9
Other Health Effects

This chapter discusses data on the possible association between exposure to the herbicides used in Vietnam (2,4-dichlorophenoxyacetic acid [2,4-D], 2,4,5-trichlorophenoxyacetic acid [2,4,5-T], picloram, and cacodylic acid and 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], a contaminant of 2,4,5-T) and the following non-cancer health outcomes: chloracne, porphyria cutanea tarda (PCT), respiratory disorders, immune system disorders, diabetes, lipid and lipoprotein disorders, gastrointestinal and digestive disease (including liver toxicity), circulatory disorders, amyloidosis, endometriosis, and adverse effects on thyroid homeostasis. Background information about each outcome is followed by a brief summary of the findings described in earlier Veterans and Agent Orange reports, a discussion of the most recent scientific literature, and a synthesis of the material reviewed. For studies new to this update that report only a single health outcome and that are not revisiting a previously studied population, their design information is summarized with their results; the design information for all other news studies can be found in Chapter 4. Within health outcome, the studies are grouped by exposure type (occupational, environmental, or Vietnam veteran). Each section ends with the Veterans and Agent Orange: Update 2004 committee’s conclusions regarding the strength of the evidence from epidemiologic studies, biologic plausibility, and evidence regarding Vietnam veterans. The categories of association and the committee’s approach to categorizing the health outcomes are discussed in Chapters 1 and 2.



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Veterans and Agent Orange: Update 2004 9 Other Health Effects This chapter discusses data on the possible association between exposure to the herbicides used in Vietnam (2,4-dichlorophenoxyacetic acid [2,4-D], 2,4,5-trichlorophenoxyacetic acid [2,4,5-T], picloram, and cacodylic acid and 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], a contaminant of 2,4,5-T) and the following non-cancer health outcomes: chloracne, porphyria cutanea tarda (PCT), respiratory disorders, immune system disorders, diabetes, lipid and lipoprotein disorders, gastrointestinal and digestive disease (including liver toxicity), circulatory disorders, amyloidosis, endometriosis, and adverse effects on thyroid homeostasis. Background information about each outcome is followed by a brief summary of the findings described in earlier Veterans and Agent Orange reports, a discussion of the most recent scientific literature, and a synthesis of the material reviewed. For studies new to this update that report only a single health outcome and that are not revisiting a previously studied population, their design information is summarized with their results; the design information for all other news studies can be found in Chapter 4. Within health outcome, the studies are grouped by exposure type (occupational, environmental, or Vietnam veteran). Each section ends with the Veterans and Agent Orange: Update 2004 committee’s conclusions regarding the strength of the evidence from epidemiologic studies, biologic plausibility, and evidence regarding Vietnam veterans. The categories of association and the committee’s approach to categorizing the health outcomes are discussed in Chapters 1 and 2.

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Veterans and Agent Orange: Update 2004 CHLORACNE Chloracne is a skin disease that is characteristic of exposure to TCDD and other cyclic organochlorine compounds. It shares some pathologic processes (the occlusion of the orifice of the sebaceous follicle) with more common forms of acne (such as acne vulgaris), but it can be differentiated by the presence of epidermoid inclusion cysts, which are caused by proliferation and hyperkeratinization (horn-like cornification) of the epidermis and sebaceous gland epithelium. Although chloracne is typically distributed over the eyes, ears, and neck, patterns of chloracne among chemical industry workers exposed to TCDD also include the trunk, genitalia, and buttocks (Neuberger et al., 1998). Chloracne has been studied extensively and is used as a marker of exposure in studies of populations exposed to TCDD and other organochlorine compounds, such as polychlorinated biphenyls (PCBs) and pentachlorophenol. It is one of the few findings consistently associated with such exposure and is a well-validated indicator of high exposure to those compounds, particularly TCDD (Sweeney et al., 1997/98). If chloracne occurs, however, it appears shortly after the chemical exposure, not after a long latency. Although it is refractory to acne treatments, it usually regresses over time. Therefore, new cases of chloracne would not be the result of exposures during Vietnam and are not a concern for this report. It also should be noted that lack of chloracne does not necessarily indicate the absence of exposure to substantial levels of TCDD, as is apparent from studies of individuals exposed in the Seveso accident. There is not necessarily a correlation between serum concentrations of TCDD and the occurrence or severity of chloracne. Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committee responsible for Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as VAO; IOM, 1994) determined there was sufficient evidence of an association between exposure to at least one compound of interest and chloracne. Additional information available to the committees responsible for Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), and Update 2002 (IOM, 2003) did not change that finding. Reviews of the studies that underlie the finding can be found in the earlier reports. Update of the Scientific Literature No relevant occupational or environmental studies have been published since Update 2002.

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Veterans and Agent Orange: Update 2004 Vietnam-Veteran Studies Kim J-S et al. (2003) conducted a cross-sectional study of Korean veterans who served in Vietnam to determine what adverse health effects might be associated with service in Vietnam and, by inference, attributable to exposure to Agent Orange. The Korean-veteran cohort consisted of 1,224 male veterans (27.6% participation rate); a non-exposed group consisted of 154 male Korean veterans (5.7% participation rate) who did not serve in Vietnam. Chloracne occurred in nine veterans who served in Vietnam; it did not occur in the veterans who served elsewhere. The prevalence of chloracne did not increase for higher exposures. Selection and recall bias could limit the usefulness of the results. Synthesis Chloracne is clearly associated with high exposure to cyclic organochlorine compounds, but because it appears shortly after exposure, a long latency would be inconsistent with information in previous studies. The study conducted by Kim J-S et al. (2003) had significant limitations and did not contribute to better understanding chloracne as it relates to organochlorines. Conclusions Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is sufficient evidence of an association between exposure to at least one compound of interest and chloracne. Biologic Plausibility As noted in previous reports, chloracne-like skin lesions have been reported to occur in several animal species in response to exposure to TCDD but not to purified phenoxyacetic herbicides. TCDD induces differentiation in human keratinocytes, and it is reported to decrease an acidic type I keratin involved in epidermal development and thus lead to keratinocyte hyperproliferation and skin irritations, such as chloracne. The data provide a biologically plausible mechanism for the induction of chloracne by TCDD. Increased Risk of Disease Among Vietnam Veterans Although there are data to suggest an association between exposure to the chemicals of interest and chloracne, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

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Veterans and Agent Orange: Update 2004 PORPHYRIA CUTANEA TARDA Porphyrias are uncommon disorders caused by deficiencies of enzymes involved in the heme (iron-containing, non-protein portion of the hemoglobin molecule) biosynthesis pathway. PCT is a heterogeneous group of disorders caused by a deficiency of a specific enzyme (uroporphyrinogen decarboxylase). PCT, the most common of the porphyries, can be inherited, but more often it is acquired. Type I PCT, which accounts for 80–90% of all cases, is an acquired disease that typically becomes evident in adulthood. Type I PCT can occur spontaneously, but more commonly it occurs in conjunction with environmental factors, such as alcohol consumption, exposure to estrogens, or use of some medications. The most significant clinical finding is cutaneous photosensitivity. Sensitivity to sunlight is thought to result from the excitation of excess porphyrins in the skin by long-wave ultraviolet light, which leads to cell damage. Fluid-filled vesicles and bullae develop on sun-exposed areas of the face and on the dorsa of the hands, feet, forearms, and legs. Other features include hypertrichosis (excess hair) and hyperpigmentation (increased pigment), especially on the face. In individuals with PCT, porphyrins are increased in the liver, plasma, urine, and stools. Iron, estrogens, alcohol, viral hepatitis, and chlorinated hydrocarbons can aggravate the disorder. Iron overload is almost always present in individuals with PCT. Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committee responsible for VAO determined that there was sufficient evidence of an association between exposure to at least one compound of interest (2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid) and PCT in genetically susceptible people. The data, however, indicated that PCT manifests shortly after exposure to TCDD. Therefore, new cases of PCT attributable to exposures during the Vietnam War will not occur. Additional information available to the committee responsible for Update 1996 led it to conclude that there was only limited or suggestive evidence of an association, and Update 1998, Update 2000, and Update 2002 did not change that conclusion. Reviews of the relevant studies are found in the earlier reports. Update of the Scientific Literature No relevant occupational or environmental studies have been published since Update 2002. Vietnam-Veteran Studies Kim J-S et al. (2003) conducted a cross-sectional study of Korean veterans who served in Vietnam to determine what adverse health effects might be associ-

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Veterans and Agent Orange: Update 2004 ated with service in Vietnam and, by inference, attributable to exposure to Agent Orange. The Korean-veteran cohort consisted of 1,224 male veterans (27.6% participation rate); a non-exposed group consisted of 154 male Korean veterans (5.7% participation rate) who served elsewhere. Uroporphyrin (a common porphyrin that is increased in persons with PCT) occurred with greater frequency in the urine of veterans who served in Vietnam than it did in non-Vietnam veterans (p < 0.0001). However, the authors did not include uroporphyrin concentrations or specify urine collection procedures (24-h urine or spot urine sample) in their report. Synthesis PCT would be an early response to TCDD; recovery would occur after exposure ceased. Although PCT has been seen after exposure to TCDD in industrial settings, Vietnam veterans enrolled in the Ranch Hand study have not exhibited symptoms suggestive of the disorder. Conclusions Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to at least one compound of interest and PCT. Biologic Plausibility PCT has not been replicated in animal studies with TCDD, although other porphyrin abnormalities have been reported. Porphyrin accumulation was found in fish and chick embryo hepatocyte cultures treated with TCDD. Increased Risk of Disease Among Vietnam Veterans Although there are data to suggest an association between exposure to the chemicals of interest and PCT in genetically susceptible people, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk. RESPIRATORY DISORDERS Non-malignant respiratory disorders comprise acute and chronic lung diseases other than cancer. Acute respiratory disorders include pneumonia and other

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Veterans and Agent Orange: Update 2004 respiratory infections. Those disorders could be increased in frequency and severity when the normal defense mechanisms of the lower respiratory tract are compromised. Chronic non-malignant respiratory disorders generally take one of two forms: Airways disease is a general term for disorders characterized by obstruction of the flow of air out of the lungs, among them asthma and chronic obstructive pulmonary disease (COPD), which includes emphysema and chronic bronchitis. Parenchymal disease, or interstitial disease, generally includes numerous disorders that cause inflammation and scarring of the deep lung tissue, including the air sacs and supporting structures. Parenchymal disease is less common than is airways disease, and its disorders are characterized by reductions in lung capacity, although they can include a component of airway obstruction. Some severe chronic lung disorders, such as cystic fibrosis, are hereditary. Because Vietnam veterans received health screenings before entering military service, few severe hereditary chronic lung disorders are expected in that population. The major risk factor for many non-malignant respiratory disorders is cigarette-smoking. Although cigarette-smoking is not associated with every disease of the lungs, it is the major cause of many airways disorders, it contributes to some interstitial disease, and it compromises host defenses in such a way that people who smoke are generally more susceptible to some types of pneumonia. Cigarette-smoking also makes almost every respiratory disorder more severe and symptomatic than would otherwise be the case. The frequency of habitual cigarette-smoking varies with occupation, socioeconomic status, and generation. For those reasons, cigarette-smoking is a major confounding factor in interpreting the literature on risk factors for respiratory disease. Vietnam veterans are reported to smoke more heavily than are non-Vietnam veterans (McKinney et al., 1997). Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to the compounds of interest (2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid) and the respiratory disorders specified above. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change that finding. Update 2000 drew attention to findings from the Seveso cohort that suggested a higher mortality from non-malignant respiratory disorders among study subjects, particularly males, who were more heavily exposed to TCDD. Those findings were not replicated in several other relevant studies, although one showed an increase that did not attain statistical significance. The committee for Update 2000 concluded that although new evidence suggested an increased risk of non-malignant respiratory disorders, particularly COPD, among people exposed to TCDD, the observation is tentative and the information insufficient to determine an association between the exposures of interest and respiratory dis-

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Veterans and Agent Orange: Update 2004 orders. Additional information available to the committee responsible for Update 2002 did not change that finding. Update of the Scientific Literature Dahlgren et al. (2003) described a cross-sectional environmental study that used questionnaires to gather information on potential adverse health effects among residents near a wood treatment plant. The plant always used creosote, and pentachlorophenol was used from 1951 to 1971. Soil and sediment samples from a ditch in the neighborhood contained dioxins and furans. The exposed population consisted of 1,269 residents of a neighborhood near the plant; they also were plaintiffs or potential plaintiffs in a lawsuit against the plant. A representative sample group of 214 residents was chosen to participate in the study. The unexposed population consisted of 139 age- and sex-matched residents of a distant neighborhood. Exposed and unexposed subjects completed questionnaires; were examined by a physician; and underwent blood, urine, and respiratory function tests. Exposed residents reported greater frequency of chronic bronchitis by history (17.8% versus 5.7%, p < 0.0001) and asthma by history (40.5% versus 11.0%, p < 0.0001). Selection bias and recall bias limit the utility of the results. Also, it is unclear whether the authors adequately controlled for history of tobacco use. In addition, multiple environmental exposures occurred in the neighborhood near the plant, and the authors could not determine which exposures were responsible for the reported adverse health effects. No relevant occupational or Vietnam-veteran studies have been published since Update 2002. Synthesis No new studies provide evidence of a direct risk of non-malignant respiratory disorders in adults since those reviewed in Update 2002. Conclusions Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and non-malignant acute or chronic respiratory disorders.

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Veterans and Agent Orange: Update 2004 Biologic Plausibility Lung tissue contains high concentrations of the aryl hydrocarbon receptor (AhR), which mediates the effects of TCDD. Recent data also show that human lung cells are responsive to TCDD in terms of altered gene expression. Therefore, it is biologically plausible that exposure to TCDD may result in acute and chronic lung disorders, but cigarette-smoking also is a major risk factor for those disorders. Cytochrome P450 (CYP) enzymes are responsible, in part, for the activation of such chemicals as those found in tobacco smoke (which also contains AhR ligands) to more toxic intermediates, so it is also biologically plausible that exposure to TCDD may synergize the toxic effects of a variety of compounds to which human lungs are exposed. Bronchiolar metaplasia of the alveolar epithelium has been observed in the lungs of rats exposed to TCDD for 2 years. Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and the respiratory disorders specified above, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk. IMMUNE SYSTEM DISORDERS The immune system defends the body against infection by viruses, bacteria, and other disease-producing microorganisms (pathogens). The immune system also operates in cancer surveillance, destroying cells that have become transformed and might otherwise develop into tumors. As it recognizes the wide array of pathogens in the environment, the immune system relies on many different cell types that operate together to generate immune responses. The immune system’s cells arise from stem cells in the bone marrow; they are found throughout the body’s lymphoid tissues, and they circulate in the blood as white blood cells (WBCs). Granulocytes are WBCs that respond quickly to infection. They display a variety of protein receptors on their surfaces that can bind to molecules on different pathogens. When the receptors are bound, they signal the granulocytes to release toxins contained in their granules that kill the pathogens. Macrophages (“large eaters”) are WBCs that ingest bacteria and other microbes; once inside the macrophage, the microbes are killed by oxidative and enzymatic processes. Natural killer (NK) cells are WBCs that recognize and kill virus-infected cells and cancer cells. Granulocytes, macrophages, and NK cells are the first line of defense against infectious disease and cancer. A second line of defense specifically targets the infecting microorganism. The response is mediated by the T and B lymphocytes. B lymphocytes produce

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Veterans and Agent Orange: Update 2004 antibodies, which bind to infectious microbes or their toxins, causing them to be destroyed by other immune system cells. There are several antibodies (immunoglobulins [Ig]): IgM, IgG, IgA, IgE, and IgD. All have different functions, but each is quite specific in action. For example, antibodies produced in response to a tuberculosis infection will bind only to tuberculosis bacteria. T lymphocytes carry out many functions: They help B lymphocytes make antibodies, activate macrophages to kill bacteria more effectively, and directly kill tumor cells and virus-infected cells. T lymphocytes regulate the magnitude of the immune response and turn it off when the infection is cleared. T cells function primarily by secreting soluble chemical messengers called interleukins and they acquire their different functions by passing through the thymus gland before entering the blood and lymph nodes. An intact T and B lymphocyte response is highly effective at preventing disease. Once a person is exposed to a particular disease organism or is vaccinated against that disease, memory T and B cells are present in larger numbers. The cells respond more quickly upon reinfection to prevent disease. When the immune system responds to a foreign substance that is not actually pathogenic, such as animal dander, pollen, or poison ivy, the immune system can generate an allergic response. Many allergic responses are associated with the production of IgE or sometimes IgG antibodies. Once produced, those antibodies bind to the surface of other cells—mast cells—that occur in tissues throughout the body, including lung airways, the gut wall, and blood vessel walls. When a person is exposed again to the allergen, the allergen binds to the antibodies on the mast cells, causing them to release histamine and leukotrienes, which cause the allergic symptoms. Allergic responses also are mediated by memory T cells that release inflammatory substances when the allergen binds to receptors. Rashes caused by contact with poison ivy or nickel are T-cell-mediated allergies. Autoimmune disease is another example of the immune system’s causing rather than preventing disease. In this case, the immune system mistakenly attacks the body’s own cells and tissues as if they were foreign. The autoimmune reaction in multiple sclerosis is directed against the myelin sheath of the nervous system; in Crohn’s disease, the gut is the target of attack; in type 1 diabetes mellitus, the insulin-producing cells of the pancreas are destroyed by the immune response. In some autoimmune diseases, B cells mistakenly make antibodies against specific cellular components. Those autoantibodies may interfere with the normal function of the tissues or cause the tissue to break down. Sometimes altered T-cell function is the underlying cause of autoimmunity. Genetic predisposition and environmental factors such as infectious diseases and stress are thought to facilitate the development of autoimmune diseases. Suppression of the immune response can result in reduced resistance to infectious disease and to increased risk of cancer. In persons suffering from allergies or autoimmune disease, immune suppression can relieve symptoms. Immune deficiencies can be congenital or acquired in a variety of ways. Infection with HIV is a well-recognized example of an acquired immune deficiency in

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Veterans and Agent Orange: Update 2004 which a specific type of T cell is the target of the virus. The decline in the number of CD4+ T cells after HIV infection correlates with an increased incidence of infectious diseases, including fatal opportunistic infections, and with an increased incidence of several types of cancer. On a more modest scale, nutritional deficiencies, chronic stress, and exposure to toxic chemicals also have been shown to suppress some functions of the immune system. However, because the immune system has considerable reserve capacity and redundancy, that modest suppression does not usually translate directly into increased disease. The ability of an individual to combat infection depends on many factors that are difficult to control in a scientific study, including the virulence of the microbe; the presence of other diseases (diabetes); age; vaccination status; stress; and exposure to toxic compounds, both intentionally (alcohol, tobacco or drug use, medications) and unintentionally (through workplace or environmental exposures). Because of those many confounding factors, few studies have been able to identify significant changes in immune response after environmental exposure in humans, and the evidence of direct links between chemical-compound-induced changes in immune function and altered disease is not strong. Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committees responsible for VAO, Update 1996, Update 1998, Update 2000, and Update 2002, concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and immune system disorders. Reviews of the studies that underlie those conclusions are presented in the previous reports (IOM, 1994, 1996, 1999, 2001, 2003). Update of the Scientific Literature Occupational Studies No relevant occupational studies of immune disorders have been published since those reviewed in Update 2002. Environmental Studies In a new study about Seveso, Italy, Baccarelli et al. (2002) measured plasma immunoglobulin and complement concentrations in a random sample of the population in the most highly exposed zone (N = 62) and in the surrounding uncontaminated area (N = 58). Plasma IgG significantly decreased with increasing TCDD concentration. That association was present after adjusting for age, sex, tobacco use, and consumption of domestic livestock and poultry. There was no effect on concentrations of IgM, IgA, or complement; IgE was not measured.

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Veterans and Agent Orange: Update 2004 Two studies have evaluated the influence of exposure to TCDD-like compounds on immune response in children. Van Den Heuvel et al. (2002) characterized the immune status of adolescent boys and girls in Flanders, Belgium, in relation to their blood concentrations of PCBs and dioxin-like compounds. The latter data were obtained using the chemical-activated luciferase expression (CALUX) bioassay. The percentages of eosinophils and NK cells in the blood and IgG concentrations in the serum were negatively correlated with increasing CALUX toxicity equivalents (TEQ). The concentrations of IgE to specific allergens were negatively correlated with CALUX TEQs, in parallel with a significant decrease in self-reported allergies. The decrease in IgE found in the adolescents might suggest a dioxin-induced suppression of the immune response, consistent with the findings in laboratory animals exposed to TCDD. In a follow-up study of 8-year-old Dutch children (N = 27) perinatally exposed to dioxin, ten Tusscher et al. (2003) found a decrease in allergy in relation to increasing dioxin exposure. They also found increased numbers of CD4+ T cells and CD45RA+ cells, a phenotype associated with naïve T cells. An increased percentage of naïve versus activated T cells is consistent with a generalized decrease in immune responsiveness associated with dioxin exposure. Vietnam-Veteran Studies Kim H-A et al. (2003) studied Korean Vietnam War veterans for evidence of immune system changes in relation to their operation in various areas of Vietnam. Study subjects were classified into three groups, based on self-reported Agent Orange exposure history and health status. A veteran patient group (N = 24) consisted of veterans exposed to Agent Orange and suffering from chronic illness; the veteran control group (N = 27) had similar exposure but no chronic illness. Control subjects (N = 36) were healthy age-matched subjects with no Vietnam War military service. A significant increase in plasma IgE was found in both groups of veterans compared with control subjects. The patient group also had significantly decreased plasma IgG1. Those changes correlated with decreased production of interferon gamma in the patient group and with increased production of interleukin 4 in both veterans’ groups when the T cells from the subjects were cultured in vitro. No changes in the plasma concentrations of antibodies against double-stranded DNA or extractable nuclear antigens, both markers of autoimmune disease, were found in the veterans, nor were changes found in frequency distribution of peripheral blood leukocyte subpopulations. Synthesis TCDD is a well-known immunosuppressive agent in laboratory animals; it is among the most potent immunotoxicants in the environment. Therefore, one would expect that exposure of humans to sufficiently high doses of TCDD would

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Veterans and Agent Orange: Update 2004 TCDD concentrations were inversely related to T3 and TSH. The association was strongest when historical, but not current, serum TCDD concentrations were considered. In a paper reviewed in Update 1998, Zober et al. (1994) examined 138 BASF workers exposed to TCDD in a 1953 industrial incident. The researchers reported that thyroid disease was increased (p < 0.05) in the exposed population. Environmental Studies No relevant environmental studies have been published since Update 2002. Vietnam-Veteran Studies Pavuk et al. (2003) examined thyroid hormone status in the AFHS cohort. At each examination (1982, 1985, 1987, 1992, 1997) there was a trend toward an increasing concentration of TSH, which was not accompanied by changes in circulating T4 or in the percentage uptake of T3 (measured only in the earlier years). In a repeated-measures linear regression adjusted for age, race, and military occupation, the low-exposure and high-exposure Ranch Hands had TSH significantly higher than did the comparison population, and the trend test showed a significant linear increase over the comparison and background-, low-, and high-exposure groups (p = 0.002). No changes in microsomal or antithyroid antibodies were observed, nor was there any evidence of changes in clinical thyroid disease. The percentage with abnormally high TSH was higher at each examination in the high-exposure Ranch Hand group than in the comparison population, but the confidence intervals were wide and included 1 at each examination (1982: OR, 1.8, 95% CI, 0.7–5.9; 1985: OR, 1.4, 95% CI, 0.7–3.2; 1987: OR, 1.9, 95% CI, 0.8–4.5; 1992: OR, 1.7, 95% CI, 0.8–3.9; 1997: OR, 1.8, 95% CI, 0.9–3.4). An earlier study of the Ranch Hand cohort (AFHS, 1991) was reviewed in VAO, but not reconsidered in Update 2002. The assessment of endocrine function in that study included a series of thyroid function tests, which showed no difference in thyroid function between exposed and control veterans. Synthesis Numerous animal experiments and several epidemiologic studies show that TCDD and dioxin-like compounds appear to exert an influence on thyroid homeostasis. The effects are hypothesized to provide a mechanism by which TCDD may affect early development of neurologic and sensory organs and of motor function when exposure occurs in utero or during lactation. However, clear effects of TCDD on thyroid homeostasis have also been observed when adult animals were exposed. Several human studies observed increases in TSH without evidence of increases in T4, indicating that the infants (selected for uncompli-

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Veterans and Agent Orange: Update 2004 cated gestation, labor, and delivery) and the Ranch Hand Air Force personnel were able to adapt to the changes in thyroid status that might have been induced by the higher body burdens of TCDD and TEQ. Conclusions Strength of Evidence from Epidemiologic Studies There is inadequate or insufficient evidence of an association between exposure to the compounds of interest and adverse effects on thyroid homeostasis. Some effects have been observed in humans, but the functional importance of those changes is unclear because adaptive capacity could be adequate to accommodate them. Biologic Plausibility TCDD affects concentrations of T4, T3, and TSH in experimental animals, but the effects lack consistency in demonstrating either a definite hyperthyroidism or hypothyroidism after exposure to TCDD. Nevertheless, long-term exposure of animals to TCDD usually results in suppressed T4 and T3 and stimulated TSH. The National Toxicology Program reported that female rats exposed chronically to TCDD demonstrated altered thyroid follicles. This was further characterized as being attributable to a reversible hypertrophic response of the follicular cell. Chapter 3 discusses recent toxicologic studies relevant to the biologic plausibility of the effects of TCDD and the herbicides on the thyroid gland. Increased Risk of Disease in Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and adverse effects on thyroid homeostasis, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk. SUMMARY On the basis of the occupational, environmental, and veterans’ studies reviewed, the committee reached one of four conclusions about the strength of the evidence regarding an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and each of the health effects discussed in this chapter. As explained in Chapter 2, the conclusions reflect the committee’s judgment that if an association between exposure and an outcome exists, it would be found in a large, well-designed epidemiologic study in which exposure to herbicides or TCDD was sufficiently high, well-characterized, and appropriately measured on

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Veterans and Agent Orange: Update 2004 an individual basis. To be consistent with the charge to the committee by the Secretary of Veterans Affairs in Public Law 102-4 and with accepted standards of scientific reviews, the distinctions between the conclusions are based on statistical association, not on causality. The committee used the same criteria that were used in VAO, Update 1996, Update 1998, Update 2000, and Update 2002 to categorize diseases by the strength of the evidence. Health Outcomes with Sufficient Evidence of an Association For diseases in this category, a positive association between exposure and outcome must be observed in studies in which chance, bias, and confounding can be ruled out with reasonable confidence. The committee regarded evidence from several small studies that are free of bias and confounding and that show an association that is consistent in magnitude and direction as sufficient to conclude that there is an association. For VAO, Update 1996, Update 1998, Update 2000, and Update 2002, the committees concluded that there was sufficient evidence of an association between exposure to at least one compound of interest and chloracne. The scientific literature continues to support the classification of chloracne in the category of sufficient evidence. On the basis of the literature, no additional health effects discussed in this chapter satisfy the criteria necessary for this category. Health Outcomes with Limited or Suggestive Evidence of Association For this category, the evidence must suggest an association between exposure and outcome, it can 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 might be inconsistent. For Update 1996, Update 1998, Update 2000, and Update 2002, the committees determined there was limited or suggestive evidence of an association between exposure to at least one compound of interest and porphyria cutanea tarda. The scientific literature continues to support the classification of this disorder in the category of limited or suggestive evidence. On the basis of its evaluation of available scientific evidence, the committee responsible for the Type 2 Diabetes report concluded that there was limited or suggestive evidence of an association between exposure to at least one compound of interest and type 2 diabetes. The committee responsible for Update 2002 reached that same conclusion. Evidence reviewed in this report continues to support that finding. No other changes have been made in the list of health outcomes in the category of limited or suggestive evidence.

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Veterans and Agent Orange: Update 2004 Health Outcomes with Inadequate or Insufficient Evidence to Determine Association The scientific data on many of the health effects reviewed by the committee were inadequate or insufficient to determine an association between exposure to the compounds of interest and the health outcome. For the health effects in this category, the available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of association. Some studies failed to control for confounding or used inadequate exposure assessment. This category includes non-malignant respiratory disorders, such as asthma in isolation, pleurisy, pneumonia, and tuberculosis; immune system disorders (immune suppression and autoimmunity); lipid and lipoprotein disorders; gastrointestinal diseases; digestive diseases; liver toxicity; circulatory disorders; AL amyloidosis; endometriosis; and thyroid homeostasis disorders. Health Outcomes with Limited or Suggestive Evidence of No Association To classify outcomes in this category, several adequate studies covering the full range of known human exposure must be consistent in not showing a positive association between exposure and outcome at any magnitude of exposure. The studies also must have relatively narrow confidence intervals. A conclusion of “no association” is inevitably limited to the conditions, magnitudes of exposure, and periods of observation covered by the available studies. The possibility of a very small increase in risk at the exposure studied can never be excluded. The committees responsible for VAO, Update 1996, Update 1998, Update 2000, and Update 2002 concluded that none of the health outcomes discussed in this chapter had limited or suggestive evidence of no association with the exposures of interest (2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid). The most recent scientific evidence continues to support that conclusion. Biologic Plausibility This section summarizes the biologic plausibility of a connection between exposure to the compounds of interest and various non-cancer health effects on the basis of data from animal and cellular studies. The preceding discussions of individual health outcomes include a discussion of biologic plausibility for the specific effects. Details of the committee’s evaluation of data from recent toxicologic studies are presented in Chapter 3. TCDD elicits a diverse spectrum of effects in animal and experimental studies, including immunotoxicity, hepatotoxicity, chloracne, loss of body weight, induction of phase I and phase II drug-metabolizing enzymes, modulation of hormone systems, and modulation of factors associated with the regulation of

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Veterans and Agent Orange: Update 2004 cellular differentiation and proliferation. Those effects depend on sex, strain, age, and species. Effects of TCDD on the liver include modulation of the rate at which hepatocytes multiply, increasing the rate of death of other types of liver cells, increasing the fat content of liver cells, decreasing bile flow, and increasing proteins and substances that are precursors to heme synthesis. TCDD also alters the amount of some enzymes in the liver, but this effect is not necessarily considered toxic. Liver toxicity is species specific; 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’s effects mediate non-cancer endpoints is not clear. TCDD has been shown to inhibit hepatocyte DNA synthesis, alter vitamin A homeostasis, decrease hepatic plasma membrane epidermal growth factor receptor, inhibit hepatic pyruvate carboxylase activity, induce porphyrin accumulation in fish and chick embryo hepatocyte cultures, and alter liver enzyme concentrations and activity. Hepatomegaly has occurred after high subchronic doses. The mechanism of TCDD hepatoxicity is not established, but most studies are consistent with the hypothesis that the effects of TCDD are mediated by the AhR, a protein in animal and human cells to which TCDD can bind. The TCDD–AhR complex is thought to bind DNA and to lead to changes in transcription (differential regulation of genes) that alter cell function. Although structural differences in the AhR have been identified in various species, the receptor operates similarly in animals and humans. Animal data support a biologic basis for TCDD’s toxic effects. Because of the many species and strain differences in TCDD responses, however, the extent to which animal data inform the evaluation of human health outcomes is controversial. There is little evidence that the cardiovascular system is a sensitive target of TCDD toxicity in adult animals. It has been proposed however, that dioxin may increase the incidence of ischemic heart disease by exacerbating its severity. For example, treatment of rats with dioxin-like chemicals was found to affect several cardiovascular risk factors including heart weight, serum cholesterol, and blood pressure. The immune system is particularly sensitive to TCDD toxicity. Studies in mice, rats, guinea pigs, and monkeys indicate that TCDD suppresses the function of some 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 suppresses cell-mediated immunity, primarily by affecting the T-cell arm of the immune response, and that results in a decrease in the number and response some types of T cells. Some recent evidence suggests that TCDD directly affects T cells and their ability to undergo activation. TCDD could indirectly affect T cells and cell-mediated immunity by altering thymus function or cytokine production. The generation of antibodies by B cells, an indication of humoral

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Veterans and Agent Orange: Update 2004 immunity, also could be affected by TCDD. The function and commitment patterns of hematopoietic stem cells may also be affected by TCDD. As with other effects of TCDD, the immunotoxic effects are species and strain specific. Increased susceptibility to infectious disease has been reported after TCDD administration. In addition, TCDD increased the number of tumors that formed in mice after injection of tumor cells. Despite considerable laboratory research, the mechanisms that underlie the immunotoxic effects of TCDD are still unclear, but most studies are consistent with the hypothesis that the effects are mediated by the AhR. TCDD’s wide range of effects on growth regulation, hormone systems, and other factors also could mediate its immunotoxicity. As with other TCDD-mediated effects, the similarity in function of the AhR among animals and humans suggests a possible common mechanism of immunotoxicity. Nevertheless, the available data have not confirmed in humans the universal immunosuppressive effects observed in laboratory animals. Although data on the health effects of the herbicides discussed in this report are not extensive, effects have been seen in several organs in laboratory animals. The liver is a target organ for 2,4-D, 2,4,5-T, and picloram, with effects 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 also has been associated with effects on blood, such as reduced heme and red 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 the interaction and its biologic consequences are unknown. 2,4,5-T has been shown to be a weak myelotoxin. Few studies have examined the potential immunotoxicity of the herbicides used in Vietnam. Effects on the immune systems of mice were reported for 2,4-D administered at doses that were high enough to produce clinical toxicity; the effects did not occur at low doses. The potential for picloram to act as a contact sensitizer (that is, to produce an allergic response on the skin) was tested, but other aspects of its immunotoxicity were not examined. The foregoing suggests that a connection between TCDD or herbicide exposure and human toxic effects is, in general, biologically plausible. However, definitive conclusions about the presence or absence of a mechanism for the induction of specific toxicity by these compounds in humans are complicated by the differences in sensitivity and susceptibility among individual animals, strains, and species; by the lack of strong evidence of organ-specific effects among species; and by differences in route, dose, duration, and timing of exposure. Investigating the biologic mechanisms that underlie TCDD’s toxic effects continues to be an area of active research, and future updates of this report might be able to present more and better information on which to base conclusions, at least for that compound.

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Veterans and Agent Orange: Update 2004 Increased Risk of Disease Among Vietnam Veterans Although there are data to suggest an association between exposure to the chemicals of interest and some of these health effects, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk. REFERENCES AFHS (Air Force Health Study). 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. AFHS. 1990. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Brooks AFB, TX: USAF School of Aerospace Medicine. USAFSAM-TR-90-2. AFHS. 1991. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Serum Dioxin Analysis of 1987 Examination Results. Brooks AFB, TX: USAF School of Aerospace Medicine. AFHS. 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. AFHS. 2000. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1997 Follow-up Examination and Results. Reston, VA: Science Application International Corporation. F41624-96-C1012. Assennato G, Cervino D, Emmett E, Longo G, Merlo F. 1989. Follow-up of subjects who developed chloracne following TCDD exposure at Seveso. American Journal of Industrial Medicine 16:119–125. Baccarelli A, Mocarelli P, Patterson DG Jr, Bonzini M, Pesatori AC, Caporaso N, Landi MT. 2002. Immunologic effects of dioxin: new results from Seveso and comparison with other studies. Environmental Health Perspectives 110(12):1169–1173. Bertazzi PA, Bernucci I, Brambilla G, Consonni D, Pesatori AC. 1998. The Seveso studies on early and long-term effects of dioxin exposure: a review. Environmental Health Perspectives 106(Suppl 2):625–633. Bertazzi PA, Consonni D, Bachetti S, Rubagotti M, Baccarelli A, Zocchetti C, Pesatori AC. 2001. Health effects of dioxin exposure: a 20-year mortality study. American Journal of Epidemiology 153(11):1031–1044. Buxbaum JN. 2004. The systemic amyloidoses. Current Opinion in Rheumatology 16(1):67–75. Calvert GM, Hornung RV, Sweeney MH, Fingerhut MA, Halperin WE. 1992. Hepatic and gastrointestinal effects in an occupational cohort exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin. Journal of the American Medical Association 267:2209–2214. Calvert GM, Willie KK, Sweeney MH, Fingerhut MA, Halperin WE. 1996. Evaluation of serum lipid concentrations among US workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Archives of Environmental Health 51(2):100–107. CDVA (Commonwealth Department of Veterans’ Affairs). 1998a. Morbidity of Vietnam Veterans: A Study of the Health of Australia’s Vietnam Veteran Community. Volume 1: Male Vietnam Veterans Survey and Community Comparison Outcomes. Canberra: Department of Veterans’ Affairs. CDVA. 1998b. Morbidity of Vietnam Veterans: A Study of the Health of Australia’s Vietnam Veteran Community. Volume 2: Female Vietnam Veterans Survey and Community Comparison Outcomes. Canberra: Department of Veterans’ Affairs.

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