, and parasites; it is involved in the rejection of allografts (tissue transplants); and it may eliminate spontaneously occurring tumors (Paul, 1993). Proper function of the immune system is exquisitely sensitive to disruptions in physiologic homeostasis. The immune response is highly redundant, and several different mechanisms may be employed to eliminate an antigen. Therefore, a toxicant can affect one facet of the immune system without altering the ability of the host to survive challenge by an infectious agent. Suppression of the immune system leads to increased susceptibility to infection and neoplasia. However, the degree of immune suppression necessary to cause disease is unknown and is the subject of intense scientific interest. Immune deficiency may result from genetic abnormalities (e.g., a deficiency in the enzyme adenosine deaminase, leading to severe combined immune deficiency), congenital malformations, surgical accidents, pregnancy, stress, disease (e.g., human immunodeficiency virus [HIV-1] can lead to AIDS), and exposure to immunosuppressive agents (Paul, 1993). Immune suppression can also occur in patients with autoimmune disease (discussed below); for example, in systemic lupus erythematosus the suppression of complement levels and leukocyte function has been noted. Impaired host defenses can result in severe and recurrent infections with opportunistic microorganisms. As noted, the immune system may prevent or limit tumor growth, and a high incidence of tumors may follow immune suppression (Paul, 1993). Allergy and Autoimmunity A number of diseases involve hyperresponsiveness of the immune system to either foreign allergens (e.g., allergy) or self-antigens (autoimmunity). Allergic

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Veterans and Agent Orange: Update 1998 responses have been noted to numerous environmental agents, including plant pollens and epithelial products of domestic animals. Allergy is the result of formation of allergen-specific immunoglobulin E (IgE) antibodies, which bind to the surface of mast cells and lead to mast-cell degranulation on subsequent exposure to antigen. The mediators of allergic reactions, such as histamine, are then released. The alterations discussed below reflect only in vitro immune parameters, not disease incidence. In fact, no increase in allergic disease related to herbicide exposure has been reported in any of the studies reviewed. In general, the immune response is directed against foreign antigens. However, in some instances antibodies can be demonstrated that react with endogenous antigens (i.e., autoantibodies). Autoimmune disease is the pathological consequence of an immune response to autologous antigen. Some autoimmune diseases result when autoantibodies activate the complement cascade or interact with "killer" mononuclear cells to induce antibody-dependent cell-mediated cytotoxicity. Others are caused by cytotoxic T cells acting directly on their targets or by injurious cytokines released by activated T cells. It is important to distinguish the mere presence of an autoimmune response from autoimmune disease. Autoimmunity, as indicated by the presence of autoantibodies, is relatively common, whereas autoimmune disease is relatively rare. Detecting autoantibodies, particularly in high titers and with high affinity, is the first step in diagnosing autoimmune disease in humans. A definite diagnosis of autoimmune disease, however, depends on careful correlation of history and clinical findings with detailed immunologic investigations. Summary of VAO and Update 1996 The effects of herbicide exposure on the level of several immune parameters were presented in studies reviewed in VAO and Update 1996 . The data are divided into two categories: immune suppression and immune enhancement. No studies investigating the association of autoimmune disease or allergy with exposure to herbicides were identified. Several studies were carried out on individuals occupationally exposed to TCDD, examining immunological markers, including immunoglobulin levels, complement components, and lymphocyte subpopulations. The changes described were marginal and varied from study to study, some showing increases and some decreases in these parameters. No changes in the incidence of infectious disease were noted. These data correlate with some of the data observed in animal studies, but much more information is required to determine the mechanism and clinical significance of these alterations in humans. Currently, the level of alteration in immune parameters necessary to affect the incidence of disease is unknown. Furthermore, since so many immune parameters were assessed in these studies, there is a high probability that at least some positive results would be noted based on chance alone, which would undermine interpretation of the few

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Veterans and Agent Orange: Update 1998 TABLE 11-4  Selected Epidemiologic Studies—Lipids and Lipoprotein Disorders Reference Study Population Exposed Cases Cholesterol Triglycerides HDL Cholesterol OCCUPATIONAL New Studies Calvert et al., 1996c Production workers 18, 16, 7 1.0 (0.5-1.7) 1.7 (0.6-4.6) 2.2 (1.1-4.7) Ott and Zober, 1996a Production workers 42 NS NS p = 0.05   Studies reviewed in VAO Martin, 1984a Production workers 53 (some exposure) p < 0.005 p < 0.05 NS     39 (chloracne) p < 0.005 p < 0.01 NS Moses et al., 1984b TCP and 2,4,5-T production workers 118 (chloracne) NS NS No data Suskind and Hertzberg, 1984a TCP production workers 204 NS NS NS May, 1982a TCP production workers 94 NS NS No data   Pazderova-Vejlupkova et al., 1981a TCP and 2,4,5-T production workers 55 NS VLDL No data         p = 0.01     ENVIRONMENTAL Studies reviewed in VAO Assennato et al., 1989a Adults exposed near Seveso 193 (chloracne) NS NS No data Mocarelli et al., 1986a Children exposed near Seveso 63 NS NS No data  

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Veterans and Agent Orange: Update 1998 Reference Study Population Exposed Cases Cholesterol Triglycerides HDL Cholesterol VIETNAM VETERANS New Studies AFHS, 1996i Longitudinal analysis (1992 exam data) 884 NS NS NS     (cholesterol: HDL ratio)   (cholesterol: HDL ratio)   O'Toole et al., 1996d Australian Vietnam veterans 20 3.0 (1.3-4.7) No data No data   Studies reviewed in VAO AFHS, 1991g Serum dioxin analysis (1987 exam data) 283-304f p = 0.175 p < 0.001h p < 0.001 AFHS, 1990f Original exposure group analysis (1987 exam data) 8-142f 1.2 (0.9-1.5) 1.3 (0.9-1.8) 1.0 (0.4-2.4) AFHS, 1984e Wolfe et al., 1990 Vietnam Veterans exposed to herbicide spraying (1982 data) 1,027 total exposed NS NS NS Estimated risk and 95% confidence interval reported unless P-values are specified NS = Not significant ap-values comparing means to controls. Univariate analysis. bP-values comparing means in production workers with subsequent chloracne to those without. cOR for abnormal lipid in highest exposure category. dCompared to Australian population. eComparing means. fNumber exposed RH with "high" lipid values. gComparing mean dioxin across lipid groups. hContinuous analysis. iComparing change over time between exposed and comparison groups.

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Veterans and Agent Orange: Update 1998 Health Outcomes with Inadequate/Insufficient Evidence to Determine Whether an Association Exists The scientific data for many of the health effects reviewed by the committee were inadequate or insufficient to determine whether an association exists. For the health effects discussed in this chapter, 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 category includes respiratory disorders, immune system disorders (immune suppression and autoimmunity), diabetes, lipid and lipoprotein disorders, gastrointestinal diseases, digestive diseases, liver toxicity, and circulatory disorders. Health Outcomes with Limited/Suggestive Evidence of No Association In VAO and Update 1996, the committee did not find any evidence to conclude that there is limited/suggestive evidence of no association between the health effects discussed in this chapter and exposure to TCDD or herbicides. The most recent scientific evidence continues to support this conclusion. In order to classify outcomes in this category, several adequate studies coveting the full range of levels of exposure that human beings are known to encounter must be mutually consistent in not showing a positive association between exposure to herbicides and the outcome at any level of exposure. These studies must also 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. Biologic Plausibility Chapter 3 details the committee's evaluation of evidence from animal and cellular-level studies regarding the biological plausibility of a connection between exposure to dioxin or herbicides and various noncancer health effects. This section summarizes that evidence. Some of the preceding discussions of other health outcomes include references to specific relevant papers. TCDD has been shown to elicit a diverse spectrum of sex-, strain-, age-, and species-specific effects, including immunotoxicity, hepatotoxicity, chloracne, loss of body weight, and numerous biological responses, including the induction of phase I and phase II drug-metabolizing enzymes, the modulation of hormone systems and factors associated with the regulation of cellular differentiation and proliferation. Effects of TCDD on the liver include modulation of the rate at which liver cells multiply, increasing the rate of cell death for other cell types, increasing fat

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Veterans and Agent Orange: Update 1998 levels in liver cells, decreasing bile flow, and increasing the levels of protein and of substances that are precursors to heme synthesis. TCDD also increases the levels of certain enzymes in the liver, but this effect in itself is not considered toxic. Mice and rats are susceptible to TCDD-induced liver toxicity, but guinea pigs and hamsters are not. It is possible that liver toxicity is associated with susceptibility to liver cancer, but the extent to which TCDD effects mediate noncancer end points is not clear. The mechanism by which TCDD induces hepatotoxicity is still under investigation. Some studies provide evidence that hepatotoxicity of TCDD involves AhR-dependent mechanisms. Specifically, there is evidence that the Ah-receptor plays a role in the co-mitogenic action of TCDD with epidermal growth factor and in the induction of liver enzymes involved in the metabolism of xenobiotics. Acute exposures to TCDD have been correlated with effects on intermediary metabolism and hepatomegaly. TCDD has been shown to inhibit hepatocyte DNA synthesis, decrease hepatic plasma membrane epidermal growth factor receptor; inhibit hepatic pyruvate carboxylase activity, and induce porphyrin accumulation in fish and chick embryo hepatocyte cultures. Studies have been conducted to examine the short-and long-term effects of TCDD on rat EROD activity and liver enzymes. Oral dosing induced EROD and glutamyltranspeptidase (GT) activity and inhibited hepatic phosphoenolpyruvate carboxykinase (PEPCK) activities. EROD and PEPCK activity reverted to normal levels after ninety days while GT activity remained elevated. Hepatomegaly has been shown to occur following high subchronic doses. The myocardium has also been shown to be a target of TCDD toxicity; impairment of a cAMP-modulated contraction has been implicated. Recent evidence suggests that the inhibition of glucose transport in adipose tissue, pancreas, and brain may be one of the major contributing factors to the wasting syndrome. In vitro studies have identified glomerular mesangial cells as sensitive cellular targets. These findings are consistent with epidemiologic reports that aromatic hydrocarbons result in glomerulonephritis. TCDD has also been shown to have a number of effects on the immune systems of laboratory animals. Studies in mice, rats, guinea pigs, and monkeys indicated that TCDD suppresses the function of certain components of the immune system in a dose-related manner; that is, as the dose of TCDD increases, its ability to suppress immune function increases. TCDD suppressed cell-mediated immunity, primarily by affecting the T-cell arm of the immune response. It is not known whether TCDD directly affects T-cells. TCDD may indirectly affect T-cells and cell-mediated immunity by altering thymus gland function or cytokine production. The generation of antibodies by B cells, an indication of humoral immunity, may also be affected by TCDD. Increased susceptibility to infectious disease has been reported following TCDD administration. In addition, TCDD increased the number of tumors that formed in mice following injection of tumor cells. It should be emphasized,

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Veterans and Agent Orange: Update 1998 however, that very little change to the overall immune competence of the intact animal has been reported. Despite considerable laboratory research, the mechanisms underlying the immunotoxic effects of TCDD are still unclear. TCDD immunotoxicity appears to be primarily mediated through Ah-receptor-dependent processes, but some components of immunosuppression have been shown to act independently of the Ah receptor. Some studies indicate that an animal's hormonal status may contribute to its sensitivity to immunotoxicity. The fact that TCDD induces such a wide variety of effects in animals suggests that it is likely to have some effect in humans as well. Generally, TCDD has a wide range of effects on growth regulation, hormone systems, and other factors associated with the regulation of activities in normal cells. These effects may influence the formation of noncancer health disorders. Studies in animals indicate that some TCDD effects are mediated through the Ah-receptor, a protein in animal and human cells to which TCDD can bind. It is hypothesized that TCDD, together with the AhR, can interact with sites on DNA and alter the information obtained from DNA in a way that transforms normal cells into abnormal cells. Although structural differences in the AhR have been identified, this receptor operates in a similar manner in animals and humans. Evidence has also begun to accumulate for non-Ah receptor mediated effects. TCDD has been shown to induce differentiation in human keratinocytes, which may be initiated by TCDD binding to the AhR. This effect is antagonized by retinoids and may involve interactions between TCDD and retinoids in the regulation of epithelial differentiation. TCDD has been reported to decrease an acidic type I Keratin involved in epidermal development, leading to keratinocyte hyperproliferation and skin irritations such as chloracne. Limited information is available on health effects of the herbicides discussed in the report. These herbicides, however, have been reported to elicit adverse effects in a number of organs in laboratory animals. The liver is a target organ for toxicity induced by 2,4-D, 2,4,5-T, and picloram, with changes reportedly similar to those induced by TCDD. Some kidney toxicity was reported in animals exposed to 2,4-D and cacodylic acid. Exposure to 2,4-D has also been associated with effects on blood, such as reduced levels of heme and red blood cells. Cacodylic acid was reported to induce renal lesions in rats. Other studies provide evidence that 2,4-D binds covalently to hepatic proteins and lipids; the molecular basis of this interaction and its biologic consequences are unknown. The potential immunotoxicity of the herbicides used in Vietnam has been studied to only a very limited extent. Effects on the immune system of mice were reported for 2,4-D administered at doses that were high enough to produce clinical toxicity, but these effects did not occur at low doses. The potential for picloram to act as a contact sensitizer (i.e., to produce an allergic response on the skin) was tested, but other aspects of immunotoxicology were not examined.

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Veterans and Agent Orange: Update 1998 The foregoing evidence suggests that a connection between TCDD or herbicide exposure and human health effects is, in general, biologically plausible. However, differences in sensitivity and susceptibility across individual animals, strains, and species; lack of strong evidence of organ-specific effects across species; and differences in route, dose, duration, and timing of exposure complicate any more definitive conclusions about the presence or absence of a mechanism for the induction of specific noncancer health disorders. Considerable uncertainty remains over how to apply this information to the evaluation of potential health effects of herbicides or dioxin exposure in Vietnam veterans. Scientists disagree over the extent to which information derived from animals and cellular studies predicts human health outcomes, and the extent to which the health effects resulting from high-dose exposure are comparable to those resulting from low-dose exposure. Research on biological mechanisms is burgeoning, and subsequent Veterans and Agent Orange updates may have more and better information on which to base conclusions. Increased Risk of Disease Among Vietnam Veterans Under the Agent Orange Act of 1991, the committee is asked to determine (to the extent that available scientific data permit meaningful determinations) the increased risk of the diseases it studies among those exposed to herbicides during their service in Vietnam. Chapter 1 presents the committee's general findings regarding this charge. Where more specific information about particular health outcomes is available, this information is related in the preceding discussions of those diseases. REFERENCES Air Force Health Study (AFHS). 1984. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Baseline Morbidity Study Results. Brooks AFB, TX: USAF School of Aerospace Medicine. NTIS AD-A138 340. Air Force Health Study. 1990. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 2 vols. Brooks AFB, TX: USAF School of Aerospace Medicine. USAFSAM-TR-90-2. Air Force Health Study. 1991. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Serum Dioxin Analysis of 1987 Examination Results. 9 vols. Brooks AFB, TX: USAF School of Aerospace Medicine. Air Force Health Study. 1992. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Reproductive Outcomes. Brooks AFB, TX: Armstrong Laboratory. AL-TR-1992-0090. Air Force Health Study. 1995. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1992 Followup Examination Results. 10 vols. Brooks AFB, TX: Epidemiologic Research Division. Armstrong Laboratory. Air Force Health Study. 1996. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Mortality Update 1996. Brooks AFB, TX: Epidemiologic Research Division. Armstrong Laboratory. AL/AO-TR-1996-0068.

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Veterans and Agent Orange: Update 1998 Wolf N, Karmaus W. 1995. Effects of inhalative exposure to dioxins in wood preservatives on cell-mediated immunity in day-care center teachers. Environmental Research 68(2):96-105. Wolfe WH, Michalek JE, Miner JC, Rahe A, Silva J, Thomas WF, Grubbs WD, Lustik MB, Karrison TG, Roegner RH, Williams DE. 1990. Health status of Air Force veterans occupationally exposed to herbicides in Vietnam. I. Physical health. Journal of the American Medical Association 264:1824-1831. World Health Organization. 1980. WHO Expert Committee on Diabetes Mellitus (Tech. Rep. Ser., No. 646). Second Report. Geneva: World Health Organization. World Health Organization. 1985. Diabetes Mellitus: Report of a WHO Study Group (Tech. Rep. Ser., No. 727). Geneva: World Health Organization. Zober A, Ott MG, Messerer P. 1994. Morbidity follow up study of BASF employees exposed to 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) after a 1953 chemical reactor incident. Occupational and Environmental Medicine 51:479-486.