9

Other Health Effects

This chapter discusses data on the possible association of 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 the contaminant of 2,4,5-T, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with the following noncancer health outcomes: chloracne, porphyria cutanea tarda, 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. When appropriate, the literature is discussed by exposure type (occupational, environmental, or Vietnam veteran). Each section ends with the committee's conclusion 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.

CHLORACNE

The skin disease chloracne is characteristic of exposure to TCDD and other cyclic organochlorine compounds. It shares some pathologic processes (for example, 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



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Veterans and Agent Orange: Update 2002 9 Other Health Effects This chapter discusses data on the possible association of 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 the contaminant of 2,4,5-T, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with the following noncancer health outcomes: chloracne, porphyria cutanea tarda, 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. When appropriate, the literature is discussed by exposure type (occupational, environmental, or Vietnam veteran). Each section ends with the committee's conclusion 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. CHLORACNE The skin disease chloracne is characteristic of exposure to TCDD and other cyclic organochlorine compounds. It shares some pathologic processes (for example, 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

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Veterans and Agent Orange: Update 2002 of epidermoid inclusion cysts, which are caused by proliferation and hyperkeratinization (horn-like cornification) of the epidermis. Although chloracne is typically distributed over the eyes, ears, and neck, patterns of chloracne among chemical-industry workers exposed to TCDD have also included the trunk, genitalia, and buttocks (Neuberger et al., 1998). Chloracne has been extensively studied 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. Summary of VAO, Update 1996, Update 1998, and Update 2000 The committee responsible for Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as VAO; IOM, 1994) found there to be sufficient information of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and chloracne. Additional information available to the committees responsible for Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), and Update 2000 (IOM, 2001) did not change that finding. Reviews of the studies underlying the finding may be found in the earlier reports. Update of the Scientific Literature No relevant occupational, environmental, or Vietnam-veteran studies have been published since Update 2000 (IOM, 2001). Synthesis Chloracne is clearly associated with high exposure to cyclic organochlorine compounds, but it appears shortly after exposure, not after a long latency. Conclusions Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there

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Veterans and Agent Orange: Update 2002 is sufficient evidence that an association exists between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and chloracne. Biologic Plausibility As noted in previous reports, chloracne has been reported in response to exposure to TCDD but not to purified phenoxyacetic herbicides. Increased Risk of Disease Among Vietnam Veterans There is sufficient evidence that chloracne is associated with TCDD exposure. However, given the lack of ability to extrapolate from exposure in studies of TCDD and chloracne to individual Vietnam veterans, it is not possible to quantify the risk of chloracne in Vietnam veterans. Furthermore, because TCDD-associated chloracne is evident shortly after exposure, there is no risk of new cases long after service in Vietnam. PORPHYRIA CUTANEA TARDA Porphyria cutanea tarda (PCT) is an uncommon disorder of porphyrin metabolism which causes thinning and blistering of the skin in sun-exposed areas, hyperpigmentation (excess pigment in skin), and hypertrichosis (excess hair growth) (Muhlbauer and Pathak, 1979; Grossman and Poh-Fitzpatrick, 1986). The condition is not completely understood, but evidence indicates that people with particular mutations associated with hemochromatosis and people with an iron-overload condition are predisposed to PCT. Known risk factors are high alcohol intake, estrogen intake (as in oral contraceptives), liver disease, hemodialysis, HIV infection, and diabetes. In addition, data suggest poor diet might be a risk factor. Summary of VAO, Update 1996, Update 1998, and Update 2000 The committee responsible for VAO found there to be sufficient information to determine that an association existed between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and PCT in genetically susceptible people. The available data, however, indicated that PCT manifests shortly after exposure to TCDD. Therefore, new cases of PCT due 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 and Update 2000 did not change that conclusion. Reviews of the studies underlying those findings may be found in the earlier reports.

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Veterans and Agent Orange: Update 2002 Update of the Scientific Literature No relevant occupational, environmental, or Vietnam-veteran studies have been published since Update 2000 (IOM, 2001). Synthesis If PCT was caused by exposure to TCDD, it would appear soon after the exposure and recovery would occur after the exposure ceased. In any case, manifestation of PCT following exposure to TCDD would have been rare. Although it has been seen after exposure to TCDD in industrial settings, Vietnam veterans enrolled in the Ranch Hand study have not been found to have symptoms suggestive of the disorder. Conclusions Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and PCT. Biologic Plausibility PCT has not been replicated in animal studies in response to TCDD, although other porphyrin abnormalities have been reported after exposure to TCDD. Increased Risk of Disease Among Vietnam Veterans Given the available data on individual exposures in both Vietnam veterans and study subjects, it is not possible to estimate the risk of PCT in individual Vietnam veterans. However, because PCT is an early response to TCDD, no new cases of PCT due to wartime exposures are expected among Vietnam veterans. RESPIRATORY DISORDERS Nonmalignant respiratory disorders comprise acute and chronic lung diseases other than cancer. Acute lung diseases include pneumonia and other lung infections and could be increased in frequency and severity when the normal defense mechanisms of the lower respiratory tract are compromised. Chronic nonmalignant respiratory disorders generally take two forms: airways disease

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Veterans and Agent Orange: Update 2002 and parenchymal disease. Airways disease is a general term for disorders characterized by obstruction of the flow of air out of the lungs and includes chronic obstructive pulmonary disease (COPD), emphysema, asthma, and chronic bronchitis. Parenchymal disease, or interstitial disease, is a general term for numerous disorders that cause inflammation and scarring of the deep lung tissue, including air sacs and supporting structures. Those disorders are less common than airways disease and are characterized by reductions in lung capacity, but they often include a component of airways obstruction. In addition, some severe chronic lung disorders, such as cystic fibrosis, are hereditary. Because Vietnam veterans underwent health screenings, no severe hereditary chronic lung disorders are expected in this population. The major risk factor for both acute and chronic respiratory disorders is cigarette-smoking. Although cigarette-smoking is not associated with every disease of the lungs, it is the major cause of airways disorders, contributes to some interstitial disease, and 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 cigarette-smoking as a habit 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 other than smoking. Vietnam veterans are reported to smoke more heavily than non-Vietnam veterans (McKinney et al., 1997). Summary of VAO, Update 1996, Update 1998, and Update 2000 The committee responsible for VAO found there to be inadequate or insufficient information to determine whether an association existed between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant 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 nonmalignant respiratory disorders among those, particularly males, 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 nonmalignant respiratory disorders, particularly COPD, among people exposed to TCDD, the observation is tentative and the information insufficient to determine whether an association exists between the exposures of interest and respiratory disorders.

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Veterans and Agent Orange: Update 2002 Update of the Scientific Literature In the one occupational study published since Update 2000, a cohort of 1,517 male employees of the Dow Chemical Company who were involved in the manufacture or formulation of 2,4-D at some time in 1945–1994 demonstrated no excess mortality from nonmalignant respiratory disorders (Burns et al., 2001). That fewer deaths were observed in all exposure categories compared to the national rates and latency groups studied than expected suggests a strong healthy-worker effect. No relevant environmental or Vietnam-veteran studies have been published since Update 2000 (IOM, 2001). Synthesis No new studies provide evidence of a direct risk of nonmalignant respiratory disorders in adults since those reviewed in Update 2000 (IOM, 2001). Conclusions Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is inadequate or insufficient evidence to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and nonmalignant acute or chronic respiratory disorders. Biologic Plausibility Lung tissue has been found to have high concentrations of the aryl hydrocarbon receptor (AhR), which mediates the effects of TCDD, and recent data have shown that both cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1A2 (CYP1A2) are expressed in lung biopsy specimens from human subjects. It is biologically plausible that exposure to TCDD may result in acute and chronic lung disorders. Furthermore, it is noted that a major risk factor for these disorders is cigarette-smoking. These 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 other chemicals to which human lung tissue is exposed.

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Veterans and Agent Orange: Update 2002 Increased Risk of Disease Among Vietnam Veterans There are insufficient data on nonmalignant respiratory disorders in Vietnam veterans to draw a specific conclusion as to whether Vietnam veterans are at increased risk for those disorders. IMMUNE SYSTEM DISORDERS The immune system is responsible for protecting the body against invasion by infectious microorganisms and the development of cancer. The two major immune responses are the innate and the adaptive responses. The innate response is more general; the adaptive response is specific and confers immunologic memory. The principle reactive cells of the immune system are the leukocytes (white blood cells), which include neutrophils, eosinophils, lymphocytes, blood monocytes, and macrophages, which are widely distributed in tissues and include histiocytes, dendritic cells, and antigen-presenting cells. The major lymphatic organs are the lymph nodes, spleen, thymus, palatine tonsil, and Peyer's patches. The immune response consists of a complex and sophisticated network of events involving cells and their secretory products, and optimal function of the immune system results from a delicate balance in cellular interactions and responses. Disruption of those events can result in a compromised immune response, with the response either suppressed or enhanced. A suppressed immune response can result in reduced resistance to infections or neoplasia. The immune system has considerable reserve, so the degree of suppression necessary for increased susceptibility to disease can depend heavily on factors involving the invading microorganism, the host response to the invasion, and the ability of the microorganism or cancer cells to escape immunosurveillance. If they are sufficiently weakened, impairment of host defenses can result in severe and recurrent infections with opportunistic microorganisms or can predispose the host to neoplasia. The immune response can also be hyperstimulated or unable to curtail a normal immune reaction, and this can result in contact hypersensitivity, allergy (atopy and asthma), and autoimmune disease. Many of those conditions are not life-threatening, but asthma and autoimmune disease can result in death. Asthma usually occurs when foreign antigen-specific immunoglobulins bind to the surface of mast cells releasing histamine which causes constriction of pulmonary airways. Autoimmune disease is the pathologic consequence of an immune response to autologous (self) antigens in which the immune system attacks its own body' s cells, tissues, or organs. This section presents information on the effects of herbicide and TCDD exposure on the human immune system and susceptibility to disease other than neoplasia. Information regarding herbicide exposure and neoplasia in humans is presented in Chapter 6.

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Veterans and Agent Orange: Update 2002 Summary of VAO and Update 1996, Update 1998, and Update 2000 The committees responsible for VAO, Update 1996, Update 1998, and Update 2000, found that there was inadequate or insufficient information to determine whether an association existed between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and immune system disorders. Reviews of the studies underlying those findings are in the previous reports (IOM, 1994, 1996, 1999, 2001). Update of the Scientific Literature No relevant occupational, environmental, or Vietnam-veteran studies have been published since Update 2000 (IOM, 2001). Synthesis TCDD is a known immunosuppressant in laboratory animals. In fact, it is one of the most potent immunotoxicants known to exist in the environment. Therefore, it would be expected to be immunosuppressive in humans. To date, however, the immune effects described in humans exposed to TCDD have been marginal and highly inconsistent, ranging from increasing the immune response to decreasing the immune response to having no effect. Furthermore, no pattern of increased infectious disease has developed in people exposed to high concentrations of TCDD or other herbicides that were used in Vietnam. Investigations in humans in the last several years, including several recent studies reviewed in Update 2000 that looked at numerous immune measures in workers exposed to TCDD and in veterans of Operation Ranch Hand, have failed to demonstrate a consistent positive association between TCDD exposure (in utero, perinatally, or postnatally) and immune effects. No studies available in humans during the last 2 years change those findings. As mentioned in Update 2000, many of the immune measures assessed in humans are related to nonfunctional end points often considered biomarkers. The consistent immunosuppressive effects observed in laboratory animals that have been exposed to TCDD have not been confirmed in humans. Conclusions Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds that there is inadequate or insufficient evidence to determine whether an association exists

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Veterans and Agent Orange: Update 2002 between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and immune suppression or autoimmunity. Biologic Plausibility A large number of studies in animals indicate that one of the organ systems most sensitive to TCDD toxicity is the immune system; the effects are species-specific and strain-specific. TCDD can alter the number and function of immune cells in some animals. Studies of the effect of exposure to TCDD on immune response in the mouse after infection with influenza A demonstrate that the humoral and cell-mediated response is suppressed and cytolytic activity is preserved. Chapter 3 discusses recent toxicologic studies that make up the biologic basis of an association between exposure to TCDD or herbicides and toxic end points. Increased Risk of Disease Among Vietnam Veterans No evidence is available to associate defects in the immune response with exposure to the herbicides or TCDD. DIABETES Primary diabetes (that is, diabetes that is not secondary to another known disease or condition, such as pancreatitis or pancreatic surgery) is a heterogeneous metabolic disorder characterized by hyperglycemia and quantitative or qualitative deficiency of insulin action (Orchard et al., 1992). Two main types have been recognized: insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). In June 1997, the American Diabetes Association (ADA, 1997) suggested a revised classification, with IDDM being termed type 1 and NIDDM termed type 2. This new terminology is used in the remainder of this review except when the older diagnostic criteria are appropriate. Type 2 diabetes accounts for about 90% of cases of primary diabetes. Onset rarely occurs before 30 years of age, but incidence increases steadily with age thereafter. It is generally accepted that the main factors for increased risk of type 2 diabetes include age (older people are at higher risk), obesity, central fat deposition, a history of gestational diabetes (if female), physical inactivity, ethnicity (for example, prevalence is greater in blacks and Hispanics), and, perhaps most important, a family history of type 2 diabetes. The relative contributions of those features, however, are controversial. The etiology of type 2 diabetes is unclear, but three major components have been proposed: peripheral insulin resistance (thought by many to be primary) in target tissues (such as muscle, adipose tissue, and liver); a defect in beta-cell

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Veterans and Agent Orange: Update 2002 insulin secretion, and hepatic glucose overproduction. Defects at many intracellular sites could account for the impaired insulin action and secretion in type 2 diabetes (Kruszynska and Olefsky, 1996). The insulin receptor itself, insulin-receptor tyrosine kinase activity, insulin-receptor substrate proteins, insulin-regulated glucose transporters, enhanced protein kinase C activity, TNF-α, rad (ras associated with diabetes), and prohormone convertase 1 (PC1) have all been proposed as potential mediators of insulin resistance. Impaired insulin secretion has been linked to hyperglycemia itself, to abnormalities of glucokinase and hexokinase activity, and to abnormal fatty-acid metabolism. Finally, an increasing number of “other” types of diabetes have been described that are linked to specific genetic mutations, such as maturity-onset diabetes of youth, which results from a variety of mutations of the beta-cell glucokinase gene. Pathogenetic diversity and diagnostic uncertainty are two of the more important problems associated with the epidemiologic study of diabetes. Given the multiple likely pathogenetic mechanisms leading to diabetes—which include diverse genetic susceptibilities (ranging from autoimmunity to obesity) and a variety of potential environmental and health-behavior factors (such as viruses, nutrition, and activity) —it is probable that many agents or behaviors contribute to diabetes risk, especially in genetically susceptible people. The multiple mechanisms may also lead to heterogeneous responses to various exposures. Because up to half the affected diabetic population is undiagnosed, the potential for ascertainment bias is high (more intensively followed groups or those with more frequent health care contact are more likely to be diagnosed), and the need for formal standardized testing (to detect nondiagnosed cases) is great. Furthermore, it may be difficult to differentiate cases that develop during early to middle age (20 –44 years) into type 1 or type 2. Summary of Previous IOM Reports The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association exists between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and diabetes. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change that finding. In 1999, in response to a request from the Department of Veterans Affairs (VA), IOM called together a committee to conduct an interim review of the scientific evidence regarding type 2 diabetes. That review, which focused on information published since the deliberations of the Update 1998 committee, resulted in the report Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (IOM, 2000). The committee responsible for that report found that there was limited or suggestive evidence of an association between type 2 diabetes and exposure to at least one of the chemicals of interest (2,4-D,

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Veterans and Agent Orange: Update 2002 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid). The committee responsible for Update 2000 upheld the finding of the Herbicide/Dioxin Exposure and Type 2 Diabetes committee. Reviews of the studies underlying those findings can be found in the earlier reports (see Table 9-1 for a summary). Update of the Scientific Literature Relatively little new information has been reported on the association between TCDD and the risk of diabetes. The potential link between TCDD and diabetes was mentioned briefly in two general review articles on the overall health effects of TCDD (Kogevinas, 2001; Sweeney and Mocarelli, 2000). A more specific review on environmental risk factors for diabetes included a detailed overview of the literature on 2,3,7,8-TCDD (Longnecker and Daniels, 2001); this review shared the conclusion of Update 2000 that the findings on TCDD and the etiology of diabetes were somewhat suggestive but still inconclusive. Occupational Studies A cross-sectional study was conducted in 1998 to assess the health status of workers exposed to high concentrations of polychlorinated dibenzo-p-dioxins (PCDD) at the Bika Center municipal waste incinerator in Japan (Kitamura et al., 2000). Data were collected on 92 of the 146 people employed at Bika Center since it was opened in 1988. Eight workers reported a history of diabetes, and a logistic-regression model (including age and body mass index) was used to assess the association between quartiles of PCDD and the prevalence of diabetes. The coefficients for the model were not shown; the authors indicated in the text that none of the ORs for diabetes in relation to PCDD were statistically significant. In another study, the association between TCDD and diabetes was re-examined in a combined analysis of data from the Ranch Hand study of Vietnam veterans and a National Institute for Occupational Safety and Health (NIOSH) study of TCDD-exposed workers at chemical plants in New Jersey and Missouri (Steenland et al, 2001). The results of those studies had been reported separately in Update 1998 (Henriksen et al., 1997) and Update 2000 (Calvert et al., 1999), respectively. The combined analysis was conducted in an attempt to improve the precision of the estimates and to address differences between the studies in definition of exposure and outcome and in adjustment for potential confounders. The NIOSH study sample of 541 was reduced by 55 subjects (31 women, 16 men from the neighborhood comparison group with TCDD above 10 ppt, and eight exposed men with missing TCDD data) to match the criteria in the Ranch Hand sample. The fasting-glucose component of the definition of diabetes in the NIOSH sample was also modified (from fasting glucose of 140 mg/dL to 126 mg/ dL) to approximate the Ranch Hand definition more closely. The Ranch Hand

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Veterans and Agent Orange: Update 2002 In a larger series (105 mother–infant pairs) in Rotterdam, the Netherlands, Koopman-Esseboom and colleagues (1994) conducted similar analyses. Blood was collected from the mothers during the last month of pregnancy and from the cord after birth for measurement of PCBs; breast milk was collected in the second week after delivery for measurement of dioxins, dibenzofurans, and planar PCBs. TEQs were calculated from those measurements. Total T4, total T3, free T4, and TSH were measured in maternal plasma taken during the last month of pregnancy and 9–14 days after delivery, and in newborn infants' plasma taken at 2 weeks and 3 months. TEQ correlated negatively with maternal pregnancy total T3 and maternal postdelivery total T3 and total T4; similar associations were seen for planar PCB TEQ and total PCB and TEQ, and the associations with total T3 were also observed for nonplanar PCB TEQ. In addition, all four TEQ measurements correlated positively with infant 2-week TSH, and all except the nonplanar PCB TEQ were positively associated with the infant 3-month TSH. Longnecker and colleagues (2000) examined PCB concentrations in breast-milk specimens, without adjustment for lipids, in relation to thyroid hormones in cord serum in a population with background exposure. They found little evidence of an association, although the direction of the coefficient for TSH in multiple-regression analysis was consistent with findings in other studies: increases in TSH with increases in PCBs. No congener-specific analysis was conducted, so no information on dioxin-like PCBs was available. Because non-dioxin-like PCBs are the most abundant, and PCBs are contaminated with furans, this study is not very informative for the effects of TCDD or the herbicides used in Vietnam. Both studies with information on TEQs suggest some alterations in thyroid-hormone homeostatis in relation to TCDD and dioxin-like compounds, but the results are only partially consistent. Both studies observe changes in total T4, but in Koopman-Esseboom et al. (1994) this finding is in maternal plasma, not cord or newborn infant 2-week or 3-month plasma, whereas Pluim et al. (1992) found higher T4 at both 1 and 11 weeks in the infant. The studies are consistent with regard to increases in TSH, which are not observed at birth (both studies) or at 1 week (Koopman-Esseboom et al., 1994), but are found at 2 weeks (Pluim et al., 1992), 11 weeks (Koopman-Esseboom et al., 1994) and 3 months (Pluim et al., 1992). According to Kimbrough and Krouskas (2001), TSH concentrations undergo large changes shortly after birth. Calvert et al. (1999) examined TCDD-exposed workers at two plants who were engaged in the production of 2,4,5-T or one of its derivatives. Referents were residents in the neighborhood of each worker, matched by age, race, and sex. Examinations were conducted in 1987–1988, and blood was collected. Serum specimens were analyzed for TCDD, total T4, TSH, and thyroid hormone binding resin, and the free T4 index was calculated. The mean TCDD concentration for the four categories of exposure were 11, 40, 135, and 729 pg/g of lipid, whereas the comparison group had a mean TCDD concentration of 7 pg/g of lipid. The results showed that workers had a significantly higher adjusted mean

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Veterans and Agent Orange: Update 2002 free T4 index than referents (p = 0.02), and the highest index was among those with the highest half-life extrapolated TCDD (p = 0.004), but a clear dose-response relationship was not observed (p = 0.02). The mean total T4 was also suggestively higher in workers than in referents (p = 0.07). No association was observed with TSH. Vietnam-Veteran studies Pavuk et al. (in press) examined thyroid-hormone status in the AFHS cohort. At each of the 1982, 1985, 1987, 1992, and 1997 examinations, 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 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 (ORs 1.4–1.9) in the high-exposure Ranch Hand group than in the comparison population, but these findings were not very precise. Synthesis Based on numerous animal experiments and several epidemiologic studies, TCDD and dioxin-like compounds exhibit an influence on thyroid homeostasis. These effects are hypothesized to provide a mechanism by which TCDD may affect early development of neurologic and sensory organs and motor function. Increases in TSH in three human studies without evidence of increases in T4 indicate that the infants (selected for uncomplicated gestation, labor, and delivery) and the Ranch Hand Air Force personnel studied were able to adapt to the changes that may have been induced by the higher body burdens of TCDD and TEQ. The possibility of neurodevelopmental effects secondary to mild hypothyroidism induced in early pregnancy by TCDD or dioxin-like compounds cannot be excluded (Vulsma, 2000). Conclusions Strength of Evidence from Epidemiologic Studies There is inadequate or insufficient evidence of an association between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and adverse effects on thyroid homeostasis. In humans,

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Veterans and Agent Orange: Update 2002 some effects on thyroid homeostasis have been observed, mainly after exposure in the perinatal period, but the functional importance of those changes is unclear because adaptive capacity may be adequate to accommodate them. Biologic Plausibility TCDD is known to affect concentrations of T4, T3, and TSH. However, the effects have lacked 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. Chapter 3 discusses recent toxicologic studies relevant to the biologic plausibility of the effects of TCDD and the herbicides on the thyroid gland. Risk in Vietnam Veterans The relevant studies conducted on thyroid alterations that focus primarily on perinatal effects mediated through the mother would be related primarily to the offspring of female Vietnam veterans. Those studies demonstrated biologic changes in TSH without accompanying effect on the health of the children. Similarly, the AFHS demonstrated biologic changes in TSH without accompanying effect on the health of the Ranch Hands. 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 association between exposure to the chemicals of interest (2,4-D, 2,4,5-T or its contaminant 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 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 to categorize diseases by the strength of the evidence as were used in VAO, Update 1996, Update 1998, and Update 2000. Health Outcomes with Sufficient Evidence of an Association For diseases in this category, a positive association between herbicides and the outcome must be observed in studies in which chance, bias, and confounding

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Veterans and Agent Orange: Update 2002 can be ruled out with reasonable confidence. The committee also 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. In VAO, Update 1996, Update 1998, and Update 2000, the committee found sufficient evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) 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 herbicides and the outcome but may be limited because chance, bias, or confounding could not be ruled out with confidence. Typically, at least one high-quality study indicates a positive association, but the results of other studies might be inconsistent. In Update 1996, Update 1998, and Update 2000, the committee found limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) 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 found that there was limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest (2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid) and type 2 diabetes. Evidence reviewed in the present 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. Health Outcomes with Inadequate or Insufficient Evidence to Determine Whether an Association Exists The scientific data on many of the health effects reviewed by the committee were inadequate or insufficient to determine whether an association exists between exposure to the chemicals 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 an association. For example, studies fail to control for confounding or

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Veterans and Agent Orange: Update 2002 have inadequate exposure assessment. This category includes nonmalignant 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 exposure that human beings are known to encounter must be consistent in not showing a positive association between exposure to herbicides and the outcome at any magnitude of exposure. The studies must also 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. In addition, 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, and Update 2000 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 or its contaminant 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 TCDD or herbicides and various noncancer 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 has been shown to elicit 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 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 increases 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

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Veterans and Agent Orange: Update 2002 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. TCDD has been shown to inhibit hepatocyte DNA synthesis, 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 (genes are differentially regulated) that alter cell function. Although structural differences in the AhR have been identified in various species, this receptor operates in a similar manner in animals and humans. Animal data support a biologic basis of 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. The myocardium has also been shown to be a target of TCDD toxicity. TCDD inhibits myocardium contraction possibly through effects on adenosine 3',5'-cyclic-monophosphate. The immune system is one of the most 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, including a decrease in the numbers and responses of some types of T cells. It is not known whether TCDD directly affects T cells. TCDD may 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 immunity, may also be affected by TCDD. Effects of arachidonic acid have been hypothesized to mediate TCDD's immunotoxicity, but recent evidence indicates that not all of TCDD's immunotoxic effects are mediated by arachidonic acid. As with other effects of TCDD, the immunotoxic effects are species-specific 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. It should be emphasized, however, that very little change in the overall immune competence of the intact animals (animals not challenged experimentally with a pathogen or tumor cells) has been reported. Despite considerable laboratory research, the mechanisms underlying 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 could also mediate its immunotoxicity. As with

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Veterans and Agent Orange: Update 2002 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. TCDD has been shown to induce differentiation in human keratinocytes. TCDD has been reported to decrease an acidic type I keratin involved in epidermal development and to lead to keratinocyte hyperproliferation and skin irritations, such as chloracne. The data provide a biologically plausible mechanism for the induction of chloracne by TCDD. Although there is not extensive data on the health effects of the herbicides discussed in this report, effects have been seen in a number of 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 has also 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 been conducted on the potential immunotoxicity of the herbicides used in Vietnam. 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 (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; the lack of strong evidence of organ-specific effects among species; and differences in route, dose, duration, and timing of exposure. Investigating the biologic mechanisms underlying TCDD's toxic effects continues to be the subject of active research, and future updates of this report might have more and better information on which to base conclusions, at least for that compound. 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 disease in veterans exposed to herbicides and TCDD during their service in Vietnam. Little is known about health risks for Vietnam veterans;

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