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Veterans and Agent Orange: Update 2008 (2009)

Chapter:9 Other Health Effects

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Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. doi: 10.17226/12662.
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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 sev- eral noncancer health outcomes: chloracne, porphyria cutanea tarda (PCT), re- spiratory disorders, immune-system disorders, diabetes, lipid and lipoprotein disorders, gastrointestinal and digestive disease (including liver toxicity), circula- tory disorders, and adverse effects on thyroid homeostasis. For each type of health outcome, background information is followed by a brief summary of the findings described in earlier reports by the Institute of Medicine (IOM) Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. In the discussion of the most recent scientific literature, studies are grouped by exposure type (Vietnam veteran, occupational, or envi- ronmental). For articles that report on only a single health outcome and that are not revisiting a previously studied population, design information is summarized with the results; design information on other studies can be found in Chapter 5. A synopsis of toxicologic and clinical information related to the biologic plausibil- ity that the chemicals of interest can influence the occurrence of a health outcome is presented next and followed by a synthesis of all the material reviewed. Each health-outcome section ends with the present committee’s conclusions regarding the strength of the evidence that supports an association with the chemicals of interest. The categories of association and the committee’s approach to categoriz- ing the health outcomes are discussed in Chapters 1 and 2. 546

OTHER HEALTH EFFECTS 547 CHLORACNE Chloracne is a skin disease that is characteristic of exposure to TCDD and other diaromatic organochlorine chemicals. It shares some pathologic processes (such as 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 hyperkera- tinization (horn-like cornification) of the epidermis and sebaceous gland epithe- lium. Although chloracne is typically distributed over the eyes, ears, and neck, it can also occur on the trunk, genitalia, and buttocks of chemical-industry workers exposed to TCDD (Neuberger et al., 1998). Chloracne has been exploited as a marker of exposure in epidemiologic studies of populations exposed to TCDD and related chemicals. It is one of the few findings in humans that are consistently associated with such exposure, and it is a well-validated indicator of high-dose exposure to TCDD and related chemicals (Sweeney et al., 1997/1998). If chloracne occurs, it appears shortly after the chemical exposure, not after a long latent period; therefore, new cases of chloracne among Vietnam veterans would not be the result of exposure during the Vietnam War. Although it is resistant to acne treatments, it usually regresses. It should be noted that absence of chloracne does not necessarily indicate ab- sence of substantial exposure to TCDD, as is apparent from studies of people with documented exposure to TCDD after the Seveso incident (Baccarelli et al., 2005a), nor is there necessarily a correlation between serum TCDD concentration and the occurrence or severity of chloracne. Conclusions from VAO and Previous Updates The committee responsible for Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994), deter- mined that there was sufficient evidence of an association between exposure to at least one chemical of interest (TCDD) and chloracne. Additional information available to the committees responsible for Veterans and Agent Orange: Up- date 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002 (IOM, 2003), Update 2004 (IOM, 2005), and Update 2006 (IOM, 2007) has not modified that conclusion. Even in the absence of full understanding of the cellular and molecular mechanisms that lead to the disease, several notable reviews (Panteleyev and Bickers, 2006; Sweeney and Mocarelli, 2000) have deemed the clinical and epi- demiologic evidence of dioxin-induced chloracne to be strong. The occupational epidemiologic literature has many examples of chloracne in workers after reported industrial exposures (Beck et al., 1989; Bond et al., 1987, 1989a,b; Cook et al., 1980; Goldman, 1972; May, 1973, 1982; Oliver, 1975; Pazderova-­Vejlupkova et al., 1981; Poland et al., 1971; Suskind and Hertzberg, 1984; ­ Suskind et al.,

548 VETERANS AND AGENT ORANGE: UPDATE 2008 1953; Zober et al., 1990). With relative risk (RR) estimates as high as 5.5 in ex- posed workers compared with referent nonexposed workers, Bond et al. (1989a) identified a dose–response relationship between probable exposure to TCDD and chloracne. Not everyone exposed to relatively high doses develop chloracne, and some with lower exposure may demonstrate the condition (Beck et al., 1989). Almost 200 cases of chloracne were recorded among those residing in the vicinity of the accidental industrial release of dioxin in Seveso, Italy; most cases were in children, were in people who lived in the highest-exposure zone, and had resolved within 7 years (Assennato et al., 1989a,b; Caramaschi et al., 1981; Mocarelli et al., 1991). No cases of chloracne were identified in conjunction with the nonextreme environmental dioxin contamination at Times Beach, Missouri (Webb et al., 1987). Exposures of Vietnam veterans were substantially lower than those observed in occupational studies and in environmental disasters, such as in Seveso. The long period since the putative exposure has imposed methodologic limitations on studies of Vietnam cohorts for chloracne. Nonetheless, the Vietnam Experience Study (VES; CDC, 1988) found that chloracne was self-reported more often by Vietnam veterans than by Vietnam-era veterans (odds ratio [OR] = 3.9). Excess risk was also found in Vietnam vs era veterans among subjects who were physi- cally examined (OR = 7.3). In comparison with a nonexposed group, Air Force Ranch Hand personnel potentially exposed to Agent Orange reported significant excess of acne (OR = 1.6) (Wolfe et al., 1990), but no cases of chloracne or postinflammatory scars were found on physical examination 20 years after the potential herbicide exposure (AFHS, 1991b). Biologic Plausibility Previous updates have reported that chloracne-like skin lesions have been observed in several animal species in response to exposure to TCDD but not to purified phenoxy herbicides. Data accruing over the last several decades demon- strated that TCDD alters differentiation of human keratinocytes, and more recent studies have illuminated how. Geusau et al. (2005) found that TCDD accelerates the events associated with early differentiation but also obstructs completion of differentiation. Panteleyev and Bickers (2006) proposed that the major mecha- nism of TCDD induction of chloracne is activation of the stem cells in the basal layer of the skin to differentiate and inhibition of their ability to commit fully to a differentiated status. Recent work with a constitutively activated form of the aryl hydrocarbon receptor (AHR) implicated additional inflammation-related mechanisms by which TCDD exposure may lead to chloracne (Tauchi et al., 2005). The data provide a biologically plausible mechanism for the induction of chloracne by TCDD.

OTHER HEALTH EFFECTS 549 Synthesis No epidemiologic data in the last decade have refuted the conclusion of prior VAO committees that the evidence of an association between exposure to dioxin and chloracne is sufficient. The formation of chloracne lesions after administra- tion of TCDD has been observed in some species of laboratory animals. Conclusion On the basis of numerous epidemiologic studies of occupationally and environmentally exposed populations and supportive toxicologic information, previous VAO committees have consistently concluded that there is sufficient evidence of an association between exposure to at least one chemical of interest and chloracne. Because TCDD-associated chloracne becomes evident shortly after exposure, there is no risk of new cases long after service in Vietnam. Given the established relationship of an association between TCDD and chloracne and the long period that has elapsed since service in Vietnam, the present committee concludes that the emergence of additional biologic or epidemiologic evidence that would merit review and deliberation by later VAO committees is unlikely. PORPHYRIA CUTANEA TARDA Porphyrias are uncommon disorders caused by deficiencies of enzymes in- volved in the pathway of biosynthesis of heme, the iron-containing nonprotein portion of the hemoglobin molecule. PCT is a heterogeneous group of disorders caused by a deficiency of a specific enzyme, uroporphyrinogen decarboxylase. PCT, the most common of this group of disorders, can be inherited but usually is acquired. Type I PCT, which accounts for 80–90% of all cases, is an acquired disease that typically becomes evident in adulthood. It can occur spontaneously but usually occurs in conjunction with environmental factors, such as alcohol consumption, exposure to estrogens, or use of some medications. The most important clinical finding in PCT is cutaneous photosensitivity. Sensitivity to sunlight is thought to result from the excitation of excess porphy- rins in the skin by long-wave ultraviolet radiation, which leads to cell damage. Fluid-filled vesicles and bullae develop on sun-exposed areas of the face and on the dorsa surfaces of the hands, feet, forearms, and legs. Other features in- clude hypertrichosis (excess hair) and hyperpigmentation (increased pigment), especially on the face. People with PCT have increased porphyrins 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 people who have PCT.

550 VETERANS AND AGENT ORANGE: UPDATE 2008 Conclusions from VAO and Previous Updates On the basis of strong animal studies and case reports demonstrating TCDD- induced PCT and resolution after cessation of exposure, the committee respon- sible for VAO determined that there was sufficient evidence of an association between exposure to TCDD and PCT in genetically susceptible people. Epidemiologic studies of occupational populations have indicated incon- sistent association between the chemicals of interest and increased urinary uro- porphyrin. Bleiberg et al. (1964) reported the increased urinary uroporphyrin in 11 of 29 workers in a factory that manufactured 2,4-D and 2,4,5-T and the manifestation of some clinical evidence of PCT in three of them. In a follow-up study of the same facility 6 years later, no abnormalities in urinary porphyrin were observed (Poland et al., 1971). Calvert et al. (1992) reported no difference in porphyrinuria or the occurrence of PCT between 281 workers in the National Institute for Occupational Safety and Health (NIOSH) cohort who were involved in the production of trichlorophenol and were exposed to TCDD and 260 nonex- posed workers. Serum TCDD concentration was not associated with uroporphyrin or coproporphyrin concentrations. Among people who were exposed to TCDD as a result of the 1976 chemical- plant explosion in Seveso, Italy, clinical PCT was observed only in a brother and a sister who had a mutant enzyme that confers susceptibility in the heterozygous state. In 1977, 60 Seveso residents were tested for increased porphyrins, and 13 had secondary coproporphyrinuria; increased concentrations persisted in only three cases that were thought to be due to liver damage and alcohol consumption (Doss et al., 1984). In the Quail Run mobile-home park in Missouri, residents ex- posed to dioxin as a result of the spraying of waste oil contaminated with TCDD were found to have higher urinary uroporphyrins than compared to controls, but no cases of clinical PCT were diagnosed (Hoffman et al., 1986; Stehr-Green et al., 1987). The baseline study of the US Air Force Ranch Hands (AFHS, 1984) showed no difference in uroporphyrin or coproporphyrin concentrations in urine between Ranch Hands and controls. There were no indications of the clinical appearance of PCT in Ranch Hands. Follow-up studies of the Ranch Hand cohort revealed that mean uroporphyrin was greater in the comparison group than in the Ranch Hands, whereas mean coproporphyrin was higher in Ranch Hands. The clinical significance of the small differences between the Ranch Hands and the compari- son groups was uncertain. The committee responsible for Update 1996 considered three additional nonpositive citations of populations that had substantial exposure to TCDD. Jung et al. (1994) presented porphyrin data on former workers in a German pesticide plant that had manufactured 2,4-D and 2,4,5-T. Of 170 men tested, 27 had pres- ent or past chloracne. The study found no difference in porphyrin concentrations between subjects with and without chloracne. There was also no relationship

OTHER HEALTH EFFECTS 551 between abnormal results of liver-function tests and porphyrin concentrations and the presence of chloracne and no relationship between porphyrin concentrations in urine, red blood cells or plasma, and TCDD concentrations in adipose tissue. Three cases of chronic hepatic porphyria (none with overt PCT and none with chloracne) were identified—a number that did not exceed the expected preva- lence in this population. Von Benner et al. (1994) found no indication of clinical porphyria in self-referred workers at six other German chemical plants. Another report on the NIOSH cohort (Calvert et al., 1994) was negative. On the basis of the cumulative findings, the committee responsible for Update 1996 concluded that there was only limited or suggestive evidence of an association. Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change the revised conclusion. Because PCT is manifested shortly after exposure to TCDD, new cases of PCT attributable to exposure during the Vietnam War are not expected to occur. Biologic Plausibility PCT has not been replicated in animal studies of effects of TCDD, although other porphyrin abnormalities have been reported. However, administration of TCDD to mice results in an accumulation of uroporphyrin that occurs in a man- ner that requires the AHR, Cytochrome P450 1A1 (CYP1A1), and CYP1A2 (Robinson et al., 2002; Smith et al., 2001; Uno et al., 2004). Synthesis No epidemiologic data have emerged in the last decade that refute the con- clusion of previous VAO committees that there is limited or suggestive evidence of an association between the chemicals of interest and PCT. Conclusion On the basis of the 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 chemical of interest and PCT. The occurrence of PCT is rare and may be influenced by genetic predisposition in people who have low concentrations of protoporphyrinogen decarboxylase. Because TCDD- associated changes in porphyrin excretion become evident shortly after exposure, there is no risk that new cases will occur long after service in Vietnam. Given the recognized association between TCDD and porphyrin excretion and the long period that has elapsed since service in Vietnam, the committee concludes that additional biologic and epidemiologic evidence meriting review and deliberation by this or by later VAO committees is unlikely to occur.

552 VETERANS AND AGENT ORANGE: UPDATE 2008 RESPIRATORY DISORDERS For the purposes of this report, nonmalignant respiratory disorders comprise acute and chronic lung diseases other than cancer. Acute nonmalignant respira- tory disorders include pneumonia and other respiratory infections; they can increase in frequency and severity when the normal defense mechanisms of the lower respiratory tract are compromised. Chronic nonmalignant respiratory disor- ders generally take two forms: airways disease and parenchymal disease. Airways disease encompasses disorders, among them asthma and chronic obstructive pul- monary disease (COPD), characterized by obstruction of the flow of air out of the lungs. COPD is also known as chronic obstructive airways disease and includes emphysema and chronic bronchitis. Parenchymal disease, or interstitial disease, generally includes disorders that cause inflammation and scarring of the deep lung tissue, including the air sacs and supporting structures; parenchymal disease is less common than airways disease and is characterized by reductions in lung capacity, although it 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 most important risk factor for many nonmalignant respiratory disorders is inhalation of cigarette smoke. Although exposure to cigarette smoke is not associated with all diseases of the lungs, it is the major cause of many airways disorders, especially COPD; 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 it would otherwise be. The frequency of habitual cigarette-smoking varies with occupa- tion, socioeconomic status, and generation. For those reasons, cigarette-smoking can be 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). It is well known that causes of death from respiratory diseases, especially chronic diseases, are frequently misclassified on death certificates. Grouping various respiratory diseases for analysis, unless they all are associated with a given exposure, will lead to attenuation of the estimates of RR and to a diminu- tion of statistical power. Moreover, deaths from respiratory and cardiovascular diseases (CVDs) are often confused. In particular, when persons have both condi- tions concurrently and both contributed to death, there may be some uncertainty about which cause should be selected as the primary underlying cause. In other instances, errors may arise in selecting one underlying cause in a complex chain of health events (for example, if COPD leads to congestive heart failure and then to respiratory failure). Many study populations were small, so investigators grouped deaths from all nonmalignant respiratory diseases into one category that combined pneumonia, influenza, and other diseases with COPD and asthma.

OTHER HEALTH EFFECTS 553 Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between ex- posure to the chemicals of interest 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 on the Seveso cohort that suggested a higher mortality from nonmalignant respiratory disorders in 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 responsible for Update 2000 concluded that although new evidence suggested an increased risk of nonmalignant respiratory disorders, particularly COPD, in people exposed to TCDD, the observation was tentative and the information insufficient to deter- mine whether there is an association between exposures to the chemicals of inter- est and respiratory disorders. Additional information available to the committee responsible for Update 2002 did not change that finding. Update 2004 included a new cross-sectional study of residents near a wood- treatment plant (Dahlgren et al., 2003). Soil and sediment samples from a ditch in the neighborhood contained dioxins and furans. Although exposed residents reported a greater frequency of chronic bronchitis by history (17.8% vs 5.7%; p < 0.0001) and asthma by history (40.5% vs 11.0%; p < 0.0001) than a “non- exposed” control group, the committee concluded that selection bias and recall bias limited the utility of the results and that there was a possibility of confound- ing in that history of tobacco use was not accounted for adequately. Update 2006 reviewed a number of studies of veterans of the Vietnam War. Mortality from respiratory diseases was not found to be higher than expected in the Centers for Disease Control and Prevention VES (Boehmer et al., 2004), in the Air Force Health Study (Ketchum and Michalek, 2005), and in two Austra- lian studies of Vietnam veterans (ADVA, 2005b,c). In contrast, in the US Army Chemical Corps cohort of Vietnam veterans, Kang et al. (2006) found that the prevalence of self-reported nonmalignant respiratory problems diagnosed by a doctor was significantly increased by about 40–60%, although no differences in the prevalence of respiratory problems was found in the subset of veterans whose serum TCDD was above 2.5 ppt. In addition, Update 2006 addressed new studies of potentially exposed oc- cupational cohorts. No associations with respiratory mortality were found in a small subcohort of New Zealand phenoxy-herbicide sprayers included in the International Agency for Research on Cancer (IARC) cohort (’t Mannetje et al., 2005). In the Agricultural Health Study (AHS), no associations between the herbicide and mortality from COPD were found in private applicators or their spouses (Blair et al., 2005). A cross-sectional analysis of the AHS with data collected at enrollment among commercial pesticide applicators showed an as-

554 VETERANS AND AGENT ORANGE: UPDATE 2008 sociation between “current” exposure to 2,4-D and the prevalence of wheeze. The committee was concerned about interpreting this finding because self-reported health conditions may not be reported accurately and there may be overreporting if people believe that their exposures were hazardous. As a result, the committee responsible for Update 2006 did not change the original conclusion. Table 9-1 summarizes the results of the relevant studies. Update of the Epidemiologic Literature Vietnam-Veteran Studies Since Update 2006, there have been no publications concerning nonmalig- nant respiratory outcomes in Vietnam veterans. Occupational Studies The continuing AHS has generated several new publications concerning respiratory health problems. A common method was used: at time of enrollment, questionnaires regarding use of pesticides and health outcomes were adminis- tered, and subjects who returned both of them (about 40%) were included in the analyses. Subjects were then classified as having different health outcomes: wheeze, chronic bronchitis, farmer’s lung, and asthma. Wheeze was defined as a positive response to the question “How many episodes of wheezing or whistling in your chest have you had in the past 12 months?” Farmer’s lung and chronic bronchitis were defined if the subject reported having a doctor’s diagnosis. Expo- sures to 40 specific chemicals used in the year before enrollment were assessed from the questionnaires. The analyses were cross-sectional studies of disease prevalence at the time of enrollment that compared the frequency of reported exposures in those who had the health outcome of interest versus the remainder of the cohort or a subset of the cohort; such an analysis is not equivalent to a case–control study. There are now two reports of wheeze from the AHS: one that was reported in Update 2006 and a new one. Wheeze is a cardinal sign of asthma. In the previous report (Hoppin et al., 2006a), the authors reported an OR of 1.3 (95% confidence interval [CI] 1.0–1.7) in commercial applicators for exposure to 2,4-D in the pre- ceding year, adjusted for age, smoking status, asthma or atopy status, and body- mass index (BMI). In the later report (Hoppin et al., 2006b), the association with 2,4-D was attenuated (OR = 1.0, 95% CI 0.7–1.3), but the covariables included in the model were different (age, smoking status, asthma or atopy status, BMI, previous use of pesticides, and exposure to the herbicide chlorimuron-ethyl); the authors noted that adjustment for use of chlorimuron-ethyl attenuated the risk of wheeze reported to be significant in commercial applicators for seven pesticides in the earlier report. No associations with 2,4-D or dicamba were found in the private applicators.

OTHER HEALTH EFFECTS 555 TABLE 9-1  Selected Epidemiologic Studies—Nonmalignant Respiratory Disease Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a VIETNAM VETERANS Studies Reviewed in Update 2006 Boehmer Vietnam Experience Cohort et al., 2004 Nonmalignant respiratory mortality (ICD-9 460–519) 20 0.8 (0.5–1.5) Ketchum and AFHS Michalek, Nonmalignant respiratory mortality (ICD-9 2005 460–519) 8 1.2 (0.6–2.5) Kang et al., US Army Chemical Corps personnel 2006 Self-reported nonmalignant respiratory problems diagnosed by doctor Deployed vs nondeployed 267 1.4 (1.1–1.8) Sprayed herbicides in Vietnam vs never 140 1.6 (1.3–2.1) ADVA, Third Australian Vietnam Veterans Mortality Study 2005b Deployed veterans vs Australian population All branches Respiratory system diseases 239 0.8 (0.7–0.9) COPD 128 0.8 (0.7–1.0) Navy Respiratory system diseases 50 0.8 (0.6–1.0) COPD 28 0.9 (0.6–1.3) Army Respiratory system diseases 162 0.8 (0.7–0.9) COPD 81 0.8 (0.7–1.0) Air Force Respiratory system diseases 28 0.6 (0.4–0.9) COPD 18 0.8 (0.4–1.2) ADVA, Australian National Service Vietnam Veterans: 2005c Mortality and Cancer Incidence Study National Serviceman (SMR) Respiratory diseases 38 0.5 (0.3–0.6) COPD 18 0.9 (0.5–1.4) National Serviceman, deployed (SMR) Respiratory diseases 18 0.5 (0.3–0.8) COPD 8 0.9 (0.4–1.8) National Serviceman, nondeployed (SMR) Respiratory diseases 20 0.4 (0.2–0.6) COPD 10 0.9 (0.4–1.7) Boehmer Vietnam Experience Cohort et al., 2004 Nonmalignant respiratory mortality (ICD-9 460–519) 20 0.8 (0.5–1.5) continued

556 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 9-1  Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a Studies Reviewed in Update 1998 Bullman and Male Vietnam veterans who were wounded in Kang, 1996 combat vs US population Nonmalignant respiratory mortality (ICD 9 460–519) 43 0.9 (0.7–1.2) O’Toole Australian Army Vietnam veterans self-reported et al., 1996 health status (1989–1990) vs Australian population—prevalence  Acute conditions that required recent medical intervention Asthma nr 1.4 (0.6–2.1) Bronchitis, emphysema nr 2.1 (0.2–4.0) Other nr 2.1 (1.6–2.8) Chronic conditions Asthma nr 0.9 (0.5–1.4) Bronchitis, emphysema nr 4.1 (2.8–5.5) Other nr 4.0 (2.2–5.9) Watanabe Mortality of US Vietnam veterans who died et al., 1996; during 1965–1988, PMR analysis of nonmalignant respiratory mortality (ICD 8 460–519) Army 648 0.8 (p < 0.05) Marine Corps 111 0.7 (p < 0.05) Crane et al., Mortality of male Australian Vietnam veterans vs 1997a Australian population  Non-malignant respiratory mortality (ICD-9 460–519) 1964–1979 3 0.1 (0.0–0.3) 1980–1994 92 0.9 (0.7–1.1)  Chronic obstructive airways disease (ICD-9 490–496) 1980–1994 47 0.9 (0.7–1.2) Crane et al., Mortality of deployed Australian National 1997b Servicemen vs those who did not serve in Vietnam 1965–1982 2 2.6 (0.2–30.0) 1982–1994 6 0.9 (0.3–2.7) AFHS, 1996 Cause-specific mortality in Rand Hand personnel vs Air Force veterans 2 0.5 (0.1–1.6) Studies Reviewed in VAO Anderson White males with Wisconsin death certificate et al., 1986 (1968–1978), mortality from nonmalignant respiratory disease (ICD-8 460–519)  Vietnam veterans vs expected deaths calculated from proportions for: Nonveterans 10 0.5 (0.3–0.8) All veterans 0.8 (0.4–1.5) Vietnam-era veteran 1.0 (0.5–1.8)

OTHER HEALTH EFFECTS 557 TABLE 9-1  Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a CDC, 1988 Cross-sectional study, with medical examinations, of US Army Vietnam veterans vs nondeployed US Army veterans  Odds ratios from pulmonary-function tests (case definition: ≤ 80% predicted value) FEV1 254 0.9 (0.7–1.1) FVC 177 1.0 (0.8–1.3) FEV1/FVC 152 1.0 (0.8–1.3) Eisen et al., Incidence in deployed vs nondeployed monozygotic 1991 twins who served in US military during Vietnam era Respiratory conditions Present at time of survey nr 1.4 (0.8–2.4) At any time since service nr 1.4 (0.9–2.0) Required hospitalization nr 1.8 (0.7–4.2) OCCUPATIONAL New Studies Hoppin US AHS—prevalence at enrollment among farm et al., 2008 women of: Atopic asthma having exposure to: 2,4-D 52 1.5 (1.1–2.1) Dicamba 11 1.1 (0.6–2.1) Nonatopic asthma having exposure to: 2,4-D 66 1.1 (0.8–1.4) Dicamba 13 0.7 (0.4–1.3) Hoppin US AHS—prevalence at enrollment of self-reported et al., 2007a farmer’s lung (hypersensitivity pneumonitis)  Private applicators exposed to phenoxy herbicides 392 1.2 (0.8–1.7)  Spouses exposed to phenoxy herbicides 16 1.4 (0.7–2.7) Hoppin US AHS—prevalence at enrollment of chronic et al., 2007b bronchitis in private applicators exposed to: 2,4-D 78 1.1 (0.9–1.4) 2,4,5-T (lifetime days) 28 1.5 (1.3–1.8) None 74 1.0 1–14 16 1.4 (1.1–1.8) 15–55 6 1.3 (0.9–1.8) > 55 4 1.0 (0.6–1.5) 2,4,5-TP (lifetime days) 9 1.7 (1.3–1.3) None 92 1.0 1–14 3 1.1 (0.7–1.8) 15–55 3 1.6 (1.0–2.8) > 55 2 1.4 (0.8–2.5) Dicamba 48 1.0 (0.8–1.2) continued

558 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 9-1  Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a Valcin et al., US AHS—prevalence at enrollment of chronic 2007 bronchitis in nonsmoking farm women exposed to: 0.9 (0.7–1.1) 2,4-D 16 1.2 (0.9–1.6) 2,4,5-T 1 1.0 (0.4–2.5) Dicamba 5 1.1 (0.6–2.0) Hoppin US AHS—prevalence at enrollment of wheeze et al., 2006b (added adjustment for exposure to herbicide chlorimuron-ethyl) Private applicators with current use of: 2,4-D nr 1.0 (0.9–1.1) Dicamba nr 1.1 (0.9–1.2) [supercedes Commercial applicators with current use of: Hoppin 2,4-D nr 1.0 (0.7–1.3) et al., Dicamba 2006a] nr 0.8 (0.6–1.1) Studies Reviewed in Update 2006 Hoppin US AHS—cross-sectional study of wheeze in et al., 2006a commercial applicators with current use of: 2,4-D 225 1.3 (1.0–1.7) Dicamba 167 1.1 (0.9–1.4) ‘t Mannetje New Zealand phenoxy herbicide workers, et al., 2005 nonmalignant respiratory mortality (ICD-9 480–519) Producers 9 0.9 (0.4–1.8) Sprayers 6 0.7 (0.2–1.2) Blair et al., US AHS—COPD mortality 2005 Private applicators 50 0.2 (0.2–0.3) Spouses 15 0.3 (0.2–0.7) Studies Reviewed in Update 2002 Burns et al., Males employees of Dow Chemical Company— 2001 manufacture exposed to 2,4-D in 1945–1994, nonmalignant respiratory mortality (ICD-8 460–519) All nonmalignant respiratory 8 0.4 (0.2–0.7) Pneumonia 4 0.6 (0.2–1.4) Studies Reviewed in Update 2000 Steenland NIOSH mortality study of chemical workers at et al., 1999 12 plants in US exposed to TCDD, nonmalignant respiratory mortality (ICD-9 460–519) 86 0.9 (0.7–1.1) Sweeney NIOSH follow-up study of workers in production of et al., sodium trichlorophenol, 2,4,5-T ester contaminated 1997/98 with TCDD, chronic bronchitis and COPD 2 nr [supersedes Calvert et al., 1991]

OTHER HEALTH EFFECTS 559 TABLE 9-1  Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a Studies Reviewed in Update 1998 Becher et al., Four German facilites for production of phenoxy 1996 herbicides, chlorophenols, nonmalignant respiratory mortality (ICD-9 460–519) Boehringer Ingelheim 10 0.5 (0.3–1.0) Bayer Uerdingen 2 0.9 (0.1–3.1) Bayer Dormagen 0 0.0 BASF Ludwigshafen 4 0.6 (0.2–1.6) Svensson Swedish fishermen exposed to TCDD, mortality et al., 1995 from bronchitis or emphysema (ICD-7 490–493) East coast 4 0.5 (0.2–1.2) West coast 43 0.8 (0.6–1.1) Ott and German workers exposed to trichlorophenol Zober, 1996 contaminated with TCDD from accident at BASF [supersedes plant, 1953–1993, nonmalignant respiratory Zober et al., mortality 1 0.1 (0.0–0.8) 1994] Ramlow Mortality of workers at Dow Chemical plant, et al., 1996 Michigan, producing PCP contaminated with PCDDs, 1940–1989  Nonmalignant respiratory mortality (ICD-8 460–519) Cumulative PCP exposure 14 0.9 (0.5–1.5) < 1 unit 3 0.6 (0.2–1.9) ≥ 1 unit 11 1.4 (0.8–2.5) Pneumonia (ICD-8 480–486) 6 1.1 (0.4–2.4) Emphysema (ICD-8 492) 4 1.3 (0.4–3.3) Kogevinas Mortality in international workers producing et al., 1997 or applying phenoxy herbicides, nonmalignant respiratory mortality (ICD-9 460–519), 1939–1992 Men 252 0.8 (0.7–0.9) Women 7 1.1 (0.4–2.2) Studies Reviewed in Update 1996 Senthilselvan Cross-sectional study of self-reported prevalence et al., 1992 of asthma in male farmers in Saskatchewan (1982–1983) Chlorinated hydrocarbons 31 0.8 (0.5–1.3) Zober et al., German workers exposed to trichlorophenol Illness episodes 1994 contaminated with TCDD from an accident at per 100 BASF plant, 1953–1989; exposed vs unexposed person-years workers—prevalence (cohort/reference)  nonmalignant respiratory diseases (ICD-9 All nr 33.7/31.0 460–51) (p = 0.22)  Upper respiratory tract infections (ICD-9 nr 12.0/9.0 460–478) (p = 0.00) continued

560 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 9-1  Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a Pneumonia or influenza (ICD-9 480–487) nr 17.4/18.8 (p = 0.08)  COPD (ICD-9 490–496) nr 8.0/7.5 (p = 0.31) Studies Reviewed in VAO Coggon Production of phenoxy herbicides, chlorophenols et al., 1991 in four British plants, mortality from nonmalignant respiratory diseases, 1963–1985 8 0.7 (0.3–1.3) Coggon British plant manufacturing MCPA, mortality et al., 1986 from nonmalignant respiratory diseases (ICD-9 460–519), 1947–1983 93 0.6 (0.5–0.8) Alavanja PMR study of USDA soil, forest conservationists, et al., 1989 mortality 1970–1979 from nonmalignant respiratory diseases (ICD-9 460–519) 80 0.8 (0.6–1.0) Calvert NIOSH cross-sectional study of workers in et al., 1991 production of sodium trichlorophenol, 2,4,5-T ester contaminated with TCDD comparing exposed with nonexposed workers; odds ratios for increase in 1 ppt of serum TCDD Chronic bronchitis nr 0.5 (0.1–2.6) COPD nr 1.2 (0.5–2.8) Suskind and Cross-sectional study of Nitro, West Virginia, plant Hertzberg, that manufactured 2,4,5-T, comparing exposed with 1984 nonexposed workers, 1979; odds ratios comparing exposed with nonexposed for “abnormal” outcome on pulmonary-functions tests: FEV1 (< 80% predicted) 32 2.82 (p = 0.02) FVC (< 80% predicted) 35 2.25 (p = 0.32) FEV1/FVC (< 70%) 32 2.97 (p = 0.01) FEF25–75 (< 80% predicted) 47 1.86 (p = 0.05) Blair et al., Licensed pesticide applicators, Florida, 1983 nonmalignant respiratory diseases, (ICD-8 460–519) Analyses by length of licensure 20 0.9 (nr) ≤ 10 years 8 0.6 (nr) 10–19 years 8 1.5 (nr) ≥ 20 years 4 1.7 (nr) ENVIRONMENTAL New Studies Consonni 25-year follow-up of Seveso residents—mortality et al., 2008 from respiratory disease (ICD-9 460–519) Zone A 9 1.4 (0.7–2.7) Zone B 48 1.0 (0.8–1.4) Zone R 341 1.0 (0.9–1.1)

OTHER HEALTH EFFECTS 561 TABLE 9-1  Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a Mortality from COPD (ICD-9 490–493) Zone A 7 2.5 (1.2–5.3) Zone B 26 1.3 (0.9–1.9) Zone R 175 1.2 (1.0–1.4) Studies Reviewed in Update 2004 Dahlgren Cross-sectional study of residents near wood- Adjusted scores et al., 2003 treatment plant (creosote, PCP) in Mississippi, who of exposed vs were plaintiffs in lawsuit against plant vs subjects in nonexposed; comparable area with no known chemical exposures (< 0 means exposed subjects had more Shortness of breath symptoms) Adults nr -2.5 (p < 0.05) Children nr -3.8 (p < 0.05) Studies Reviewed in Update 2000 Bertazzi 20-year follow-up of Seveso residents—mortality et al., 2001 from respiratory disease (ICD-9 460–519) 44 1.0 (0.8–1.4) Zone A 9 1.9 (1.0–3.6) Zone B 35 1.3 (0.9–2.0) COPD (ICD-9 490–493) 29 1.5 (1.1–2.2) Zone A 7 3.3 (1.6–6.9) Zone B 22 1.3 (0.9–2.0) Bertazzi 15-year follow-up of Seveso residents—mortality et al., 1998; from respiratory disease (ICD-9 460–519) Pesatori Zone A et al., 1998 Men 5 2.4 (1.0–5.7) (results from Women 2 1.3 (0.3–5.3) Bertazzi) Zone B Men 13 0.7 (0.4–1.2) Women 10 1.0 (0.5–1.9) Zone R Men 133 1.1 (0.9–1.3) Women 84 1.0 (0.8–1.2) COPD (ICD-9 490–493) Zone A Men 4 3.7 (1.4–9.8) Women 1 2.1 (0.3–14.9) Zone B Men 9 1.0 (0.5–1.9) Women 8 2.5 (1.2–5.0) Zone R Men 74 1.2 (0.9–1.5) Women 37 1.3 (0.9–1.9) continued

562 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 9-1  Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a Studies Reviewed in VAO Bertazzi 10-year follow-up on Seveso residents—mortality et al., 1989a; from respiratory disease (ICD-9 460–519) Bertazzi Men 55 1.0 (0.7–1.3) et al., 1989b Women 24 1.0 (0.7–1.6) (results from Pneumonia (ICD-9 480–486) Bertazzi Men 14 0.9 (0.5–1.5) et al., Women 9 0.8 (0.4–1.6) 1989a) COPD (ICD-9 490–493) Men 31 1.1 (0.8–1.7) Women 8 1.0 (0.5–2.2) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid; AFHS, Air Force Health Study; AHS, Agricultural Health Study; CI, confidence interval; COPD, chronic obstructive pulmonary disease; FEF25–75, forced midexpiratory flow; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; ICD-8, International Classification of Diseases, 8th revision; ICD-9, International Clas- sification of Diseases, 9th revision; MCPA, 2-methyl-4-chlorophenoxyacetic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p- d ­ ioxin; PCP, pentachlorophenol; PMR, proportionate mortality ratio; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; USDA, US Department of Agriculture. aGiven when available; results other than estimated risk explained individually. Studies in italics have been superseded by newer studies of same cohort. In another publication from the AHS, Hoppin et al. (2008) conducted an analysis of the 702 women among the 25,814 farm women who reported at enrollment that they had had a diagnosis of asthma after the age of 19 years. Of the 702, 282 had atopic asthma (asthma with eczema or hay fever), and 420 had nonatopic asthma. A significantly increased risk of atopic asthma was observed in association with exposure to 2,4-D (OR = 1.4, 95% CI 1.1–1.8) but not with exposure to dicamba (OR = 1.1, 95% CI 0.9–1.3). For nonatopic asthma, the risk associated with exposure to 2,4-D was increased slightly (OR = 1.1, 95% CI 0.9–1.3), and no association was found with exposure to dicamba. In a study of the prevalence of farmer’s lung (hypersensitivity pneumonitis) at enrollment in the AHS population, Hoppin et al. (2007a) did not find signifi- cantly increased risks among private pesticide applicators (OR = 1.2, 95% CI 0.8–1.7) or their spouses (OR = 1.4, 95% CI 0.7–2.7) who had ever been exposed to phenoxy herbicides. Adjustment was made for age, state, smoking, and all other exposures. Chronic bronchitis was the outcome of interest in two publications from the AHS. Among the 20,908 private pesticide applicators (who were mostly male

OTHER HEALTH EFFECTS 563 farmers), Hoppin et al. (2007b) found significant increases in the prevalence of self-reported chronic bronchitis that was diagnosed by a physician in people more than 19 years old who had been exposed to 2,4,5-T (OR = 1.5, 95% CI 1.3–1.8) or to 2-(2,4,5-trichlorophenoxy) propionic acid (2,4,5-TP) (OR = 1.7, 95% CI 1.3–2.3). Statistically significant associations with exposures to 2,4-D and di- camba were not observed. Analyses according to the number of days on which 2,4,5-T or 2,4,5-TP was sprayed did not reveal monotonic increases in the odds of prevalence, but there were few exposed cases in each category of use, so the statistical power to detect monotonic trends was low. Similar analyses of 21,541 nonsmoking women in the AHS by Valcin et al. (2007) did not find increased risks of chronic bronchitis in those exposed to 2,4-D, to 2,4,5-T, or to dicamba. Environmental Studies In the 25-year follow-up of the mortality of the Seveso population through 2001, Consonni et al. (2008) estimated associations by using Poisson regression for three exposure zones (A, B, and R) and comparing rates among residents of nonexposed areas in 11 surrounding municipalities. They found that mortality from all types of respiratory disease (International Classification of Diseases, 9th revision [ICD-9] 460–493) was not increased, although there was an increase in the most highly exposed but relatively small group from Zone A (RR = 1.4, 95% CI 0.7–2.7). For the more specific diagnosis of COPD (ICD-9 490–493), however, there was a marked increase in Zone A (RR = 2.5, 95% CI 1.2–5.3), and increased rates were found in the intermediate-exposure Zone B (RR = 1.3, 95% CI 0.9–1.9) and the least exposed Zone R (RR = 1.2, 95% CI 1.0–1.4). Biologic Plausibility Acute nonmalignant respiratory disorders, including pneumonia and other respiratory infections, can be increased in frequency and severity when the normal defense mechanisms of the lower respiratory tract are compromised. Thus expo- sure to chemicals that affect those mechanisms could exacerbate respiratory disor- ders. There is no evidence that the herbicides used in Vietnam alter such defense mechanisms. However, inasmuch as TCDD has been shown to suppress immune function in a variety of animal models, exposure to TCDD could be expected to increase the incidence or severity of respiratory infections. Several laboratory studies have shown that treatment of mice with TCDD increased their mortal- ity after infection with influenza virus (Burleson et al., 1996; Lawrence et al., 2003). Treatment with TCDD also suppressed the animals’ ability to generate an immune response to the virus (Mitchell and Lawrence, 2003). The mechanism underlying increased influenza mortality was not related to the suppression of the immune response to influenza by TCDD but appeared to involve an increase in the inflammatory response associated with an increased flow of neutrophils into the lung (Mitchell and Lawrence, 2003). Neutrophils produce several toxic

564 VETERANS AND AGENT ORANGE: UPDATE 2008 products (which kill pathogens), so it is possible that excess numbers of neutro- phils in the lung produce excess collateral damage and pathologic changes that increase mortality. Later studies to test that hypothesis showed that prevention of the neutrophilia (increase in the number of neutrophils) with an antineutrophil antibody provided partial protection of TCDD-treated mice from influenza-in- duced mortality (Teske et al., 2005). Furthermore, the increased mortality and increased neutrophilia were AHR-dependent and not observed in TCDD-treated AHR-knockout mice (Teske et al., 2005). However, TCDD exposure did not alter the concentrations of common lung neutrophil chemoattractants, the expression of adhesion molecules, or the normal neutrophil apoptotic process. Likewise, concentrations of reactive oxygen species and myeloperoxidase activity were normal in neutrophils from TCDD-treated mice (Teske et al., 2005). In the absence of evidence of TCDD effects at the level of neutrophil recruit- ment or function, several indicators of lung damage were assessed (Bohn et al., 2005). TCDD exposure did not alter the concentration of lactate dehydrogenase (a marker of lung-cell damage) or increase edema (measured by protein in bron- chioalveolar lavage fluid and wet-weight to dry-weight ratios). Although AHR expression was shown to be required for TCDD to increase neutrophils in the lungs, the cells expressing AHR were not the neutrophils themselves or other immune cells, and this suggests that lung parenchyma was being directly affected by TCDD (Teske et al., 2008). However, the concentra- tion of Clara cell secretory protein, an inflammatory mediator produced by lung-associated Clara cells, was not altered by TCDD. Thus, the mechanisms underlying the increase in mortality after influenza infection remain to be deter- mined. Despite the lack of functional changes in the lung, TCDD induced cyto- chrome P450 1A1 (CYP1A1) expression in the Clara cells of the lung, in lung endothelial cells, and in type II pneumocytes—indications of the ability of TCDD to affect the lung directly via AHR activation (Bohn et al., 2005). CYP1A1 and CYP1B1 were also induced in the lungs of rats given a single dose (5 µg/kg of body weight) of TCDD 4 hours before termination (Harrigan et al., 2006). On the basis of those findings, it is biologically plausible that exposure to TCDD results in exacerbation of acute lung disease that is associated with reduced im- mune responses or of chronic lung diseases including COPD, that is associated with increased inflammatory responses. It is also plausible that the induction of CYP1A1 and CYP1B1 enzymes in the lung by TCDD result in the metabolism of several chemicals found in tobacco smoke to more toxic intermediates. Exposure to TCDD would thus increase the toxic effects of tobacco smoke and increase respiratory disease. Synthesis Results of the studies of mortality from nonmalignant respiratory diseases reported in Update 2006 and earlier VAO reports (ADVA, 2005b,c; Anderson et al., 1986; Becher et al., 1996; Blair et al., 1983, 2005; Bullman and Kang,

OTHER HEALTH EFFECTS 565 1996; Burns et al., 2001; Coggon et al., 1986, 1991; Crane et al., 1997a; Ketchum and Michalek, 2005; Kogevinas et al., 1997; Ott and Zober, 1996; Ramlow et al., 1996; Steenland et al., 1999; Svensson et al., 1995; ’t Mannetje et al., 2005; Zober et al., 1994) do not support the hypothesis that herbicides are associated with respiratory mortality. The recent studies of the Seveso incident showed a positive association (Consonni et al., 2008) based on nine deaths in the high-exposure area (Zone A); this finding could have been due to chance or to misclassification of causes of death. More important, as the committee recognizes that mortality studies are limited by small numbers of events and misclassification of causes of death (especially respiratory conditions), it does not believe that scientific conclu- sions can be based on health outcomes that are defined vaguely, for example, by combining a wide array of disparate respiratory health outcomes into one large category. In Update 2006, when Kang et al. (2006) compared deployed to nonde- ployed Vietnam-era veterans in a study of US Army Chemical Corps personnel, they found an association between exposure and the prevalence of self-reported physician-confirmed respiratory problems (OR = 1.41, 95% CI 1.13–1.76). The association was also significant when those who reported spraying herbicides in Vietnam were compared to those who did not (OR = 1.62, 95% CI 1.26–2.05). In the subset of subjects for whom serum TCDD concentrations had been deter- mined, individuals with respiratory problems were evenly distributed above and below the median, which argues against the association arising from herbicide exposure. As in the case of the mortality studies cited in the preceding paragraph, the issue of nonspecificity is key to interpreting this study. The nonspecific- ity of the types of respiratory conditions reported in Kang et al. (2006) makes it exceedingly difficult to draw any conclusions regarding specific respiratory conditions. The present committee found an additional five papers on the prevalence of various respiratory conditions, all from the AHS. Those respiratory outcomes now include wheeze, asthma, COPD, and farmer’s lung. The following summa- rizes the evidence on those outcomes. • COPD. The findings from the Seveso incident showed increased risks of death from COPD (Consonni et al., 2008), with higher RRs found in the zone (A) closest to the accident and slightly lower RRs for the outly- ing zones. No associations with mortality from COPD were found in the recent Australian studies (ADVA, 2005b,c; Crane et al., 1997a). A 4-fold excess prevalence in chronic bronchitis and emphysema was found in a health-status study of Australian army Vietnam veterans (O’Toole et al., 1996). In the AHS, Hoppin et al. (2007b) found associations between ex- posure to 2,4,5-T and 2,4,5-TP and the prevalence of physician-diagnosed COPD in private applicators, and Valcin et al. (2007) found that the prevalence of physician-diagnosed COPD in nonsmoking farm women was 20% higher in those persons exposed to 2,4-D. Other cross-sectional

566 VETERANS AND AGENT ORANGE: UPDATE 2008 prevalence studies considered in previous updates that bear on this mat- ter include the study of an accident at a BASF plant (Zober et al., 1994) that showed no association of exposure with episodes of COPD and the NIOSH cross-sectional study of production workers exposed to 2,4,5-T ester contaminated with TCDD (Calvert et al., 1991) that also did not show an increase in COPD associated with serum TCDD concentration. In addition, the study of residents exposed environmentally to emissions from a plant that produced creosote and pentachlorophenol (Dahlgren et al., 2003) showed positive associations with chronic bronchitis, but the study was judged in Update 2004 to have been biased. • Wheeze and asthma. These related health outcomes were the subject of two reports from the AHS (Hoppin et al., 2006a,b). The study new to the present update (Hoppin et al., 2006b) stated that the first study’s associations between “current” exposure to 2,4-D and several other pes- ticides and the prevalence of self-reported wheeze (adjusted OR = 1.3) did not persist (OR = 1.0) after adjustment for exposure to chlorimuron- ethyl. Previous updates noted that a cross-sectional study in Saskatchewan (Senthilselvan et al., 1992) showed no association between exposure to chlorinated hydrocarbons and the prevalence of self-reported asthma. The study by Hoppin et al. (2006b) is unclear about what wheeze represents: the definition of wheeze was very broad and included any episode in the year before administration of the questionnaire, and the authors reported that only 28% of subjects with wheeze reported having asthma or atopic conditions. • Farmer’s lung. There was only one study on this outcome (Hoppin et al., 2007a), and no conclusions can be drawn. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence of an association between exposure to the chemicals of interest and mortality from all nonmalignant respiratory diseases or the prevalence of wheeze or asthma, COPD, and farmer’s lung. IMMUNE-SYSTEM DISORDERS The immune system defends the body against infection by pathogens— v ­ iruses, bacteria, and other disease-producing microorganisms. It also plays a role in cancer surveillance, destroying mutated cells that might otherwise develop into tumors. To recognize the wide array of pathogens in the environment, the im- mune system relies on many cell types that operate together to generate immune responses. Those cells arise from stem cells in the bone marrow, they are found

OTHER HEALTH EFFECTS 567 throughout the body’s lymphoid tissues, and they circulate in the blood as white blood cells (WBCs). The main types of WBCs are granulocytes, monocytes, and lymphocytes. Immune Suppression Suppression of immune responses can reduce resistance to infectious disease and increase the risk of cancer. Infection with the human immunodeficiency virus (HIV) is a well-recognized example of an acquired immune deficiency in which a specific type of lymphocyte (CD4+ T cells) 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. Treatment of cancer patients with toxic chemotherapeutic drugs suppresses the immune system by inhibiting the generation of new WBCs from the bone marrow and by blocking prolifera- tion of lymphocytes during an immune response. Immune suppression can result from exposure to chemicals in the workplace or in the environment, including dioxin (see Chapter 4). However, unless the immune suppression is severe, it is often difficult to obtain clinical evidence that directly links chemical-induced changes in immune function to increased infectious disease or cancer, because many confounding factors can influence a person’s ability to combat infection. Such confounders include age, vaccination status, the virulence of the pathogen, the presence of other diseases (such as diabetes), stress, smoking, and the use of drugs or alcohol. Allergy The immune system sometimes responds to a foreign substance that is not pathogenic. Such immunogenic substances are called allergens. The response to some allergens, such as pollen and bee venom, results in the production of immu- noglobulin E (IgE) antibodies. Once produced, IgE antibodies bind to specialized cells—mast cells—that occur in tissues throughout the body, including lung air- ways, the intestinal 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 produce the symptoms associated with an allergic response. Other allergens, such as poison ivy and nickel, activate allergen-specific lymphocytes at the site of contact (usually the skin) that release substances that cause inflammation and tissue damage. Although inflammation is advantageous in fighting infectious diseases, tissue damage can result when it is inappropriately increased or prolonged. Inflammation is known to contribute to coronary arterial disease and appears to play a role in promoting the growth of cancer.

568 VETERANS AND AGENT ORANGE: UPDATE 2008 Autoimmune Disease Autoimmune disease is another example of the immune system’s causing rather than preventing disease. The immune system attacks the body’s own cells and tissues as though they are foreign, and this leads to the generation of inflam- matory substances that cause damage to the tissues. For example, the autoimmune reaction in multiple sclerosis is directed against the myelin sheath of the nervous system; in Crohn’s disease, the intestine is the target of attack; in type 1 diabetes mellitus, the insulin-producing cells of the pancreas are destroyed by the immune response. Rheumatoid arthritis (RA) is an autoimmune disease that arises from immune attack on the joints. Genetic predisposition and such environmental fac- tors as infectious diseases and stress are thought to facilitate the development of autoimmune diseases. Systemic lupus erythematosus (SLE) is an autoimmune disease that has no specific target organ of immune attack. Instead, patients have a variety of symptoms that often occur in other diseases, and this makes diagnosis difficult. A characteristic rash across the cheeks and nose and sensitivity to sunlight are common symptoms; oral ulcers, arthritis, pleurisy, proteinuria, and neurologic disorders may be present. Almost all people who have SLE test positive for anti- nuclear antibodies in the absence of drugs known to induce them. The causes of SLE are unknown, but environmental and genetic factors have been implicated. Some of the environmental factors that may trigger it are infections, antibiotics (especially those in the sulfa and penicillin groups) and some other drugs, ultra- violet radiation, extreme stress, and hormones. Occupational exposures to such chemicals as crystalline silica, solvents, and pesticides have also been associated with SLE (Cooper and Parks, 2004; Parks and Cooper, 2005). Conclusions from VAO and Previous Updates The committees responsible for VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 concluded that there was inadequate or insufficient information to determine whether there is an associa- tion between exposure to the chemicals of interest and immune-system disorders. Reviews of the studies that underlay that conclusion are presented in the previ- ous reports (IOM, 1994, 1996, 1999, 2001, 2003, 2005, 2007). The committee responsible for Update 2006 reviewed a report by Boehmer et al. (2004) that found no excess in postservice mortality in male US Army Vietnam veterans related to endocrine, nutritional, and metabolic diseases or to immune disorders and concurred with the conclusion of the previous review committees. Update of the Epidemiologic Literature No Vietnam-veteran or occupational studies addressing exposure to the chemicals of interest and the immune system have been published since Update 2006.

OTHER HEALTH EFFECTS 569 Environmental Studies One study of potential effects on the immune system of adults has been published since Update 2006. In addition, two studies of perinatal and childhood exposures have been described. Lee DH et al. (2007a) investigated the concentrations of persistent organic pollutants in adipose tissue of 1,721 adults in the 1999–2002 National Health and Nutrition Examination Survey (NHANES), their effect on the immune sys- tem, and the possibility of an association with self-reported arthritis, either RA or osteoarthritis. The study focused on pollutants that were found in at least 60% of study subjects, which included three polychlorinated dibenzo-p-dioxins (PCDDs) and four dioxin-like polychlorinated biphenyls (PCBs, PCB-74, -118, -126, and -169). Women had higher serum concentrations of all classes of those organic pollutants, including the PCDDs and their dioxin-like congeners, than man. PCDDs were not associated with arthritis in either sex. However, women who had higher concentrations of dioxin-like PCBs had a higher prevalence of arthritis. After adjustment for possible confounders, ORs for all types of arthritis were 1.0, 2.1, 3.5, and 2.9 across quartiles of dioxin-like PCBs (quartiles 2–4 each significantly higher than quartile 1; p for trend = 0.02). The adjusted ORs for RA specifically were 1.0, 7.6, 6.1, and 8.5 for dioxin-like PCBs (quartiles 2–4 each significantly higher than quartile 1; p for trend = 0.05). For the nondioxin- like PCBs, however, the individual quartile risks of RA were not as high, but the pattern was monotonic: 1.0, 2.2, 4.4, and 5.4 (not significantly higher in quartile 2; p for trend < 0.01). No associations of dioxin-like PCBs or other substances with RA were observed in men. Smith AG et al. (2008) reported on the consequences of exposure of 13 members of two Spanish families poisoned by cooking oil greatly contaminated with highly chlorinated dioxins (PCDD). Originally, all the people had chloracne as an early symptom. Analyses of the pattern of lymphocyte subpopulations were performed on whole blood. In family members with the highest body burdens of hexachlorinated to octachlorinated PCDDs, no changes in immunologic markers in comparison with a reference population were noted. Four of the children had significantly higher numbers of total blood lymphocytes. Biologic Plausibility Exposure of laboratory animals to phenoxy herbicides or cacodylic acid has not been associated with immunotoxicity. In contrast, the immune system has been recognized as a sensitive target for the toxicity of TCDD in laboratory animals for many years. Many cell types make up the immune system, and most of the cells have been shown to express the AHR, which is required for initiating the toxicity of TCDD (see Chapter 4). Identifying the specific cells of the immune system that are altered by TCDD and how they contribute to TCDD-induced alterations in immune function is of great interest to the research community.

570 VETERANS AND AGENT ORANGE: UPDATE 2008 Understanding how TCDD affects the immune system in rodents increases the ability to extrapolate experimental results to assessment of human risks. TCDD is a potent immunosuppressive chemical in laboratory animals, and exposure to it has been shown to increase the incidence and severity of various infectious diseases and to increase the development of cancer. Consistent with its immunosuppressive effects, TCDD exposure suppresses the allergic immune re- sponse of rodents, and this in turn results in decreased allergen-associated patho- logic lung conditions and has recently been shown to suppress the development of experimental autoimmune disease (Quintana et al., 2008). Thus, depending on the particular disease, TCDD exposure could result in exacerbation or amelioration of symptoms. The demonstration in recent studies that AHR activation by TCDD leads to the development of regulatory T cells helps to explain the diversity of effects seen after exposure to TCDD (Funatake et al., 2008; Marshall et al., 2008; Quintana et al., 2008). In contrast, under some conditions, exposure of laboratory animals to TCDD has been associated with increased inflammatory responses and increased produc- tion of inflammatory mediators. That could potentially increase the severity of autoimmune disease and promote the growth of cancer cells. The AHR appears to regulate the expression of several genes associated with inflammation that could explain the influence of TCDD on inflammatory diseases. Taken together, results of experimental laboratory studies indicate that TCDD exposure can have diverse effects on the immune response—some that are detrimental to health and others that appear to be beneficial, depending on the disease in question. Synthesis TCDD is a well-known immunosuppressive agent in laboratory animals. Therefore, one would expect exposure of humans to substantial doses of TCDD to result in immune suppression. However, several studies of various measures of human immune function failed to reveal consistent correlations with TCDD exposure, probably because the exposures were inadequate to produce immune suppression. No detectable pattern of an increase in infectious disease has been documented in veterans exposed to TCDD or the herbicides used in Vietnam. Suppression of the immune response by TCDD might increase the risk of some kinds of cancer in Vietnam veterans, but there is no evidence to support that connection. Epidemiologic studies have been inconsistent with regard to TCDD’s influ- ence on IgE production in humans. No animal or human studies have specifically addressed the influence of TCDD on autoimmune disease. In studying postservice mortality, Boehmer et al. (2004) found no increase in deaths of Vietnam veterans that could be attributed to immune-system disorders. The present review included a study that found a significant association between concentrations of dioxin-like

OTHER HEALTH EFFECTS 571 PCBs and the prevalence of arthritis (thought to be an autoimmune disorder) in women but not in men (Lee DH et al., 2007a). There is no experimental evidence to support that finding, and future studies are needed to determine a potential mechanism of TCDD-induced RA. Few effects of phenoxy herbicide or cacodylic acid exposure on the immune system have been reported in animals or humans, and no clear association be- tween such exposure and autoimmune or allergic disease has been found. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and immune suppression, allergy, or autoimmune disease. TYPE 2 DIABETES Diabetes mellitus is a group of heterogeneous metabolic disorders character- ized by hyperglycemia and quantitative or qualitative deficiency of insulin action (Orchard et al., 1992). Although all forms share hyperglycemia, the pathogenic processes involved in its development differ. Most cases of diabetes mellitus are in one of two categories: type 1 diabetes is characterized by a lack of insulin caused by the destruction of insulin-producing cells in the pancreas (β cells), and type 2 diabetes is characterized by a combination of resistance to the actions of insulin and inadequate secretion of insulin (called relative insulin deficiency). In old classification systems, type 1 diabetes was called insulin-dependent diabetes mellitus or juvenile-onset diabetes mellitus, and type 2 was called non–insulin- dependent diabetes mellitus or adult-onset diabetes mellitus. The modern clas- sification system recognizes that type 2 diabetes can occur in children and can require insulin treatments. Long-term complications of both types can include CVDs, nephropathy, retinopathy, neuropathy, and increased vulnerability to in- fections. Keeping blood sugar concentrations within the normal range is crucial for preventing complications. About 90% of all cases of diabetes mellitus are of type 2. Onset can occur before the age of 30 years, and incidence increases steadily with age. The main risk factors are age, obesity, central fat deposition, a history of gestational diabe- tes (in women), physical inactivity, ethnicity (prevalence is greater in blacks and Hispanics than in whites), and—perhaps most important—family history. The relative contributions of those features are not known. Prevalence and mortality statistics in the US population for 2006 are presented in Table 9-2. The etiology of type 2 diabetes is unknown, but three major components have been identified: peripheral insulin resistance (thought by many to be pri- mary) in target tissues (muscle, adipose tissue, and liver), a defect in β-cell se-

572 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 9-2  Prevalence and Mortality in United States for 2006 from Diabetes, Lipid Disorders, and Circulatory Disorders Prevalence (% of Americans 20 years old Mortality (no. and older) deaths, all ages) ICD-9 Range Diseases of Circulatory System Men Women Men Women 250 Diabetes nr nr 36,500 38,600 Physician-diagnosed 7.4a 8.0a nr nr Undiagnosed 3.8a 2.1a nr nr Prediabetes 31.7a 19.9a nr nr Lipid disorders Total cholesterol ≥ 200 mg/dL 42.6 47.1. nr nr Total cholesterol ≥ 240 mg/dL 13.8 17.3 nr nr LDL cholesterol ≥ 130 mg/dL 33.8 31.7 nr nr HDL cholesterol < 40 mg/dL 24.9 6.7 nr nr 390–459 All circulatory disorders 37.6 34.9 409,900 454,600 390–398 Rheumatic fever and rheumatic heart disease nr nr 1,022 2,226 401–404b Hypertensive disease 24,000 33,300 401 Essential hypertension nr nr nr nr 402 Hypertensive heart disease nr nr nr nr 403 Hypertensive renal disease nr nr nr nr 404 Hypertensive heart and renal disease nr nr nr nr 410–414, 429.2 Ischemic, coronary heart disease 8.6 6.8 232,100 213,600 410, 412 Acute, old myocardial infarction 4.7 2.7 80,100 70,900 411  Other acute, subacute forms of ischemic heart disease nr nr nr nr 413 Angina pectoris 4.3 4.5 nr nr 414  Other forms of chronic ischemic heart disease nr nr nr nr 429.2 Cardiovascular disease, unspecified 8.6 6.8 232,100 213,600 415–417b Diseases of pulmonary circulation nr nr nr nr 420–429 Other forms of heart disease (such as pericarditis, endocarditis, myocarditis, cardiomyopathy) nr nr nr nr 426–427 Arrhythmias nr nr nr nr 428 Heart failure 3.2 2.0 126,200 166,100 430–438b Cerebrovascular disease (such as hemorrhage, occlusion, transient cerebral ischemia; includes mention of hypertension in ICD-401) 2.6 3.2 56,600 87,000 440–448b Diseases of arteries, arterioles, capillaries nr nr nr nr 451–459 Diseases of veins, lymphatics, other diseases of circulatory system nr nr nr nr ABBREVIATIONS: HDL, high-density lipoprotein; ICD, International Classification of Diseases; LDL, low-density lipoprotein; nr, not reported. aFor ages 18 years and above. bGap in ICD-9 sequence follows. SOURCE: AHA, 2009 (pp. e175–e176).

OTHER HEALTH EFFECTS 573 cretion of insulin, and overproduction of glucose by the liver. In states of insulin resistance, insulin secretion is initially higher for each concentration of glucose than in people without diabetes. That hyperinsulinemic state is a compensation for peripheral resistance and in many cases maintains normal glucose concentra- tions for years. Eventually, β-cell compensation becomes inadequate, and there is progression to overt diabetes with concomitant hyperglycemia. Why the β cells cease to produce sufficient insulin is not known. Type 1 diabetes occurs as a result of immunologically mediated destruction of β cells in the pancreas, which often occurs during childhood but can occur at any age. As in many autoimmune diseases, genetic and environmental fac- tors influence pathogenesis. Some viral infections are believed to be important environmental factors that can trigger the autoimmunity associated with type 1 diabetes. Pathogenetic diversity and diagnostic uncertainty are among the important problems associated with epidemiologic study of diabetes mellitus. Given the multiple likely pathogenetic mechanisms that lead to diabetes mellitus—which include diverse genetic susceptibilities (as varied as autoimmunity and obesity) and all sorts of potential environmental and behavioral factors (such as viruses, nutrition, and activity)—many agents or behaviors can contribute to risk, espe- cially in genetically susceptible people. The multiple mechanisms also can lead to heterogeneous responses to various exposures. Because up to half the cases of diabetes are undiagnosed, the potential for ascertainment bias in population-based surveys is high (more intensively followed groups or those with more frequent health-care contact are more likely to get the diagnosis); this emphasizes the need for formal standardized testing (to detect undiagnosed cases) in epidemiologic studies. Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether an association between exposure to the chemicals of interest and diabetes mellitus exists. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change that conclusion. In 1999, in response to a request from the Department of Veterans Affairs, IOM called together a committee to conduct an interim review of the scientific evidence regarding type 2 diabetes. That review focused on information pub- lished after the deliberations of the Update 1998 committee and resulted in the report Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Dia- betes, hereafter referred to as Type 2 Diabetes (IOM, 2000). The committee re- sponsible for that report determined that there was limited or suggestive evidence of an association between exposure to at least one chemical of interest and type 2 diabetes. The committees responsible for Update 2000, Update 2002, Update

574 VETERANS AND AGENT ORANGE: UPDATE 2008 2004, and Update 2006 upheld that finding. Reviews of the pertinent studies are found in the earlier reports; Table 9-3 presents a summary. Update of the Epidemiologic Literature Vietnam-Veteran Studies Michalek and Pavuk (2008) published an updated analysis of the Air Force Health Study (AFHS) that related participation in Operation Ranch Hand to the onset of diabetes, incorporated additional follow-up time (through December 31, 2004), and refined the stratification of exposure categories compared with those used in the previous report (Henriksen et al., 1997). The study population in- cluded military personnel who were part of Operation Ranch Hand, did not have a diagnosis of diabetes before the end of their service in Vietnam, and participated in at least one of five in-person examinations conducted in 1982–1997. Data on a comparison cohort of other Air Force veterans who served in Southeast Asia (SEA) in 1962–1971 and were not involved in spraying herbicides were included. TCDD exposure was estimated by extrapolating TCDD concentrations measured in 1987 to the time of the end of the tour of duty, assuming a half-life of 7.6 years. Relative exposure effects were also assessed by date of service (through 1969 or after 1969) and number of days of spraying that occurred while participants were stationed in Vietnam (fewer than 90 days and 90 days or more). The authors hy- pothesized that Agent Orange was more heavily contaminated earlier in the war, but their choice of differing cutpoints for analogous analyses in their paper sug- gests that they were selected in a fashion that influenced the results. (In contrast with what was done for diabetes, for cancer, 1968 or before was the cutpoint for the date-of-service variable, days of spraying were counted through 1967 and the distribution was partitioned at 30 days.) Measured TCDD was significantly lower (p < 0.001) in AFHS participants who served after 1969 or were exposed to fewer than 90 days of spraying. Overall, the RR of diabetes was 21% higher in AFHS participants than in the SEA comparison cohort (RR = 1.21, p = 0.16) after adjustment for BMI at follow-up and during the qualifying tour in Vietnam or SEA, family history of diabetes, smoking history in 1982, year of birth, last year of service in the Ranch Hand Unit or in SEA, ratio of the number of days spent in Vietnam to the number spent in SEA, and military occupation. Among those who served before 1970, AFHS participants had a 65% higher risk of diabetes than the SEA comparison group (RR = 1.65, p = 0.005). No association with diabetes was seen in those serving after 1970 (RR = 0.85, p = 0.45). Similarly, AFHS participants who had at least 90 days of spraying had a 32% higher risk of diabetes (RR = 1.32, p = 0.04). A proportional-hazards model of time-to-diabetes applied to the individual log(TCDD) values of all the Ranch Hand and SEA subjects generated a signifi- cant slope for diabetes incidence with serum dioxin (hazard ratio [HR] = 1.29,

OTHER HEALTH EFFECTS 575 TABLE 9-3  Selected Epidemiologic Studies—Diabetes and Related Health Outcomes Estimated Relative Risk Reference Study Population Exposed Casesa (95% CI)a VIETNAM VETERANS New Studies Michalek AFHS—follow-up through 2004 and Pavuk, Ranch Hand veterans vs SEA comparison 2008 group Calendar period in Vietnam During or before 1969 130 1.7 (p = 0.005) Background (serum TCDD ≤ 10 ppt) 39 1.3 (0.8–2.0) Low (10–91 ppt) 40 1.9 (1.2–2.9) High (> 91 ppt) 51 2.0 (1.3–3.1) After 1969 50 0.9 (p = 0.45) Spraying during tour ≥ 90 days 170 1.3 (p = 0.04) Background (serum TCDD ≤ 10 ppt) 42 1.0 (0.7–1.4) Low (10–91 ppt) 60 1.5 (1.0–2.0) High (> 91 ppt) 68 1.6 (1.1–2.2) < 90 days 10 0.6 (p = 0.12) Studies Reviewed in Update 2006 Kang et al., US Army Chemical Corps personnel 2006 Deployed vs nondeployed 226 1.2 (0.9–1.5) Sprayed herbicides in Vietnam vs never 123 1.5 (1.1–2.0) AFHS, 2005 AFHS—2002 examination cycle Ranch Hand veterans—relative risk with 2-fold increase in 1987 TCDD 1.3 (1.1–1.5) ADVA, Australian Vietnam veterans vs Australian 2005b population—mortality 55 0.5 (0.4–0.7) Navy 12 0.5 (0.3–0.9) Army 37 0.5 (0.4–0.7) Air Force 6 0.5 (0.2–1.0) ADVA, Australian men conscripted into 2005c Army National Service—deployed vs nondeployed—mortality 6 0.3 (0.1–0.7) Boehmer Follow-up of CDC Vietnam Experience et al., 2004 Cohort Kern et al., AFHS—Ranch Hand–comparison subject 2004 pairs—within-pair differences: lower Ranch Hand insulin sensitivity with greater TCDD levels 1997 examination (29 pairs) (p = 0.01) 2002 examination (71 pairs) (p = 0.02) continued

576 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 9-3  Continued Estimated Relative Risk Reference Study Population Exposed Casesa (95% CI)a CDC, 1988 VES—deployed vs nondeployed Interviewed—self-reported diabetes 155 1.2 (p > 0.05) Subset with physical examinations Self-reported diabetes 42 1.1 (p > 0.05) geometric means (mg/dL) Fasting serum glucose 93.4 vs 92.4 (p < 0.05) Studies Reviewed in Update 2004 Kim JS Korean veterans of Vietnam—Vietnam et al., 2003 veterans 154 2.7 (1.1–6.7) Michalek Air Force Ranch Hand veterans (n = 343) 92 ns et al., 2003 Studies Reviewed in Update 2000 AFHS, AFHS—1997 exam cycle (Numerous analyses discussed in 2000b Ranch Hand veterans and comparisons the text of Type 2 Diabetes) Longnecker AFHS—comparison veterans only, OR by and quartiles of serum dioxin concentration Michalek, Quartile 1: < 2.8 ng/kg 26 1.0 2000b Quartile 2: 2.8– < 4.0 ng/kg 25 0.9 (0.5–1.7) Quartile 3: 4.0– < 5.2 ng/kg 57 1.8 (1.0–3.0) Quartile 4: ≥ 5.2 ng/kg 61 1.6 (0.9–2.7) CDVA, Cases expected 1998ab Australian Vietnam veterans—male (95% CI)  Self-report of doctor’s diagnosis 2,391 1,780 (proportion of respondents) (6%) (1,558–2,003) CDVA, Cases expected 1998bb Australian Vietnam veterans—female (95% CI)  Self-report of doctor’s diagnosis 5 10 (proportion of respondents) (2%) (9–11) Studies Reviewed in Update 1998 Henriksen AFHS—through 1992 examination cycle et al., 1997b Ranch Hand veterans—high-exposure group Glucose abnormalities 60 1.4 (1.1–1.8) Diabetes prevalence 57 1.5 (1.2–2.0) Use of oral medications for diabetes 19 2.3 (1.3–3.9) Serum insulin abnormalities 18 3.4 (1.9–6.1) O’Toole Australian Vietnam veterans et al., 1996 Self-report of doctor’s diagnosis 12 1.6 (0.4–2.7) Studies Reviewed in VAO AFHS, 1991 AFHS—1987 examination cycle—elevation Significance of in blood glucose with serum TCDD slope Ranch Hand veterans and comparisons 85 p = 0.001, p = 0.028

OTHER HEALTH EFFECTS 577 TABLE 9-3  Continued Estimated Relative Risk Reference Study Population Exposed Casesa (95% CI)a AFHS, 1984 AFHS—1982 examination cycle—elevation in blood glucose with serum TCDD Ranch Hand veterans and comparisons 158 p = 0.234 OCCUPATIONAL New Studies Montgomery US AHS—self-reported incident diabetes et al., 2008 (1999–2003) in licensed applicators 2,4-D 73 0.9 (0.8–1.1) 2,4,5-T 28 1.0 (0.9–1.2) Saldana US AHS—self-reported gestational diabetes et al., 2007 in wives of licensed applicators  Documented exposure during 1st ORs read from trimester graph 2,4-D 10 ~1.0 (ns) 2,4,5-T 3 ~5 (p < 0.05) 2,4,5-TP 2 ~7 (p < 0.05) Dicamba 7 ~3 (p ~ 0.06) Studies Reviewed in Update 2006 Blair et al., US Agriculture Health Study—mortality 2005 Private applicators (male and female) 26 0.3 (0.2–0.5)  Spouses of private applicators (> 99% female) 18 0.6 (0.4–1.0) Studies Reviewed in Update 2002 Steenland Ranch Hand veterans, workers exposed to et al., 2001 TCDD-contaminated products compared with nonexposed comparison cohorts Ranch Hands 147 1.2 (0.9–1.5) Workers 28 1.2 (0.7–2.3) Kitamura Workers exposed to PCDD at municipal et al., 2000 waste incinerator 8 nr, but ns Studies Reviewed in Update 2000 Calvert Workers exposed to 2,4,5-T, derivatives 26 1.5 (0.8–2.9) et al., 1999b Serum TCDD pg/g of lipid < 20 7 2.1 (0.8–5.8) 20–75 6 1.5 (0.5–4.3) 75–238 3 0.7 (0.2–2.6) 238–3,400 10 2.0 (0.8–4.9) Steenland Highly exposed industrial cohorts et al., 1999b (n = 5,132) Diabetes as underlying cause 26 1.2 (0.8–1.7) Diabetes among multiple causes 89 1.1 (0.9–1.3) Chloracne subcohort (n = 608) 4 1.1 (0.3–2.7) Vena et al., IARC cohort of production workers and 1998b sprayers in 12 countries—mortalityc 33 2.3 (0.5–9.5) continued

578 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 9-3  Continued Estimated Relative Risk Reference Study Population Exposed Casesa (95% CI)a Steenland NIOSH cohort of dioxin-exposed et al., 1992b workers—mortalityc Diabetes as underlying cause 16 1.1 (0.6–1.8) Diabetes among multiple causes 58 1.1 (0.8–1.4) Studies Reviewed in Update 1998 Sweeney Dioxin-exposed workers in two chemical et al., plants 1.1, p < 0.003 1997/1998 Ramlow PCP production workers—mortality 4 1.2 (0.3–3.0) et al., 1996 Studies Reviewed in Update 1996 Ott et al., TCP production workers p = 0.06 1994 Von Benner West German chemical production workers nr nr et al., 1994 Zober et al., BASF production workers 10 0.5 (0.2–1.0) 1994 Studies Reviewed in VAO Sweeney NIOSH production workers 26 1.6 (0.9–3.0) et al., 1992 Henneberger Paper and pulp workers 9 1.4 (0.7–2.7) et al., 1989 Cook et al., Production workers—mortality 4 0.7 (0.2–1.9) 1987 Moses et al., 2,4,5-T, TCP production workers with 1984 chloracne 22 2.3 (1.1–4.8) May, 1982 TCP production workers 2 nr Pazderova- 2,4,5-T, TCP production workers 11 nr Vejlupkova et al., 1981 ENVIRONMENTAL New Studies Consonni Seveso residents (men and women)— et al., 2008 25-year mortality follow-up Zone A 3 1.0 (0.3–3.1) Zone B 26 1.3 (0.9–1.9) Zone R 192 1.3 (1.1–1.5) Everett NHANES 1999–2002 participants et al., 2007 Total diabetes (self-report or HbA1c > 6.1%) HxCDD (TEF = 0.1) > 42.0–99.1 pg/g 1.8 (1.1–2.8) > 99.1 pg/g 2.0 (0.9–4.4) PCB 126 (TEF = 0.1) > 31.3–83.8 pg/g 1.7 (1.0.–2.7) > 83.8 pg/g 3.7 (2.1–6.5)

OTHER HEALTH EFFECTS 579 TABLE 9-3  Continued Estimated Relative Risk Reference Study Population Exposed Casesa (95% CI)a Uemura Survey of Japanese adults et al., 2008a Total dioxins (pg TEQ/g lipid) ≥ 20.00–31.00 17 2.1 (0.9–5.4) ≥ 31.00 39 3.8 (1.6–10.1) Lee DH NHANES 1999–2002 participants et al., 2006 HpCDD > 90th percentile vs nondetectable 46 2.7 (1.3–5.5) OCDD > 90th percentile vs nondetectable 31 2.1 (0.9–5.2) Studies Reviewed in Update 2006 Chen HL Residents around 12 municipal waste et al., 2006 incinerators in Taiwan—prevalence of physician-diagnosed diabetes with TEQs for serum TCDD/Fs in logistic model adjusted for age, sex, smoking, BMI 29 2.4 (0.2–31.9) Baccarelli Children residing in Seveso at time of et al., 2005b incident—development of diabetes 101 with chloracne 1 nr 211 without chloracne 2 nr Studies Reviewed in Update 2004 Fierens Belgium residents (142 women, 115 men) et al., 2003 exposed to dioxins, PCBs Subjects in top decile for dioxins 5.1 (1.2–21.7) Studies Reviewed in Update 2002 Masley Population-based survey in Saskatchewan 28 nr et al., 2000 Studies Reviewed in Update 2000 Bertazzi Seveso residents—20-year follow-up et al., 2001 Zones A, B males — 6 0.8 (0.3–1.7) —females 20 1.7 (0.1–2.7) Cranmer Vertac/Hercules Superfund site residents (n et al., 2000b = 62)—OR for high insulin in nondiabetic subjects at various times, levels for TCDD > 15 ppt compared with persons with TCDD < 15 ppt Fasting (insulin > 4.5 μIU/mL) 3 8.5 (1.5–49.4) 30-min (insulin > 177 μIU/mL) 3 7.0 (1.3–39.0) 60-min (insulin > 228 μIU/mL) 4 12 (2.2–70.1) 120-min (insulin > 97.7 μIU/mL) 6 56 (5.7–556) Bertazzi Seveso residents—15-year follow-up et al., 1998b Zone A—females 2 1.8 (0.4–7.0) Zone B males — 6 1.2 (0.5–2.7) —females 13 1.8 (1.0–3.0) continued

580 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 9-3  Continued Estimated Relative Risk Reference Study Population Exposed Casesa (95% CI)a Pesatori Zone R males — 37 1.1 (0.8–1.6) et al., 1998b —females 74 1.2 (1.0–1.6) ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) preopionic acid; AFHS, Air Force Health Study; AHS, Agricultural Health Study; BMI, body mass index; CDC, Centers for Disease Control and Preven- tion; CI, confidence interval; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HpCDD, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin; HxCDD, 1,2,3,6,7,9-hexachlorodibenzo-p-dioxin; IU, international unit; NHANES, National Health and Nutrition Examination Survey; NIOSH, Na- tional Institute for Occupation Safety and Health; nr, not reported; ns, not significant; OCDD, 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCP, pentachlorophenol; SEA, Southeast Asia; TCDD, 2,3,7,8- tetrachlorodibenzo-p-dioxin; TCDD/Fs, dioxins and furans combined; TCDF, tetrachlorodibenzo- furan; TCP, trichlorophenol; TEF, toxicity equivalency factor; TEQ, total equivalent quotient; VES, Vietnam Experience Study. aGiven when available; results other than estimated risk explained individually. bStudy is discussed in greater detail in Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (IOM, 2000). cIncludes some subjects covered in other references cited in the category occupational cohorts. Studies in italics have been superseded by newer studies of same cohort. p < 0.001). The results were very similar in the strata expected to have a greater potential for high exposure and strongest when limited to subjects in the “high” group for both calendar time and number of spraying days (HR = 1.39, 95% CI 1.21–1.58). Occupational Studies Saldana and colleagues reported (2007) on the cross-sectional relationship between pesticide and herbicide exposure and a history of gestational diabetes in the AHS, a study of licensed pesticide applicators and their spouses who lived in Iowa and North Carolina. Women (n = 11,273) were asked about their health during their pregnancies closest to enrollment, and 506 (4.5%) reported gesta- tional diabetes. Exposure to 2,4,5-T and 2,4-D was assessed by questionnaire. Data on women exposed to 2,4-D and 2,4,5-T were shown only for 337 women with documented exposure during the first trimester of pregnancy and then only in graphic form. The figure provided indicates that self-reported 2,4-D exposure

OTHER HEALTH EFFECTS 581 was not associated with gestational diabetes but that 2,4,5-T exposure was asso- ciated after adjustment for BMI, mother’s age, parity, race, state and commonly used pesticides. Also in the AHS, Montgomery et al. (2008) reported on the relationship between pesticide and herbicide exposure and self-reported incident diabetes in 31,787 licensed pesticide applicators and their spouses. Physician-diagnosed incident diabetes (n = 1,176) was assessed during a follow-up by questionnaire. With adjustment for age, BMI, and state, neither the use of 2,4,5-T nor the use of 2,4-D was associated with the 5-year risk of diabetes (OR = 1.02, 95% CI 0.88–1.19; and OR = 0.92, 95% CI 0.79–1.06, respectively). Environmental Studies Consonni and colleagues (2008) reported on the 25-year mortality follow-up of persons exposed to dioxin accidentally in Seveso, Italy. Mortality experience was assessed relative to residence and intensity of exposure. Over the 25 years of follow-up, only three residents of the highest-exposed location died of diabetes mellitus (ICD-9 250). In comparison with nonexposed residents of surrounding localities, the estimated risk of diabetes mortality adjusted for sex, age, and pe- riod (5-year intervals for time of death) was significantly increased only in the most populated but least exposed zone (RR = 1.01, 95% CI 0.33–3.14; RR = 1.32, 95% CI 0.89–1.94; and RR = 1.26, 95% CI 1.08–1.47 for the highest-exposed, middle-exposed, and lowest-exposed zones, respectively). Several surveys of diabetes and diabetes-related metabolic changes in rela- tion to exposure to PCBs with dioxin-like activity have been published in the 2 years since Update 2006. Four studies analyzed NHANES data from 1999–2002. The NHANES data are based on a series of probability samples of the noninstitu- tionalized US population. In the 1999–2002 survey, dioxins, furans, and coplanar PCBs were measured in a random one-third sample of people at least 20 years old (n = 2,016). Lee DH et al. (2006) studied the association between blood concentrations of six persistent organic pollutants including two dioxin congeners (1,2,3,4,6,7,8- heptacholorodibenzo-p-dioxin [HpCDD] and 1,2,3,4,6,7,8,9-octachlorodibenzo- p-dioxin [OCDD]), selected from 49 assessed. The six chemicals were selected because at least 80% of the study subjects had concentrations more than the limit of detection of the analytic method. A history of diabetes was reported by 217 of the 2,016 subjects analysed in this study. The authors reported that there was no association between diabetes and TCDD, but no statistics were presented because TCDD concentrations were above the limit of detection for only 7% of the population studied. The prevalence of diabetes was high in those who had HpCDD at or above the 90th percentile (26%) compared with those who did not have detectable HpCDD (4.6%). The adjusted prevalence OR was 2.7 (95% CI 1.3–5.5) and the test of trend for a dose–response relationship was significant (p = 0.007). A similar finding was reported for OCDD although the test for trend

582 VETERANS AND AGENT ORANGE: UPDATE 2008 was not statistically significant (p = 0.094). However, association with diabetes was not specific to dioxin-like compounds inasmuch as the four non–dioxin-like organic pollutants assessed (PCB-153, oxychlorodane, p,p′-dichlorodiphenyltri- chloroethane [DDT], and trans-nonachlor) were all more strongly related to the prevalence of diabetes than either OCDD or HpCDD. Everett et al. (2007) reported on the association between hexachlorodibenzo- p-dioxin, PCB-126, and p,p′-dichlorodiphenyltrichloroethane (DDT). PCB-126 has dioxin-like activity, but DDT does not. Serum concentrations were related to diagnosed and undiagnosed diabetes (based on a reading of hemoglobin A1c [HbA1c] over 6.1%). Lipid-adjusted concentrations of all three chemicals were associated with diagnosed diabetes, and PCB-126 and DDT were associated with undiagnosed diabetes. In a multivariate analysis in which all three substances were included to predict total diabetes, PCB-126 and DDT remained significantly associated. Uemura et al. (2008a) assessed the association between exposure to per- sistent organic pollutants and the prevalence of diabetes in a survey of 1,274 Japanese adults 15–73 years old. Participants were required to have lived in their area for at least 10 years and not to have a known occupational exposure to dioxins. Participants were volunteers recruited through a mass-media campaign in the sample areas. The authors used the measurements of 29 pollutants with dioxin-like activity to calculate a dioxin TEQ that weights the concentration of a substance by the relative strength of its dioxin-like activity. There was a strong association between total dioxin TEQs and the prevalence of diabetes (OR = 3.81, 95% CI 1.56–10.1) after adjustment for age, sex, the log of BMI, region, residential area, and survey year. The association was stronger for dioxin-like PCBs (OR = 6.82, 95% CI 2.59–20.1) than for PCDDs and PCDFs (OR = 2.21, 95% CI 1.02–5.04) although the population was exposed to a higher dioxin TEQ from PCDDs and PCDFs than from PCBs. Total dioxin TEQs was also correlated with HbA1c (r = 0.103; p < 0.001). Other Reviewed Studies Rather than investigating the occurrence of diabetes itself, several additional studies addressed association of serum concentrations of persistent environmental pollutants to two indicators of increased diabetes risk: insulin resistance (Chen JW et al., 2008; Lee DH et al., 2007b) and the metabolic syndrome (Lee DH et al., 2007c). The reporting with respect to dioxin-like chemicals in several other studies of diabetes (Codru et al., 2007; Karouna-Renier et al., 2007; Wang et al., 2008) did not meet the threshold for the committee’s evidentiary database. The results of these studies were not entered in the results table for diabetes (Table 9-3), but the committee did considered them as supportive information. Insulin resistance was assessed in 749 nondiabetic participants by using a homeostasis-model assessment of insulin resistance (HOMA-IR) that is based on

OTHER HEALTH EFFECTS 583 fasting glucose and insulin measurements (Lee DH et al., 2007b). The pollutant analysis was restricted to 19 substances that were above the assay limit of detec- tion in at least 60% of the samples. Individual pollutants were combined on the basis of chemical class: three polychlorinated dibenzo-p-dioxins (PCDDs), three polychlorinated dibenzofurans (PCDFs), four dioxin-like PCBs, five non–dioxin- like PCBs, and four organochlorine (OC) pesticides. After adjustment for age, sex, race, and economic status, there was an association between HOMA-IR and PCDDs (p = 0.05) and OC pesticides (p < 0.01) but not the other three classes of compounds. Adjustment for body composition, smoking, exercise, and alcohol consumption reduced the association between HOMA-IR and PCDDs substan- tially (p = 0.25). Further analysis in which HOMA-IR was dichotomized into high and low showed that very high exposures to all the chemical classes except for OC pesticides were associated with a very high HOMA-IR; none of the associa- tions was statistically significant. The metabolic syndrome is a collection of metabolic changes, including increased waist circumference, blood pressure, serum triglyceride, and fasting glucose and reduced serum high-density lipoprotein cholesterol. People who have three or more of those abnormalities are said to have the metabolic syndrome, which is associated with the risk of diabetes and CVD. Lee DH et al. (2007c) found that dioxin-like PCBs, non–dioxin-like PCBs, and OC pesticides were as- sociated with the metabolic syndrome, but PCDDs and PCDFs were not. Chen JW et al. (2008) assessed the relationship between concentrations of 29 PCDDs, PCDFs, and PCBs and insulin sensitivity in 40 pregnant women from a contaminated part of Tainan City, Taiwan. In their small sample, neither PCDD TEQs nor PCDF TEQs correlated with measures of insulin sensitivity. PCB TEQs correlated inversely with insulin sensitivity (r = -0.42; p = 0.009). Of the 12 PCBs examined, only the dioxin-like PCBs-123, -126, and -169 were associated with both measures of insulin sensitivity—HOMA-IR and the quantitative insulin sensitivity check index. Dioxins and furans were among the soil contaminants at a Superfund site in Pensacola, Florida, resulting from operations at a wood-treating company that was in operation from 1942 to 1982. In 2000, Karouna-Renier et al. (2007) gathered health and exposure histories and measured serum concentrations of 17 PCDD and PCDF congeners in 47 potentially exposed people. The study sample was selected in a nonsystematic fashion from among former workers, their families, and residents. Logistic analysis of the prevalence of several health problems in terms of toxicity equivalents (TEQs) with adjustment for age, race, sex, BMI, tobacco and alcohol use, and worker status permitted investigation of dose–response relationships. No significant association was found between ex- posure to the chemicals in question and the occurrence of diabetes (statistics not provided), defined by self-report, use of prescribed mediation, or serum glucose greater than 126 mg/dL. Codru et al. (2007) report on the association between hexachlorobenzene,

584 VETERANS AND AGENT ORANGE: UPDATE 2008 PCB-153, PCB-74, and DDE and diabetes in a cross-sectional sample of 352 adult Americans Indians. The serum concentrations of all four chemicals were as- sociated with the prevalence of diabetes, although none has dioxin-like activity. Wang et al. (2008) reported on the 24-year follow-up of the Yucheng cohort in Taiwan. The cohort was exposed to high concentrations of PCBs and PCDFs (some congeners of both have dioxin-like activity) through contaminated rice oil. Cohort members were matched to a nonexposed referent population matched on age, sex, and neighborhood. In men, there was no association between being in the Yucheng cohort and diabetes risk. Women in the Yucheng cohort had over twice the odds of developing diabetes. The study also contrasted the lifetime prevalence of several medical conditions on the basis of whether the Yucheng cohort members had a history of chloracne. The risk of diabetes was higher in men (OR = 1.7, 95% CI 0.7–4.6) and in women (OR = 5.5, 95% CI 2.3–13.4) who had chloracne than in cohort members who had not had chloracne; the risks in those with chloracne compared with the referent population would be more extreme. The results of the study were not reported in terms of dioxin-like activ- ity, so they do not directly contribute to the evidence considered for Vietnam veterans; however, in light of the well-known association between chloracne and AHR activation and dioxin-like activity, they are consistent with an association between exposure to the chemicals of interest and diabetes. Biologic Plausibility The toxicity of TCDD in laboratory animals has been historically linked with body-weight loss through inhibition of gluconeogenesis and increased lipid metabolism. Despite alterations in those key metabolic processes, diabetes has not been reported in TCDD-exposed rodents. Several biologic mechanisms that have been studied in cell culture and ani- mal models may explain the potential diabetogenic effects of TCDD in humans. TCDD is known to alter glucose and lipid metabolism in animal models (Dalton et al., 2001), to modify expression of genes related to insulin transport and sig- naling pathways in human adipose tissue (Fujiyoshi et al., 2006), and to produce oxidative stress at high concentrations (Kern et al., 2002; Matsumura, 2003). The present committee’s literature review included several new studies that had increased mechanistic biologic plausibility. Sato et al. (2008) found that exposure of mice to dioxin resulted in significant changes in genes that are expressed in the liver and code for cholesterol biosynthesis, lipogenesis, and glucose metabolism. Dabir et al. (2008) found that glucose stimulates AHR signaling pathways associ- ated with the expression of thrombospondon-1, which is associated with athero- sclerosis. Arsenescu et al. (2008) found that the dioxin-like PCB-77 increased body weight in C57BL/6 ApoE mice, altered serum lipid profiles, and increased atherosclerosis. Those investigators found that PCB-77 in vitro stimulated the release of inflammatory cytokines and adipokines and increased the maturation of

OTHER HEALTH EFFECTS 585 3T3-L1 adipocytes. Thus, numerous mechanisms associated with insulin signal- ing, glucose, and lipid metabolism may be under the influence of the AHR and can be modulated by TCDD. Many of them are also risk factors for hypertension and ischemic heart disease. Synthesis A large number of relevant studies have been published since Update 2006. Michalek and Pavuk (2008) updated a series of reports on the AFHS. Their work is important because of its direct relevance to Vietnam veterans, its longitudinal design, and the dose–response analyses included. The primary dose–response analysis is related to categories of putative exposure based on serum TCDD measured in 1987. In this analysis, Ranch Hand veterans with higher circulating concentrations clearly are at higher risk. About 19% of potentially eligible Ranch Hand veterans were not included in the study, including some 10% who were excluded because of nonparticipation in the follow-up examinations. Hypotheti- cally, if Ranch Hand veterans who had diabetes and high exposure were more likely to participate in the follow-up examinations than those in the SEA veteran comparison group, the association between Agent Orange exposure and TCDD would be overestimated. Such a bias could also generate spurious evidence on a dose–response relationship. The concern is mitigated by the inclusion of alterna- tive analyses of the diabetes risk of Ranch Hand veterans based on calendar year of service and days of spraying. Differential-selection effects would be less likely in such an internal comparison. From the publication, it can be calculated that the risk of diabetes was 19.8% (130 of 657 in Ranch Hand veterans who served in 1969 or before) compared with 13.8% (50 of 363) in those who served after 1969. Similarly, the risk of diabetes was 18.7% (170 of 909) in those exposed to 90 days or more of spraying compared with 9.0% (10 of 111) in those exposed less than 90 days. The authors did not calculate adjusted RRs, but both unadjusted RRs are statistically significant (1.4 and 2.1, respectively; p < 0.05). Consonni et al. (2008) updated previous analyses of findings from Seveso, Italy. The data provide some evidence of an excess of diabetes deaths in Seveso residents, but the residents in the most intensely exposed zone did not have higher mortality than the reference population; however, diabetes is a relatively unusual cause of death, and few such deaths were reported in the small population of the high-exposure zone. An analysis of gestational diabetes in the wives of pesticide applicators in the AHS cohort (Saldana et al., 2007) found evidence of significantly increased risks among women who were exposed to 2,4,5-T or to 2,4,5-T during the first trimester of pregnancy, but these finding were based on only three and two exposed cases, respectively. With ten exposed cases, exposure to 2,4-D during this period had a neutral risk of gestational diabetes, whereas the risk associated with exposure to the related herbicide, dicamba, approached significance (seven

586 VETERANS AND AGENT ORANGE: UPDATE 2008 exposed cases). (The estimated risks and confidence intervals in this paper were only presented graphically, so precise statistics cannot be presented.) Neither 2,4,5-T nor 2,4-D was associated with incident diabetes in a 5-year follow-up of the entire AHS cohort (Montgomery et al., 2008). The confidence intervals are narrow; this indicates good precision for ruling out all but the most modest increases in risk. However, exposure estimates are based on questionnaire results, so exposure misclassification could lead to estimates biased toward no effect. There were a number of surveys of blood concentrations of various persistent organic pollutants that have dioxin-like activity and the prevalence of diabetes or related metabolic derangements (such as insulin resistance and the metabolic syndrome). The series of papers from NHANES (Everett et al., 2007; Lee DH et al., 2006, 2007b,c) show that prevalent diabetes is associated with at least some substances that have dioxin-like activity. However, the effect is nonspecific in that several pollutants with and without dioxin-like activity are associated with diabetes. That suggests that there is something about the diabetic phenotype that is associated with either greater accumulation or slower elimination of fat-soluble organic pollutants. BMI, a measure of adiposity, is associated with a longer PCDD elimination half-life and is also a strong risk factor for diabetes. Because those studies are cross-sectional, the temporal relationship between pollutant con- centrations and diabetes cannot be determined. However, TCDD was not related to either insulin resistance or the metabolic syndrome as would be expected if dioxin caused diabetes (Lee DH et al., 2007b,c). The statistical analyses of the NHANES data did not weight exposures according to the extent of their dioxin- like activity (TEQ). If that had been done, and if the associations with diabetes had been stronger, this would have helped to address the specificity issue. The Japanese survey (Ueruma et al., 2008a,b) used TEQs to analyze data and found a strong overall association with diabetes prevalence. The data are not en- tirely consistent with the hypothesis that dioxin increases diabetes risk, inasmuch as the association was seen strongly for TEQs from PCBs, but not TEQs from PCDDs even though the population was exposed to more TEQs from PCDDs. The strong and preferential cross-sectional association between PCBs with dioxin-like activity and diabetes or insulin resistance was seen in several other studies (Chen et al., 2008; Everett et al., 2007; Lee DH et al., 2007b), and thus suggests a basis for the association other than a dioxin-mediated mechanism. In the aggregate, the newly added studies do not counter previous findings with respect to the association between exposure and diabetes risk. The new data suggest that the herbicides 2,4,5-T and 2,4-D are not important contributors to diabetes risk. The new data are broadly consistent with the view that PCDDs may increase diabetes risk. The new longitudinal data reviewed represent updates of previously considered studies and therefore cannot be considered to be com- pletely new. Thus, the new studies are not sufficient to merit a stronger conclusion with respect to the association.

OTHER HEALTH EFFECTS 587 Conclusion On the basis of the 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 chemical of interest and diabetes. LIPID AND LIPOPROTEIN DISORDERS Concentrations of plasma lipid—notably cholesterol—have been shown to predict CVD and are considered fundamental to the underlying atherosclerotic process (Roberts, 2000). Cholesterol and triglycerides, the two major types of lipids, are carried in the blood attached to proteins to form lipoproteins, which are classified by density. Very-low-density lipoprotein (VLDL, the major tri- glyceride particle) is produced in the liver and is progressively catabolized (hy- drolyzed), mainly by an insulin-stimulated enzyme (lipoprotein lipase), to form intermediate-density lipoprotein (IDL), or VLDL remnants. Most of the VLDL remnants are rapidly cleared by low-density lipoprotein (LDL) receptors (types B and E) in the liver, and the rest form LDL, the major “bad cholesterol.” LDL is cleared by LDL receptors in the liver and other tissues. High-density lipoprotein (HDL), the “good cholesterol,” is produced in the small intestine and liver. It also results from the catabolism of VLDL. LDL is involved in the delivery of choles- terol to the tissues, and HDL is involved in “reverse” transport and facilitates the return of cholesterol to the liver for biliary excretion (Vergès, 2005). Disorders of lipoprotein metabolism usually result from overproduction or decreased clearance of lipoproteins or both. Common examples are hyper- cholesterolemia, which can be familial (because of an LDL-receptor genetic defect) or polygenic (because of multiple minor genetic susceptibilities); famil- ial hypertriglyceridemia (sometimes linked to susceptibility to diabetes); and mixed hyperlipidemias, in which both cholesterol and triglycerides are high. The mixed hyperlipidemias include familial combined hyperlipidemia, which could result from hepatic overproduction of VLDL and apoprotein B, and type III dyslipidemia, which involves defective clearance of IDL and VLDL remnants and a buildup of these atherogenic particles. Although the bulk of blood lipid concentration is genetically determined, diet, activity, and other factors (such as concurrent illness, use of drugs, age, sex, and hormones) have major effects. In particular, the saturated-fat content of the diet might raise LDL concentrations through decreased LDL-receptor activity; obesity and a high-carbohydrate diet can increase VLDL and possibly are linked to insulin resistance and reduced lipoprotein lipase activity. Diabetes mellitus and the metabolic syndrome are associated with increased triglycerides and decreased HDL. Other diseases (thy- roid and renal disorders) often result in hypercholesterolemia. It is evident that multiple host and environmental factors influence lipid and lipoprotein concen- trations and must be considered before the effect of a new factor can be assessed

588 VETERANS AND AGENT ORANGE: UPDATE 2008 (Verges, 2005). Any analysis should control for obesity as a primary determinant of triglyceride and TCDD concentrations. Finally, the ability of chronic diseases to raise triglycerides, glucose, and LDL or to lower HDL must be recognized. Table 9-2 presents statistics on the 2006 US prevalence of readings in the ranges that define various lipid disorders. Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of concern and lipid and lipoprotein disorders. Ad- ditional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclusion. Table 9-4 provides a summary of relevant studies that have been reviewed. Update of the Epidemiologic Literature No Vietnam-veteran or occupational studies concerning exposure to the chemicals of interest and lipid and lipoprotein disorders have been published since Update 2006. Environmental Studies Two environmental studies relevant to lipid and lipoprotein disorders have been published since Update 2006. Uemura et al. (2008b) examined metabolic and dietary correlates of serum concentrations of persistent organic pollutants in a survey of 1,274 Japanese adults 15–73 years old. The authors used the measurements of 29 pollutants with dioxin-like activity to calculate a dioxin TEQ weighs the concentration of a substance by the relative strength of its dioxin-like activity. After adjustment for BMI alanine aminotransferase, creatinine, meat and egg consumption, fish and shellfish consumption, green-yellow vegetable consumption, and cigarette- smoking—and parity and breastfeeding status for women—there was a weak association between dioxin TEQs and log-triglyceride concentrations in men and a moderately strong association with total cholesterol concentrations in women. Using data from the NHANES, Lee DH et al. (2007c) studied the association between blood concentrations of 19 persistent organic pollutants (of 49 assessed by the survey) and components of the metabolic syndrome, including increased triglyceride concentrations and low HDL-cholesterol concentrations. The 19 ana- lytes were selected because at least 60% of the study subjects had concentrations of them that were greater than the limits of detection of the analytic method. After adjustment for age, sex, race, income, cigarette-smoking, serum cotinine, alcohol

OTHER HEALTH EFFECTS 589 TABLE 9-4  Selected Epidemiologic Studies—Lipid and Lipoprotein Disorders Exposed Estimated Relative Reference Study Population Casesa Risk (95% CI)a VIETNAM VETERANS Studies Reviewed in Update 2006 AFHS, Air Force Ranch Hand veterans (2002 exam data) 762 2005 Model 3: low + high TCDD exposure vs comparisons Cholesterol reduced, p = 0.039 Model 1: Ranch Hand vs comparisons Triglycerides increased in enlisted groundcrew, p = 0.034 Model 3: low + high TCDD exposure vs comparisons Triglycerides increased, p = 0.001 Model 4: Ranch Hand subjects’ 1987 serum TCDD concentrations Triglycerides increased, p = 0.02 Studies Reviewed in Update 2000 AFHS, Air Force Ranch Hand veterans (1997 exam data) 858 2000 Cholesterol ns Triglycerides ns Studies Reviewed in Update 1998 AFHS, Air Force Ranch Hand veterans (1992 exam data)— 1996 change over time, Ranch Hand vs comparison group 884 Cholesterol (cholesterol:LDL ratio) ns Triglycerides ns HDL cholesterol (cholesterol:HDL ratio) ns O’Toole Australian Vietnam veterans compared with et al., 1996 Australian population 20 Cholesterol 3.0 (1.3–4.7) Studies Reviewed in VAO AFHS, Air Force Ranch Hand veterans (1987 exam data)— 1991 Ranch Hands subjects with “high” lipid values 283–304 Serum-dioxin levels over lipid groups Cholesterol p = 0.175 Triglycerides p < 0.001 HDL cholesterol p < 0.001 AFHS, Air Force Ranch Hand veterans (1987 exam data) 1990 Model 1: Ranch Hand vs comparisons Cholesterol 1.2 (0.9–1.5) Triglycerides 1.3 (0.9–1.8) HDL cholesterol 1.0 (0.4–2.4) continued

590 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 9-4  Continued Exposed Estimated Relative Reference Study Population Casesa Risk (95% CI)a AFHS, Air Force Ranch Hand veterans (1982 exam data) 1984; Wolfe Model 1: Ranch Hand vs comparisons 1,027 et al., 1990 Cholesterol ns Triglycerides ns HDL cholesterol ns OCCUPATIONAL Studies Reviewed in Update 2004 Hu et al., Workers exposed to PCDD/Fs in Taipei City— 2003 above median vs below median 133 Total cholesterol 2.8 (1.0–7.9) Triglycerides 1.5 (0.5–4.3) Pelclová Workers exposed to TCDD in Spolana, Czech et al., 2002 Republic 12  Maximum value (1968–2001) vs 1966 serum Correlation TCDD level coefficient Cholesterol r = 0.78, p = 0.01 Triglycerides r = 0.66, p = 0.02 Studies Reviewed in Update 2002 Kitamura Workers exposed to PCDDs—hyperlipidemia 8 6.1, p = 0.02 et al., 2000 Studies Reviewed in Update 1998 Calvert Workers exposed to 2,4,5-T derivatives vs matched et al., 1996 referents OR Abnormal total cholesterol Overall 95 1.1 (0.8–1.6) High TCDD 18 1.0 (0.5–1.7) Abnormal HDL cholesterol Overall 46 1.2 (0.7–2.1) High TCDD 16 2.2 (1.1–4.7) Abnormal mean total; HDL cholesterol ratio Overall 131 1.1 (0.8–1.6) High TCDD 36 1.5 (0.8–2.7) Abnormal mean triglyceride Overall 20 1.0 (0.5–2.0) High TCDD 7 1.7 (0.6–4.6) Ott and Production workers exposed to TCDD 42 Zober, 1996 Cholesterol nsb Triglycerides nsb HDL cholesterol Increased; p = 0.05 Studies Reviewed in VAO Martin, Production workers exposed to TCDD vs controls 1984 No chloracne 53 Cholesterol Increased; p < 0.005 Triglycerides Increased; p < 0.005

OTHER HEALTH EFFECTS 591 TABLE 9-4  Continued Exposed Estimated Relative Reference Study Population Casesa Risk (95% CI)a HDL cholesterol ns With chloracne 39 Cholesterol Increased; p < 0.05 Triglycerides Increased; p < 0.01 HDL cholesterol ns Moses TCP and 2,4,5-T production workers—those who et al., 1984 developed chloracne vs those who did not 118 Cholesterol ns Triglycerides ns Suskind and TCP production workers Hertzberg, Cholesterol 204 ns 1984 Triglycerides ns HDL cholesterol ns May, 1982 TCP production workers 94 Cholesterol ns Triglycerides ns Pazderova- TCP, 2,4,5-T production workers 55 Vejlupkova Cholesterol ns et al., 1981 Triglycerides Increased VLDL; p = 0.01 ENVIRONMENTAL New Studies Uemura Survey of Japanese Adults—regression of log regression et al., 2008b measured lipid with log of total dioxins (pg TEQ) coefficients Men Cholesterol 0.08 (p = 0.47) HDL cholesterol 0.04 (p = 0.68) Triglycerides 0.09 (p = 0.04) Women Cholesterol 0.39 (p < 0.01) HDL cholesterol –0.13 (p = 0.18) Triglycerides –0.05 (p = 0.32) Lee DH NHANES cross-sectional survey of persistent et al., 2007c organic pollutants (≥ 75th percentile vs < 25th percentile) HDL (< 1.1 mmol/L in men or < 1.4 mmol/L in women) PCDDs 0.8 (0.5–1.5) PCDFs 0.9 (0.5–1.5) Dioxin-like PCBs 1.1 (0.6–2.1) Triglycerides (≥ 1.7 mmol/L) PCDDs 1.0 (0.6–1.8) PCDFs 0.7 (0.4–1.2) Dioxin-like PCBs 2.0 (1.1–3.9) continued

592 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 9-4  Continued Exposed Estimated Relative Reference Study Population Casesa Risk (95% CI)a Studies Reviewed in VAO Assennato Seveso Zone A adult subjects, chloracne 193 et al., 1989a Cholesterol ns Triglycerides ns Mocarelli Children exposed near Seveso 63 et al., 1986 Cholesterol ns Triglycerides ns ABBREVIATIONS: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; CI, confidence interval; HDL, high- density lipoprotein; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Ex- amination Survey; ns, not significant; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDD/F, dioxins and furans combined; PCDF, polychlorinated d ­ ibenzofuran; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; TEQ, toxicity equivalent quotient; VLDL, very-low-density lipoprotein. aGiven when available; results other than estimated risk explained individually. use, and exercise, HDL levels were not found to be associated with dioxin-like PCBs, PCDDs, or PCDFs; triglyceride concentrations were found to increase only with the levels of dioxin-like PCBs, but not PCDDs or PCDFs. Biologic Plausibility The induction of lipid mobilization and alterations in lipid metabolism are well-known effects of high-dose exposure to TCDD in laboratory animals that result in hyperlipidemia and loss of body fat. For example, Boverhof et al. (2005) found that exposure of mice to a single high dose of TCDD (30 µg/kg of body weight) increased serum triglycerides 1–7 days after exposure, and the increase was associated with changes in hepatic gene expression that were consistent with mobilization of peripheral fat. Similarly, Dalton et al. (2001) found that exposure of mice to a cumulative TCDD dose of 15 µg/kg over 3 days increased serum triglycerides and LDL that were measured 4 weeks after exposure. Increases in serum triglycerides have also been seen in TCDD-exposed rhesus monkeys (Rier et al., 2001). The mechanism underlying altered lipid metabolism has not been elucidated, but the high-dose studies in animal models provide some evidence of biologic plausibility that TCDD exposure can directly alter serum lipid and lipoprotein concentrations. Synthesis Previously reviewed literature showed inconsistent changes in serum lipids or lipoproteins after exposure to the chemicals of interest, and in most cases the sample sizes were insufficient to support any conclusions. The recently reviewed

OTHER HEALTH EFFECTS 593 relevant literature does not clarify the situation with respect to the effect of Agent Orange on lipid and lipoprotein levels. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is insufficient or inadequate evidence to determine whether there is an association between exposure to the chemicals of interest and lipid or lipoprotein disorders. GASTROINTESTINAL AND DIGESTIVE DISEASE, INCLUDING LIVER TOXICITY This section discusses a variety of conditions encompassed by ICD-9 520– 579: diseases of the esophagus, stomach, intestines, rectum, liver, and pancreas. Details on peptic ulcer and liver disease, the two conditions most often discussed in the literature reviewed, are provided below. The symptoms and signs of gastro- intestinal disease and liver toxicity are highly varied and often vague. The essential functions of the gastrointestinal tract are to absorb nutrients and eliminate waste. Those complex tasks involve numerous chemical and molecular interactions on the mucosal surface and complex local and distant neural and endocrine activity. One common condition of the gastrointestinal tract is motility disorder, which might be present in 15% of adults. The most convenient way to categorize diseases that affect the gastrointestinal system is according to the af- fected anatomic segment. Esophageal disorders predominantly affect swallowing; gastric disorders are related to acid secretion; and conditions that affect the small and large intestines are reflected in alterations in nutrition, mucosal integrity, and motility. Some systemic disorders (inflammatory, vascular, infectious, and neoplastic conditions) also affect the gastrointestinal system. Peptic-Ulcer Disease Peptic-ulcer disease refers to ulcerative disorders of the gastrointestinal tract that are caused by the action of acid and pepsin on the stomach or duodenal mu- cosa. Peptic-ulcer disease is characterized as gastric or duodenal ulcer, depending on the site of origin. Peptic-ulcer disease occurs when the corrosive action of gastric acid and pepsin overcomes the normal mucosal defense mechanisms that protect against ulceration. About 10% of the population have clinical evidence of duodenal ulcer at some period in life; a similar percentage are affected by gastric ulcer. The incidence of duodenal ulcer peaks in the 5th decade, and the incidence of gastric ulcer about 10 years later. Evidence increasingly indicates that the bacterium Helicobacter pylori is linked to peptic-ulcer disease (both duodenal and gastric). H. pylori colonizes the gastric mucosa in 95–100% of patients with duodenal ulcer and in 75–80%

594 VETERANS AND AGENT ORANGE: UPDATE 2008 of patients with gastric ulcer. Healthy subjects in the United States under 30 years old have gastric colonization rates of about 10%. Over the age of 60 years, colonization rates exceed 60%. Colonization alone, however, is not sufficient for the development of ulcer disease; only 15–20% of subjects with H. pylori colo- nization will develop ulcers in their lifetimes. Other risk factors include genetic predisposition (such as some blood and HLA [human leukocyte antigen] types), cigarette-smoking, and psychologic factors (chronic anxiety and stress). Liver Disease Blood tests that reflect liver function are the mainstay of diagnosis of liver disease. Increases in serum bilirubin and in the serum concentrations of some hepatic enzymes—aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and γ-glutamyltransferase (GGT)—are commonly noted in liver disorders. The relative sensitivity and specificity of those enzymes for diagnos- ing liver disease vary, and diagnosis can require several tests. The only regularly reported abnormality in liver function associated with TCDD exposure in humans is an increase in GGT. Estimated serum activity of that enzyme is a sensitive indicator of a variety of conditions, including alcohol and drug hepatotoxicity, infiltrative lesions of the liver, parenchymal liver disease, and biliary tract ob- struction. Increases are noted after many chemical and drug exposures that are not followed by evidence of liver injury. The confounding effects of alcohol use (often associated with increased GGT) make interpretation of changes in GGT in exposed people difficult (Calvert et al., 1992). An increase in GGT can be consid- ered a normal biologic adaptation to chemical, drug, or hormone exposure. Cirrhosis is the most commonly reported liver disease in epidemiologic studies of herbicide or TCDD exposure. Cirrhosis is irreversible chronic injury of the liver with extensive scarring and resulting loss of liver function. Clinical symptoms and signs include jaundice, edema, abnormalities in blood clotting, and metabolic disturbances. Cirrhosis can lead to portal hypertension with associ- ated gastroesophageal varices, enlarged spleen, abdominal swelling attributable to ascites, and ultimately hepatic encephalopathy that can progress to coma. It generally is impossible to distinguish the various causes of cirrhosis by using clinical signs and symptoms or pathologic characteristics. The most common cause of cirrhosis in North America and many parts of western Europe and South America is excessive alcohol consumption. Other causes are chronic viral infection (hepatitis B or hepatitis C), the poorly understood condition primary biliary cirrhosis, chronic right-sided heart failure, and a variety of less common metabolic and drug-related conditions. Conclusions from VAO and Previous Updates Studies that have been reviewed by previous committees have consisted of those focusing on liver enzymes and others that have reported specific liver

OTHER HEALTH EFFECTS 595 diseases. Evaluation of the effect of herbicide and TCDD exposure on noncancer gastrointestinal ailments is challenging in that clinical experience suggests that medical history and physical examination are undependable diagnostic tools for some ailments, so incidence data are sometimes problematic. The strong interde- pendence among the characteristics of a given person (such as weight and labora- tory indexes of hepatic function and health) and TCDD body burden complicates the already difficult task of assessing association. Most of the analyses of occupational or environmental cohorts have had insufficient numbers of cases to support confident conclusions. The International Agency for Research on Cancer cohort of phenoxy herbicide and chlorophe- nol production workers and sprayers (Vena et al., 1998), the only study with a relatively large number of observations, found less digestive system disease and cirrhosis mortality in exposed workers than in nonexposed controls. A study comparing Australian veterans to the general population (O’Toole et al., 1996) suggested a higher incidence of stomach and duodenal ulcers in both men and women, but the information was self-reported and the analyses were not con- trolled for confounding influences. A report from the AFHS (2000) found a significantly higher percentage of other liver disorders in the Ranch Hand veterans in the high-dioxin category than in the SEA comparison subjects. The excesses were primarily of transaminase and other nonspecific liver abnormalities. Data were consistent with an interpretation of a dose–response relationship, but other explanations were also plausible. Stud- ies continue to report some abnormalities in liver enzymes in the Ranch Hand cohort (AFHS, 2005) including decreasing C4 complement as dioxin increased. Abnormal triglyceride concentrations increased as the 1987 dioxin concentration increased. A study of Vietnam veterans reported in Update 2006 found an increased rate of hepatitis associated with Vietnam service but not with a history of spraying herbicide (Kang et al., 2006). Likewise, the Australian Vietnam-veterans study (ADVA, 2005b) did not find an increase in liver disease in military personnel who served in Vietnam compared with the general population of Australia. Mortality studies of the Ranch Hand cohort have not found increased mortality related to gastrointestinal or liver disease (Ketchum and Michalek, 2005). The reports to date have been inconsistent, and interpretation of individual studies is difficult because of a lack of information on alcohol consumption and other risk factors. In the studies that showed the strongest association between potential exposure and gastrointestinal disease (specifically cirrhosis), there was strong evidence that excess alcohol consumption was the cause of the cirrhosis. The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and gastrointestinal and digestive disease, including liver toxicity. Additional information available to the committees re- sponsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclusion.

596 VETERANS AND AGENT ORANGE: UPDATE 2008 Update of the Epidemiologic Literature No Vietnam-veteran or occupational studies addressing gastrointestinal dis- orders have been published since Update 2006. Environmental Studies Consonni et al. (2008) reported on mortality in the cohort exposed to high environmental TCDD contamination in Seveso, Italy, starting in 1976 and fol- lowed up through 2001. The study cohort of 273,108 subjects who were resident at the time of the incident or immigrated or were born in the 10 years thereafter were analyzed according to three zones with increasing soil TCDD. In the overall sample, no statistically significant increases in deaths related to digestive diseases (ICD-9 520–579) were observed. In Zone A (highest TCDD contamination), five deaths from digestive disease were observed (RR = 0.72, 95% CI 0.30–1.74); the middle-contamination zone had 45 deaths from digestive disease (RR = 0.99, 95% CI 0.74–1.33); and the lowest-contamination zone had 366 deaths from digestive disease (RR = 1.11, 95% CI 1.00–1.24). The analysis of the subset of deaths related to cirrhosis did not find any statistically significant associations. Karouna-Renier et al. (2007) gathered health and exposure histories from 47 potentially exposed people at a dioxin- and furan-contaminated Superfund site in Pensacola, Florida. Serum concentrations of 17 PCDD and PCDF congeners were measured. Analysis of covariance was used to assess the relationship between TEQ and several measures of liver function (alanine amino transferase, aspartate amino transferase, and GGT) with adjustment for age, sex, BMI, and alcohol use. No significant associations were found (statistics were not provided). Biologic Plausibility The liver is a primary target for the toxicity of many chemicals. It is the first organ that encounters chemicals absorbed from the gastrointestinal tract and is re- sponsible for metabolizing them to water-soluble chemicals that can be excreted in the urine. Because the liver has many detoxifying enzymes that efficiently me- tabolize many chemicals, liver toxicity is usually associated only with high-dose acute exposure or chronic exposure to lower doses. The liver can be damaged if metabolism of a chemical results in the production of a reactive intermediate that is more toxic than the parent chemical. Changes in serum concentrations of liver enzymes are biomarkers for liver toxicity, and their magnitude correlates with the degree of liver damage. Exposure of laboratory animals to high doses of 2,4-D, 2,4,5-T, and TCDD is known to cause liver damage. The mechanisms by which the phenoxy herbicides damage the liver is based on inhibition of mitochondrial function by blocking of oxidative phosphorylation; this leads to loss of generation of adenosine triphosphate, and death of cells, and hepatic necrosis and fibrosis.

OTHER HEALTH EFFECTS 597 TCDD-induced hepatotoxicity is mediated by activation of the AHR, which leads to changes in gene transcription and associated changes in cell function. Changes in gene expression are associated with several physiologic processes, oxidative stress, and apoptosis (Boverhof et al., 2005, 2006). Histopathology of the liver after high doses of TCDD shows the development of a fatty liver associated with mobilization of peripheral fat and increased uptake of fatty acids in the liver. Exposure of rats to lower doses of TCDD over a 2-year period (NTP, 2004) also produced several changes in the liver, including hepatocyte hypertrophy, multinucleated hepatocytes, inflammation, pigmentation, diffuse fatty change, necrosis, bile duct hyperplasia, bile duct cyst, nodular hyperplasia, portal fibrosis, and cholangiofibrosis. Few health-relevant effects of phenoxy herbicides or TCDD on the gastro- intestinal tract, even after high levels of exposure, have been reported. Thus, the animal data do not support a plausible link between herbicide exposure and gastrointestinal toxicity in Vietnam veterans. Synthesis There is no evidence that Vietnam veterans are at greatly increased risk for serious liver disease, and reports of increased risk of abnormal liver-function tests have been mixed. Although increased rates of gastrointestinal disease have not been reported, the possibility of a relationship between dioxin exposure and subtle alterations in the liver and in lipid metabolism cannot be ruled out. Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and gastrointestinal and digestive diseases. CIRCULATORY DISORDERS This section covers a variety of conditions encompassed by ICD-9 390–459, such as acute and chronic rheumatic fever (ICD-9 390–398), hypertension (ICD-9 401–404), ischemic heart disease (ICD-9 410–414), heart failure (ICD-9 428), cerebrovascular disease (ICD-9 430–438), and peripheral vascular disease (ICD-9 443). Coronary heart disease is a specific term related to atherosclerosis; isch- emic heart disease is a broader term and typically includes atherosclerosis and its symptoms. The American Heart Association reports mortality related to coronary heart disease, not to its symptoms, which include angina and myocardial infarc- tion. Table 9-2 contains estimates of prevalence of and mortality from individual disorders of the circulatory system in the US population in 2006.

598 VETERANS AND AGENT ORANGE: UPDATE 2008 The methods used in morbidity studies can involve the direct assessment of the circulatory system, including analysis of symptoms or history, physical exam- ination of the heart and peripheral arteries, Doppler measurements of peripheral pulses, electrocardiography (ECG), and chest radiography. Doppler measure- ments and physical examination of pulses in the arms and legs are used to detect decreases in pulse strength, which can be caused by thickening and hardening of the arteries. ECG can be used to detect heart conditions and abnormalities, such as arrhythmias (abnormal heart rhythms), heart enlargement, and heart attacks. Chest radiography can be used to assess the consequences of ischemic heart disease and hypertension, such as the enlargement of the heart seen with heart failure. However, clinical testing is often nonspecific; various medical conditions can yield similar test results. It is also sometimes difficult to determine the time of onset of clinical findings, so the temporal relationship between exposure and disease occurrence may be uncertain. Cardiovascular-disease epidemiologists prefer to observe cohorts over time for the incidence of discrete clinical events, such as an acute myocardial infarction (ideally verified on the basis of changes in ECG readings and enzyme concentrations) and death due to heart disease. The onset of new angina symptoms or the performance of a revascularization proce- dure in a person without a history of disease is also used as evidence of incident disease. In many occupational studies, only mortality information is available. The attribution of death to a vascular cause is often based on a death certificate, whose accuracy can be uncertain. Conclusions from VAO and Previous Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and circulatory disorders. Additional infor- mation available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. The committee responsible for Update 2006 reviewed both new studies and intensively revisited all the studies related to ischemic heart disease and hyper- tension that had been discussed in previous updates and concluded that there is limited or suggestive evidence to support an association between exposure to the herbicides used in Vietnam and hypertension. That committee was unable to reach a consensus as to whether that was also the case for ischemic heart disease, however, so that outcome remained in the category of inadequate evidence. The previous studies and studies published since Update 2006 are all summarized in Table 9-5.

TABLE 9-5  Selected Epidemiologic Studies—Circulatory Disorders Exposed Estimated Relative Risk Referencea Study Populationb Casesc (95% CI)c Comments Studies of Vietnam Veterans Studies of US Vietnam veterans Kang et al., 2006 Army Chemical Corps—morbidity Diagnoses not confirmed by and supplemental medical record review. data Vietnam veterans vs nonVietnam veterans Hypertension requiring medication 496 1.06 (0.89–1.27) Adjusted for age, race, rank, Heart disease diagnosed by physician 243 1.09 (0.87–1.38) BMI, and smoking. Sprayers vs nonsprayers Serum TCDD levels were All (diabetics, nondiabetics) measured in a subset of Hypertension requiring medication 247 1.26 (1.00–1.58) subjects, and those self- Heart disease diagnosed by physician 129 1.41 (1.06–1.89) reported to have been sprayers did have significantly higher All veterans, contribution of spraying to logistic concentrations than others. regression model Therefore, the sprayer All (diabetics, nondiabetics) category is regarded as a Hypertension requiring medication 1.32 (1.08–1.61) valid surrogate for elevated Heart disease diagnosed by physician 1.52 (1.18–1.94) exposure. Non-diabetics only Hypertension requiring medication 1.23 (0.99–1.52) Heart disease diagnosed by physician 1.52 (1.14–2.01) Controlling for diabetic status Hypertension requiring medication 1.27 (1.04–1.55) Heart disease diagnosed by physician 1.45 (1.13–1.86) 599 continued

TABLE 9-5  Continued 600 Exposed Estimated Relative Risk Referencea Study Populationb Casesc (95% CI)c Comments Thomas and Kang, Army Chemical Corps vs US male 1990 population—mortality Circulatory diseases (ICD 390–458) 6 0.55 Not adjusted for known risk factors. AFHS, 2005 Air Force Health Study, 2002 exam cycle (1,951 [Largely supersedes participants)—morbidity AFHS, 1984, 1987, [results largely supersede those of 1982, 1985, 1990, 1992, 1995, 1987, 1997, and 1997 exams cycles] 2000] Number in analysis Model 1: RH subjects vs SEA comparisons (also available separately for officer, enlisted flyer, enlisted groundcrew) 1,885 Essential hypertension 412 of 759 0.92 (0.53–1.13) All analyses adjusted for age, 1,902 Heart disease (except essential hypertension) 644 of 767 1.20 (0.94–1.54) race, rank, smoking, alcohol 308 Enlisted flyer 120 of 131 2.46 (1.19–5.11) history, HDL, cholesterol, 1,902 Myocardial infarction 77 of 767 0.81 (0.59–1.12) cholesterol HDL ratio, 1,902 Stroke or transient ischemic attack 29 of 767 1.39 (0.82–2.34) uric acid, diabetes, BMI or percent body fat, waist-hip Model 2: RH subjects with extrapolated initial Relative risk for 2-fold increase ratio, family history of heart serum TCDD (> 10 ppt in 1987) in serum TCDD disease. 406 Essential hypertension 244 1.12 (0.91–1.37) 411 Heart disease (except essential hypertension) 344 1.08 (0.85–1.38) 411 Myocardial infarction 42 1.31 (0.97–1.77) 411 Stroke or transient ischemic attack 17 1.26 (0.78–2.03)

Model 3: All subjects with serum TCDD readings (RH group vs comparisons) 1,344 Essential hypertension Comparison 644 1.0 RH background (< 10 ppt, 1987) 168 0.88 (0.67–1.16) RH low (10–118 ppt, initial) 109 0.74 (0.53–1.04) RH high (> 118 ppt, initial) 135 1.32 (0.94–1.87) 1,355 Heart disease (except essential hypertension) Comparison 937 1.0 RH background (< 10 ppt, 1987) 299 1.33 (0.94–1.89) RH low (10–118 ppt, initial) 171 1.03 (0.68–1.54) RH high (> 118 ppt, initial) 173 1.21 (0.81–1.82) 1,355 Myocardial infarction Comparison 132 1.0 RH background (< 10 ppt, 1987) 34 0.81 (0.53–1.25) RH low (10–118 ppt, initial) 18 0.60 (0.34–1.04) RH high (> 118 ppt, initial) 24 1.04 (0.63–1.74) 1,355 Stroke or transient ischemic attack Comparison 36 1.0 RH background (< 10 ppt, 1987) 12 1.21 (0.59–2.45) RH low (10–118 ppt, initial) 7 1.10 (0.47–2.57) RH high (> 118 ppt, initial) 10 2.16 (0.98–4.77) Model 4: RH subjects with 1987 serum TCDD Relative risk for 2-fold increase readings in serum TCDD 748 Essential hypertension 1.11 (0.98–1.25) 755 Heart disease (except essential hypertension) 0.90 (0.78–1.06) 755 Myocardial infarction 1.03 (0.85–1.24) 755 Stroke or transient ischemic attack 1.04 (0.76–1.44) 601 continued

TABLE 9-5  Continued 602 Exposed Estimated Relative Risk Referencea Study Populationb Casesc (95% CI)c Comments Ketchum and Air Force Health Study—circulatory Michalek, 2005 disease—mortality [Supersedes Ranch Hand subjects vs all SEA veterans 66 1.3 (1.0–1.6) Not adjusted for known risk Michalek et al., Pilots and navigators 18 1.1 (0.7–1.8) factors. 1990, 1998] Administrative officers 2 1.8 (0.4–7.8) Enlisted flight engineers 6 0.5 (0.2–1.1) Ground crew 40 1.7 (1.2–2.4) Atherosclerosis 28 1.7 (1.1–2.5) Hypertensive disease 2 2.5 (0.6–10.8) Stroke 5 2.3 (0.9–6.0) Subjects with serum TCDD measures Adjusted for smoking and SEA comparison group 31 1.0 family history of heart disease. Background (0.6–10.0 ppt) 8 0.8 (0.4–1.8) Low (10.0–29.2 ppt) 12 1.8 (0.9–3.5) High (18.0–617.8 ppt) 9 1.5 (0.7–3.3) Cypel and Kang, Female US Vietnam-era veterans—mortality 2008—new study (through 2004) [Supersedes Circulatory system diseases Thomas et al., Vietnam vs non-SEA veterans 129 0.8 (0.6–1.0) Adjusted for duration of 1991; Dalager Nurses only 102 0.8 (0.6–1.0) service, year of birth, race. et al., 1995] Watanabe and US Army and Marine Corps Vietnam-era Kang, 1996 veterans—mortality (PMR, 1965–1988) Served in Vietnam vs never-deployed to SEA Circulatory diseases (ICD-8 390–458) Army 5,756 0.97 (p > 0.05) Not adjusted for known risk Marine Corps 1,048 0.92 (p < 0.05) factors.

Bullman and Kang, US wounded Vietnam veterans vs US men— 1996 mortality (through 1981, focus on suicide) Circulatory disease 246 0.72 (0.55–0.91) Boehmer et al., CDC Vietnam Experience Study—mortality 2004 Deployed vs nondeployed Circulatory disease 185 1.01 (0.82–1.24) Year of death 1970–1984 nr 0.56 (0.28–1.15) Adjusted for age, race, 1985–2000 (partition at 1970 arbitrary) nr 1.06 (0.85–1.32) military occupation. Discharged before 1970 nr 0.83 (0.62–1.12) Discharged after 1970 125 1.43 (1.02–1.99) Ischemic heart diseases 8 0–15 years since discharge 117 0.77 (0.31–1.55) > 15 years since discharge 1.14 (0.87–1.50) CDC, 1988 CDC Vietnam Experience Study—morbidity Deployed vs nondeployed Hypertension after discharge Interviewed 2,013 1.3 (p < 0.05) Not adjusted for known risk Examined 623 1.2 (p < 0.05) factors. Stellman et al., American Legionnaires serving during Vietnam 1988 era—morbidity Service in SEA vs not, with medically diagnosed High blood pressure 592 1.12 (p > 0.05) Not age adjusted. Heart disease 97 1.45 (p < 0.05) Age adjusted. 603 continued

TABLE 9-5  Continued 604 Exposed Estimated Relative Risk Referencea Study Populationb Casesc (95% CI)c Comments Anderson et al., Wisconsin Vietnam veterans—all diseases of 1986 circulatory system—mortality White male Vietnam veterans vs 100 National population 0.69 (p < 0.05) State population 0.62 (p < 0.05) Nonveterans 0.58 (p < 0.05) All veterans 0.86 (p > 0.05) Vietnam-era veterans 0.99 (0.80–1.20) Kogan and Clapp, Massachusetts Vietnam-era veterans (1958– 1985 1973)—mortality (1972–1983) Deployed vs nondeployed Deaths 1972–1983 Circulatory system (except cerebrovascular) 139 PMR = 0.88 (p > 0.05) Not adjusted for age; Vietnam Cerebrovascular 28 PMR = 1.11 (p > 0.05) veterans thought to be younger. Deaths 1978–1983 Circulatory system (except cerebrovascular) 85 PMR = 0.80 (p < 0.05) Expected less “diluted” effect Cerebrovascular 19 PMR = 1.64 (p < 0.05) for later time. Studies of Australian Vietnam veterans ADVA, 2005b Australian Vietnam veterans vs general male population—mortality Circulatory disease 1,767 0.88 (0.84–0.92) Pattern of increasing risks 1963–1979 186 0.69 (0.59–0.79) with time could perhaps 1980–1990 546 0.88 (0.80–0.95) indicate dissipation of healthy 1991–2001 1,035 0.93 (0.87–0.99) warrior effect.

Ischemic heart disease 1,297 0.94 (0.89–0.99) 1963–1979 124 0.70 (0.58–0.82) 1980–1990 421 0.95 (0.86–1.04) 1991–2001 753 0.99 (0.92–1.06) Stroke 223 0.80 (0.70–0.91) 1963–1979 35 0.81 (0.54–1.07) 1980–1990 59 0.73 (0.54–0.92) 1991–2001 129 0.83 (0.69–0.97) ADVA, 2005c Australian National Service veterans—deployed vs nondeployed—mortality Circulatory disease 208 1.05 (0.87–1.27) Ischemic heart disease 159 1.18 (0.94–1.47) Stroke 15 0.61 (0.30–1.15) Crane et al., 1997a Australian Vietnam veterans—mortality [largely superseded (1980–1994) by ADVA, 2005b] Circulatory disease 0.96 (0.88–1.05) Not adjusted for known risk Ischemic heart disease 1.04 (0.94–1.14) factors. Cerebral hemorrhage 0.80 (0.53–1.22) Crane et al., 1997b Australian National Service Vietnam-era [largely superseded veterans—mortality (1982–1994) by ADVA, 2005c] Deployed vs nondeployed Circulatory disease 77 0.95 (0.70–1.28) Not adjusted for known risk Ischemic heart disease 57 0.97 (0.68–1.39) factors. Cerebral hemorrhage 3 0.96 (0.14–5.66) Other 17 0.88 (0.44–1.69) 605 continued

TABLE 9-5  Continued 606 Exposed Estimated Relative Risk Referencea Study Populationb Casesc (95% CI)c Comments O’Toole et al., 1996 Australian male Army Vietnam veterans (random sample)—morbidity Self-report in telephone interview 99% CIs Adjusted for non-response, Hypertension nr 2.17 (1.71–2.62) but not adjusted for known Heart disease nr 1.98 (0.91–3.05) risk factors. Other circulatory diseases (excluding above and hemorrhoids) nr 2.39 (1.61–3.17) Kim JS et al., 2003 Korean veterans of Vietnam—morbidity Concerns of selection bias, quality of diagnosis, low Deployed vs nondeployed (unadjusted) participation. Gross pooling Valvular heart disease 8 p = 0.0019 of blood samples made TCDD Congestive heart failure 5 p = 0.5018 concentrations useless. Ischemic heart disease 34 p = 0.0045 Hypertension 383 p = 0.0143  Adjusted for age, smoking, alcohol, BMI, education, and marital status 2.29 (1.33–3.95) Occupational Studies Pelclová et al., 2,4,5-T production workers at Spolana plant in 2007—new study Czech Republic 1965–1968—vascular function measured by microvascular reactivity in response to 15 Reactivity lower in workers Concerns about selection bias flow-mediated or thermal hyperemia compared to controls (p < 0.05) and the role of comorbidity. McLean et al., 2006 IARC cohort of pulp and paper workers— circulatory disease—mortality Never exposed to nonvolatile organochlorines 2,727 0.92 (0.89–0.96) Not adjusted for known risk Ever exposed to nonvolatile organochlorines 2,157 0.99 (0.95–1.04) factors.

Blair et al., 2005 US Agricultural Health Study—mortality Adjusted for age, race, state, Private applicators (farmers), spouses sex, and calendar year of Circulatory disease (1994–2000) 619 0.5 (0.5–0.6) death. ’t Mannetje et al., New Zealand phenoxy herbicide Not adjusted for known risk 2005 workers—mortality factors. [IARC subcohort] Producers (1969–2000) Circulatory disease 51 1.0 (0.7–1.3) All-causes SMR = 1.0 Hypertensive disease 0 0.0 (0.0–3.5) (0.8–1.2). Ischemic heart disease 38 1.0 (0.7–1.4) Sprayers (1973–2000) Circulatory disease 33 0.5 (0.4–0.7) All-causes SMR = 0.6 Hypertensive disease 1 0.8 (0.0–4.5) (0.5–0.8). Ischemic heart disease 22 0.5 (0.3–0.8) Vena et al., 1998 IARC cohort of phenoxy herbicide workers— [same dataset as mortality (1939–1992) Kogevinas et al., All male phenoxy herbicide workers 1997 (emphasis on All circulatory disease (ICD 390–459) 1,738 0.91 (0.87–0.95) Not adjusted for known risk cancer) reviewed in Ischemic heart disease (ICD 410–414) 1,179 0.92 (0.87–0.98) factors. Update 1998] Cerebrovascular disease (ICD 430–438) 254 0.86 (0.76–0.97) Other diseases of heart (ICD 415–429) 166 1.11 (0.95–1.29) All female phenoxy herbicide workers All circulatory disease (ICD 390–459) 48 1.00 (0.73–1.32) Ischemic heart disease (ICD 410–414) 24 1.07 (0.68–1.59) Cerebrovascular disease (ICD 430–438) 9 0.73 (0.33–1.38) Other diseases of heart (ICD 415–429) 6 0.92 (0.34–2.00) Workers with phenoxy herbicide exposure only All circulatory disease (ICD 390–459) 588 0.86 (0.79–0.93) Ischemic heart disease (ICD 410–414) 394 0.85 (0.77–0.94) 607 continued

TABLE 9-5  Continued 608 Exposed Estimated Relative Risk Referencea Study Populationb Casesc (95% CI)c Comments Cerebrovascular disease (ICD 430–438) 96 0.86 (0.70–1.05) Other diseases of heart (ICD 415–429) 32 0.80 (0.55–1.13) TCDD-exposed workers All circulatory disease (ICD 390–459) 1,170 0.94 (0.88–0.99) Ischemic heart disease (ICD 410–414) 789 0.97 (0.90–1.04) Cerebrovascular disease (ICD 430–438) 162 0.84 (0.71–0.98) Other diseases of heart (ICD 415–429) 138 1.20 (1.01–1.42) Contribution of TCDD exposure to Poisson regression analysis All circulatory disease 1,151 1.51 (1.17–1.96) Adjusted for age, timing of Ischemic heart disease 775 1.67 (1.23–2.26) exposure. Cerebrovascular disease 161 1.54 (0.83–2.88) Hooiveld et al., Dutch herbicide factory workers (IARC 1998 subcohort)—mortality (1955–1991) 549 exposed vs 482 nonexposed male workers All circulatory diseases (ICD 390–459) 45 1.4 (0.8–2.5) Adjusted for age, timing of TCDD > 124 ng/kg nr 1.5 (0.8–2.9) exposure. Ischemic heart diseases (ICD 410–414) 33 1.8 (0.9–3.6) TCDD > 124 ng/kg nr 2.3 (1.0–5.0) Cerebrovascular diseases (ICD 430–438) 9 1.4 (0.4–5.1) TCDD > 124 ng/kg nr 0.8 (0.2–4.1) Other heart disease (ICD 415–429) 3 0.7 (0.1–4.3) TCDD > 124 ng/kg nr 0.4 (0.0–4.9)

Flesch-Janys et al., Hamburg, Germany herbicide production Gas workers provide a more 1995 workers (IARC subcohort) vs gas workers— appropriate comparison group mortality (1952–1992; estimated blood PCDD, for the data on production PCDF, TCDD from work history, measures on 190 workers than the national of 1,189 men, divided into four lowest quintiles, top population data used in the two deciles) analysis in Flesch-Janys, 1997/1998; Flesch-Janys et al., 1998. Estimated final PCDD, PCDF TEQs (ng/kg) Circulatory disease (ICD 390–459) 156 1.0–12.2 0.93 (0.57–1.50) Not adjusted for known risk 12.3–39.5 0.92 (0.59–1.46) factors. 39.6–98.9 1.48 (1.01–2.17) 99.0–278.5 1.55 (1.07–2.24) 278.6–545.0 1.63 (1.01–2.64) 545.1–4361.9 2.06 (1.23–3.45) p-trend < 0.01 Potential for exposure misclassification. Ischemic heart disease (ICD 410–414) 76 1.0–12.2 1.02 (0.54–1.95) 12.3–39.5 0.96 (0.51–1.82) 39.6–98.9 0.97 (0.52–1.81) 99.0–278.5 1.13 (0.64–2.00) 278.6–545.0 1.73 (0.92–3.27) 545.1–4361.9 2.72 (1.49–4.98) p-trend < 0.01 609 continued

TABLE 9-5  Continued 610 Exposed Estimated Relative Risk Referencea Study Populationb Casesc (95% CI)c Comments Estimated final TCDD (ng/kg) Circulatory disease (ICD 390–459) 156 0–2.8 1.22 (0.81–1.83) 2.81–14.4 0.88 (0.54–1.44) 14.5–49.2 1.35 (0.91–2.01) 49.3–156.7 1.64 (1.12–2.39) 156.8–344.6 1.53 (0.95–2.44) 344.7–3890.2 1.96 (1.15–3.34) p-trend = 0.01 Ischemic heart disease (ICD 410–414) 76 0–2.8 1.43 (0.83–2.44) 2.81–14.4 0.81 (0.41–1.61) 14.5–49.2 1.18 (0.65–2.16) 49.3–156.7 0.90 (0.47–1.75) 156.8–344.6 1.61 (0.85–3.04) 344.7–3890.2 2.48 (1.32–4.66) p-trend < 0.01 Becher et al., 1996 Phenoxy herbicide workers at four German [mortality plants (four IARC subcohorts, including through 1992 for Hamburg)—mortality (through 1989) Hamburg plant Circulatory diseases (ICD 390–458) reported above by Bayer Uerdingen 12 0.74 (0.38–1.30) Flesch-Janys] Bayer Dormagen 3 0.34 (0.07–0.99) BASF Ludwigshafen 32 0.78 (0.53–1.10)

Coggon et al., 1991 British Chemical Manufacturers at four plants (four IARC subcohorts)—mortality Circulatory disease 74 1.16 (0.91–1.46) Plant A (1975–1987) 34 1.67 (adjusted = 1.39, p ≈ 0.05) Plant B (1969–1987) 5 0.95 Plant C (1963–1987) 12 0.84 Plant D (1969–1987) 23 0.97 Coggon et al., 1986 British MCPA manufacturers (5th of seven UK IARC cohorts)—mortality Hypertensive, ischemic heart disease (ICD 401–414, 428–429) 337 vs national rates 0.81 (0.73–0.90) with rural adjustment 0.86 (0.77–0.96) US cohorts in NIOSH cohort (also in IARC cohort) Burns et al., 2001 Dow 2,4-D production workers—mortality [part of IARC & (1945–1994) NIOSH cohorts] Circulatory disease 0 years latency 158 0.95 (0.80–1.11) Not adjusted for known risk ≥ 20 years latency 130 1.05 (0.87–1.24) factors. Ramlow et al., Dow PCP workers (1930–1980) (subcohort)— 1996 mortality (1940–1989) Circulatory diseases (ICD 390–458) 115 0.95 (0.79–1.14) Arteriosclerotic heart disease (ICD 410–414) 86 1.02 (0.82–1.26) Cerebrovascular disease (ICD 430–438) 15 1.02 (0.57–1.68) 611 continued

TABLE 9-5  Continued 612 Exposed Estimated Relative Risk Referencea Study Populationb Casesc (95% CI)c Comments Steenland et al., NIOSH cohort (subcohorts of IARC cohort at 12 1999 US plants)—mortality (through 1993) Total cohort (5,132) vs US population Cerebrovascular disease (ICD 430–438) 69 0.96 (0.74–1.21) Not adjusted for known risk Ischemic heart disease (ICD 410–414) 456 1.09 (1.00–1.20) factors. Chloracne subcohort (608) vs US population 92 1.17 (0.94–1.44) Exposure subcohort (3,538) < 19 cumulative TCDD nr 1.0 Adjusted for age. 19–139 nr 1.23 (0.75–2.00) 139–580 nr 1.34 (0.83–2.18) No units given for exposure 581–1,649 nr 1.30 (0.79–2.13) derived from job–exposure 1,650–5,739 nr 1.39 (0.86–2.24) matrix. 5,740–20,199 nr 1.57 (0.96–2.56) ≥ 20,200 nr 1.75 (1.07–2.87) p-trend cumulative exposure = 0.05 p-trend log[cumulative exposure] < 0.001 Calvert et al., 1998 Two US chemical plants (part of NIOSH, IARC cohorts)—morbidity Verified conditions TCDD-exposed (281) vs nonexposed (260) Myocardial infarction 17 1.33 (0.62–2.84) Not adjusted for known risk Current systolic hypertension 64 1.05 (0.70–1.58) factors. Current diastolic hypertension 77 1.23 (0.83–1.82)

TCDD effect vs nonexposed in logistic model Self-reported and verified conditions combined Myocardial infarction Serum TCDD < 238 pg/g of lipid nr 1.14 (0.29–4.49) Adjusted for age, sex, BMI, Serum TCDD ≥ 238 pg/g of lipid nr 1.09 (0.23–5.06) smoking, drinking, diabetes, Hypertension triglycerides, total cholesterol, Serum TCDD < 238 pg/g of lipid nr 1.34 (0.89–2.02) HDL, family history of heart Serum TCDD ≥ 238 pg/g of lipid nr 1.05 (0.58–1.89) disease, and chemical plant. Verified conditions Current systolic hypertension Serum TCDD < 238 pg/g of lipid nr 1.09 (0.65–1.83) Serum TCDD ≥ 238 pg/g of lipid nr 1.20 (0.61–2.34) Current diastolic hypertension Serum TCDD < 238 pg/g of lipid nr 1.35 (0.88–2.09) Serum TCDD ≥ 238 pg/g of lipid nr 0.97 (0.51–1.87) Suskind and Monsanto workers at Nitro, West Hertzberg, 1984 Virginia—morbidity Workers exposed to 2,4,5-T production (204) vs nonexposed (163) (self-report) Hypertension 70 (p > 0.05) Adjusted for age. Coronary artery disease 22 (p > 0.05) Zack and Gaffey, Monsanto workers at Nitro, West Virginia 1983 (884)—mortality (1955–1977) Circulatory diseases (ICD 390–458) 92 1.11 (p > 0.05) Not adjusted for known risk Atherosclerosis and CHD (ICD 410–413) 79 1.33 (p < 0.05) factors. All other 13 0.56 (p < 0.05) 613 continued

TABLE 9-5  Continued 614 Exposed Estimated Relative Risk Referencea Study Populationb Casesc (95% CI)c Comments Zack and Suskind, Monsanto workers at Nitro, West Virginia— 1980 mortality (1955–1978) Workers with chloracne (121) Circulatory diseases (ICD 390–458) 17 0.68 (p > 0.05) Not adjusted for known risk Atherosclerosis and CHD (ICD 410–413) 13 0.73 (p > 0.05) factors. Swaen et al., 2004 Dutch licensed herbicide applicators—mortality [Supersedes Swaen (1980–2000) et al., 1992] Circulatory disease 70 0.68 (0.53–0.86) Ott and Zober, Cleanup workers at German TCP reactor 1996 (BASF)—mortality (1953–1992) [Supersedes Zober Circulatory diseases 37 0.8 (0.6–1.2) Reliability of estimated body et al., 1994 and < 0.1 estimated TCDD μg/kg bw 13 0.8 (0.4–1.4) burden is questionable. Von Benner et al., 0.1–0.99 11 1.0 (0.5–1.7) 1994 (translation ≥ 1.0 13 0.8 (0.4–1.3) from German)] Ischemic heart disease 16 0.7 (0.4–1.1) < 0.1 estimated TCDD μg/kg bw 7 0.9 (0.3–1.8) 0.1–0.99 4 0.7 (0.2–1.7) ≥ 1.0 5 0.6 (0.2–1.3) Other Occupational Studies Kitamura K et al., Municipal waste-incinerator workers—morbidity 2000 Hypertension by PCDD, PCDF 14 of 94 No increases observed Adjusted for age, BMI, and smoking.

Gambini et al., Italian rice growers—mortality (1957–1992) 1997 (Phenoxy herbicide use common 1960–1980) Myocardial infarction 67 0.72 (0.56–0.92) Other ischemic heart diseases 72 0.41 (0.32–0.52) Stroke 155 0.96 (0.81–1.12) Alavanja et al., US forest and soil conservationists—mortality 1989 PMRs Ischemic heart disease (ICD 410–414) 543 1.0 (0.9–1.1) Not adjusted for known risk Cerebrovascular disease (ICD 430–438) 99 0.9 (0.8–1.1) factors. Blair et al., 1983 Florida, US licensed pesticide applicators—mortality Circulatory diseases (ICD 390–458) 159 0.88 (p > 0.05) Not adjusted for known risk factors. Environmental Studies Consonni et al., Seveso, Italy—mortality—25 years (1976–2001) 2008—new study Zone A, sexes combined [Supersedes Betazzi All circulatory diseases (ICD 390–459) 45 1.1 (0.8–1.4) Adjusted for gender, age, et al., 1989a,b, Chronic rheumatic heart diseases (ICD 393–398) 3 5.7 (1.8–18.0) period. 1998, 2001; Hypertension (ICD 400–405) 5 2.2 (0.9–5.3) Pesatori et al., Ischemic heart diseases (ICD 410–414) 13 0.8 (0.5–1.4) 1998] Acute myocardial infarction (ICD 410) 6 0.6 (0.3–1.4)  Chronic ischemic heart diseases (ICD 412, 414) 7 1.1 (0.5–2.3) Cerebrovascular diseases (ICD 430–438) 11 0.9 (0.5–1.6) 615 continued

TABLE 9-5  Continued 616 Exposed Estimated Relative Risk Referencea Study Populationb Casesc (95% CI)c Comments Zone B, sexes combined All circulatory diseases (ICD 390–459) 289 1.0 (0.9–1.1) Chronic rheumatic heart diseases (ICD 393–398) 1 0.3 (0.0–2.2) Hypertension (ICD 400–405) 11 0.7 (0.4–1.3) Ischemic heart diseases (ICD 410–414) 102 1.0 (0.8–1.2) Acute myocardial infarction (ICD 410) 54 0.9 (0.7–1.1)  Chronic ischemic heart diseases (ICD 412, 414) 47 1.1 (0.8–1.4) Cerebrovascular diseases (ICD 430–438) 101 1.2 (1.0–1.5) Zone R, sexes combined All circulatory diseases (ICD 390–459) 2,357 1.1 (1.0–1.1) Chronic rheumatic heart diseases (ICD 393–398) 24 1.0 (0.6–1.5) Hypertension (ICD 400–405) 144 1.1 (1.0–1.4) Ischemic heart diseases (ICD 410–414) 842 1.1 (1.0–1.1) Acute myocardial infarction (ICD 410) 447 1.0 (0.9–1.1)  Chronic ischemic heart diseases (ICD 412, 414) 390 1.2 (1.0–1.3) Cerebrovascular diseases (ICD 430–438) 695 1.1 (1.0–1.2) Lee DH et al., NHANES, 1999–2002—721 nondiabetics ≥ 20 2007c—new study years old with fasting blood samples and measured ≥ 75th percentile vs those with POPs high blood pressure (≥ 130/85 mmHg) nr nondetectable levels PCDDs 1.7 (1.0­–3.1) Adjusted for age, race, sex, HxCDD 1.2 (0.7–2.2) income, cigarette-smoking, HpCDD 2.6 (1.3–5.0) serum cotinine, alcohol OCDD 1.1 (0.6–2.0) consumption, exercise.

PCDFs 1.9 (1.2–3.3) PtCDF 1.3 (0.7–2.4) HxCDF 2.3 (1.3–4.0) HpCDF 1.4 (0.8–2.3) Dioxin-like PCBs 1.4 (0.8–2.7) PCB-74 1.2 (0.6–2.4) PCB-118 1.8 (1.0–3.5) PCB-126 2.1 (1.2–3.7) PCB-169 0.6 (0.3–1.1) Everett et al., NHANES, 1999–2004—prevalent hypertension See text for determination 2008b—new study (self-report that told by doctor, ≥ 140/90 mmHg, of cutpoints or antihypertensive medications)—3,398–3,712 individuals depending on congener [supercedes Everett PCB-118 (ng/g of lipid) (TEF = 0.0001) et al., 2008a] ≤ 12.5 1.0 Adjusted for age, sex, > 12.5–27.5 1.4 (1.1–1.8) race, smoking status, BMI, > 27.5 2.0 (1.3–3.0) exercise, total cholesterol, PCB-126 (pg/g of lipid) (TEF = 0.1) family history of myocardial ≤ 26.1 1.0 infarction. 26.1–59.1 1.1 (0.9–1.4) > 59.1 1.8 (1.2–2.6) PCB-156 (ng/g of lipid) (TEF = 0.0005) ≤ 12.5 1.0 12.5–15.4 1.3 (0.9–1.9) > 15.4 1.2 (0.8–1.9) PCB-169 (pg/g of lipid) (TEF = 0.01) ≤ 27.0 1.0 27.0–46.4 1.1 (0.9–1.5) > 46.4 1.3 (0.9–1.9) 617 continued

TABLE 9-5  Continued 618 Exposed Estimated Relative Risk Referencea Study Populationb Casesc (95% CI)c Comments Ha et al., 2007— NHANES, 1999–2002—self-reported ≥ 75th percentile vs < 25th new study cardiovascular disease (excluding hypertension)— percentile 889 nondiabetics ≥ 40 years old Men HxCDD 18 2.5 (0.8–7.7) Adjusted for age, race, HpCDD 18 2.4 (0.5–10.3) income, BMI, cigarette- OCDD 16 2.1 (0.6–7.7) smoking, serum cotinine, PCDDs 23 2.2 (0.8–6.1) alcohol, exercise HDL, total PCDFs 19 0.7 (0.3–1.7) cholesterol, triglycerides Dioxin-like PCBs 22 1.7 (0.6–5.5) hypertension, C-reactive Women protein. HxCDD 21 2.8 (0.9–8.6) HpCDD 14 1.9 (0.3–10.8) OCDD 17 0.7 (0.2–2.8) PCDDs 19 2.0 (0.7–6.4) PCDFs 15 1.0 (0.3–2.8) Dioxin-like PCBs 23 5.0 (1.2–20.4) Karouna-Renier Superfund site caused by wood-treatment et al., 2007—new facility in Pensacola, Florida—47 workers, study residents—prevalence Hypertension defined by self-report, medication use, 1.1 (1.1–1.2) [error likely; Adjusted for age, race, sex, or two readings of systolic blood pressure greater published OR and lower BMI, tobacco and alcohol use, than 140 mmHg or diastolic blood pressure greater confidence limit identical to worker status. than 90 mmHg three decimal places] Serum PCDD/F (TEQs in logistic model)

Chen HL et al., Residents around 12 municipal waste 2006 incinerators in Taiwan—prevalence Hypertension diagnosed by a physician 118 5.6 (1.6–19.6) Adjusted for age, sex, Serum PCDD/F (TEQs in logistic model) 0.9 (0.2–3.7) smoking, BMI. ABBREVIATIONS: BMI, body mass index; CDC, Centers for Disease Control and Prevention; CHD, coronary heart disease; HDL, high-density lipoprotein; HpCDD, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin; HpCDF, 1,2,3,4,6,7,8-heptachlorodibenzofuran; HxCDD, 1,2,3,6,7,8-hexachlorodibenzo-p-dixion; HxCDF, 1,2,3,4,7,8-hexachlorodibenzofuran; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, 2-methyl- 4,chlorophenoxyacetic acid; NHANES, National Health and Nutrition Examination Survey; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; OCDD, 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin; PCDD/F, dioxins and furans combined; PCDF, polychlorinated dibenzofuran; PCP, pentachlorophenol; PMR, proportional mortality ratio; POP, persistent organic pollutant; PtCDF, 2,3,4,7,8-pentachlorodibenzofuran; RH, Ranch Hand; SEA, Southeast Asia; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorod- ibenzo-p-dixoin; TCP, trichlorophenol; TEF, toxicity equivalency factor for individual congener; TEQ, toxicity equivalent quotient. aNew citations labeled as such and bolded; section shaded for citations with dose-response information on TCDD.. bSubjects male unless otherwise noted. cGiven when available; results other than estimated risk explained individually. 619

620 VETERANS AND AGENT ORANGE: UPDATE 2008 Update of the Epidemiologic Literature The practice of evaluating the evidence on hypertension separately from that on other circulatory diseases, established in Update 2006, is continued in this update. Hypertension No Vietnam-veteran or occupational studies addressing hypertension have been published since Update 2006. Environmental Studies  Consonni and colleagues (2008) reported the 25-year mortality follow-up of people exposed to dioxin accidentally in Seveso, Italy. The area surrounding the point of release has been divided into Zones A, B, and R in descending order of soil contamination. For analysis, deaths were allocated to people’s zones of residence at the time of the incident. The aggregate experience of the residents was compared with that of residents of surrounding localities. The RRs for mortality from hypertension were 2.2 (95% CI 0.9–5.2), 0.7 (95% CI 0.4–1.3), and 1.2 (95% CI 1.0–1.4) for the zones ranked from highest to low- est exposure and adjusted for sex, age, and period (5-year intervals for time of death). Several papers reported on association between blood concentrations of organic pollutants and the prevalence of hypertension in the ongoing NHANES. The NHANES data are collected from probability samples of the noninstitution- alized US population. Lee DH et al. (2007c) studied the association between blood concentra- tions of dioxins, furans, and coplanar PCBs and components of the metabolic syndrome in a random one-third sample of people at least 20 years old from the 1999–2002 NHANES. The five defining components of the metabolic syndrome included high blood pressure (blood pressure above 135/85 mmHg or use of an- tihypertensive medication). Of the 49 persistent organic pollutants measured in the survey, the 19 analytes studied in detail were selected because at least 60% of the study subjects had concentrations of them greater than the limit of detection of the analytic method: three PCDDs, four dioxin-like PCBs, five non–dioxin- like PCBs, three PCDFs, and four organochlorine pesticides. Those who had combined concentrations of the three PCDDs at or above the 75th percentile had a 70% higher odds of having high blood pressure (OR = 1.7, 95% CI 1.0–3.1) than those who had combined concentrations below the 25th percentile after adjustment for age, sex, race, income, cigarette-smoking, serum cotinine, alco- hol consumption, and exercise. Those who had high concentrations of the three PCDFs also had a higher prevalence of high blood pressure (OR = 1.9, 95% CI 1.2–3.3), but those who had high concentrations of the four dioxin-like PCBs did not have significantly high blood pressure (OR = 1.4, 95% CI 0.8–2.7). When the

OTHER HEALTH EFFECTS 621 individual analytes were examined, only 1,2,3,4,6,7,8-HpCDD and 1,2,3,4,7,8- HxCDF were associated with high blood pressure (OR = 2.6, 95% CI 1.3–5.0 and OR = 2.3, 95% CI 1.3–4.0, respectively); other analytes of these classes with higher dioxin-like toxicity, 1,2,3,6,7,8-HxCDD and 1,2,3,4,7,8-HxCDF, were not so associated. Of the four PCBs with dioxin-like toxicity, high concentrations of only PC-118 and PCB-126 were associated with high blood pressure (OR = 1.8, 95% CI 1.0–3.5; OR = 2.1, 95% CI 1.2–3.7, respectively). There were no associa- tions between any of the five non–dioxin-like PCBs or four other organochlorine pesticides assessed and high blood pressure. The analytic approach makes the data difficult to interpret with respect to the effects of dioxin on blood pressure. The data were analyzed according to their distribution in the sample, not on the basis of measured concentrations. That makes null associations difficult to inter- pret because, for a given analyte, a reading in a high range of the distribution may still be too low to cause the outcome of interest; this is particularly relevant for assessing dioxin-like activity because the individual chemicals have estimates of dioxin-like activity (toxicity equivalency factors, TEFs) that range over several orders of magnitude. Everett et al. (2008a) also analyzed the data on people who were at least 20 years old from a one-third stratified subsample of the 1999–2002 NHANES. They focused on 11 PCBs and their relationships with hypertension defined on the basis of a physician diagnosis, the use of antihypertensive medications, or blood pres- sure above 140/90 mmHg. Of the 11 PCBs, four (PCB-169, PCB-126, PCB-118, and PCB-156) had dioxin-like toxicity. The distribution of serum concentrations of each PCB was partitioned into three ranges, of which the lowest was used as the referent group for those who had intermediate and high readings. The cutpoints for “high” concentrations were defined as concentrations that provided 95% sensitivity for identifying prevalent cases of hypertension. The explanation of how a cutpoint for “low” readings was determined is problematic in that it is said to have minimized both false positives and false negatives for hypertension, and this cannot be done simultaneously. In addition, selection of cutpoints that depends on the outcome measure could lead to invalid statistical inference by overstating statistical significance. Estimated ORs were adjusted for age, sex, race and ethnicity, smoking status, BMI, exercise, total cholesterol, and family history of heart attack. For the 1999–2002 NHANES data analyzed by Everett et al. (2008a), both intermediate and high concentrations of all four dioxin-like PCBs were associ- ated with prevalent hypertension, and the low concentrations were not, but the associations were statistically significant only for the high concentrations of PCB-126 (OR = 2.4, 95% CI 1.5–4.0) and PCB-118 (OR = 2.3; 95% CI 1.3–4.1). It should be noted that high concentrations of five of the seven PCBs that did not have dioxin-like activity were also found to be significantly associated with hypertension. The lack of specificity of the association suggests that there is a nonspecific PCB effect on hypertension rather than one linked specifically to

622 VETERANS AND AGENT ORANGE: UPDATE 2008 dioxin-like activity. A general PCB effect would not further our understanding of the health effects of Agent Orange because PCBs were not known contaminants of Agent Orange. Everett et al. (2008b) reported the results obtained when analyses using the methods described earlier (Everett et al., 2008a) were repeated to include an additional 2 years’ worth of data. In the committee’s evidence database, the more comprehensive results for the 6 years 1999–2004 (presented in Table 9-5) subsume those reported earlier, which are given in the text above for compari- son. The new findings did not show any great perturbations from the findings for 1999–2004, but the ORs for the higher concentrations of each congener tended to decrease slightly. The two of the four dioxin-like PCBs that had shown significant associations continued to show them; for five of the seven non–dioxin-like con- geners that had been significantly associated for the years 1999–2002, however, only one still was when the additional data were included. That reduces somewhat the concern expressed above regarding the findings for 1999–2002. Karouna-Renier et al. (2007) gathered health and exposure histories and measured serum concentrations of 17 PCDD and PCDF congeners in 47 people potentially exposed at a Superfund site in Pensacola, Florida, that was contami- nated with dioxins and furans. The study sample was selected in a nonsystematic fashion from among former workers, their families, and residents. Dose–response relationships were investigated with logistic analysis of the prevalence of several health problems in terms of TEQs and were adjusted for age, race, sex, BMI, to- bacco and alcohol use, and worker status. A significant association was reported between TEQ and hypertension (OR = 1.1, 95% CI 1.1–1.2 [an error is likely inasmuch as the published OR and lower confidence limit were identical to three decimal places]), defined by self-report, use of prescribed medication, or two readings of systolic blood pressure greater than 140 mmHg or diastolic blood pressure greater than 90 mmHg. Other Reviewed Studies  Wang et al. (2008) reported on the 24-year follow-up of the Yucheng cohort in Taiwan. The cohort was exposed to high concentrations of PCBs and PCDFs (some congeners of both have dioxin-like activity) through contaminated rice oil. A nonexposed referent population was matched on age, sex, and neighborhood. In both men and women, there was no association between being in the Yucheng cohort and having hypertension. The study also contrasted the lifetime prevalence of several medical conditions on the basis of whether the Yucheng cohort member had a history of choracne. The rate of hypertension was not higher in men (OR = 0.6, 95% CI 0.3–1.1) who had chloracne than in cohort members who did not but it was significantly higher in women who had chloracne than in women who did not (OR = 3.5, 95% CI 1.7–7.2); the rate in those who had chloracne vs the referent population would be more extreme. The results of the study were not reported in terms of dioxin-like activity, so they do not contribute directly to the evidence on Vietnam veterans; however, in light of the well-known

OTHER HEALTH EFFECTS 623 association between chloracne and AHR activation and dioxin-like activity, they are consistent with an association between exposure to the chemicals of interest and hypertension in women. Circulatory Diseases Vietnam-Veteran Studies  Cypel and Kang (2008) analyzed mortality patterns in female Vietnam-era veterans. They linked service files with the master death file from the Social Security Administration and the Department of Veterans Affairs Beneficiary Identification and Records Locator Subsystem to determine vital status as of December 31, 2004. Female veterans who served in Vietnam had lower mortality from circulatory system diseases than female veterans who did not serve in Vietnam after adjustment for duration of military service, age, and race (RR = 0.78, 95% CI 0.6–1.0). The authors considered the subset of veterans who were nurses on the basis of the premise that this group was likely to have been closer to the conflict than women with other job classifications. The results were unchanged when only the mortality experience of nurses was considered. They say little about the potential relationship between dioxin and vascular disease. Circulatory system diseases as an underlying cause of death make up heterogeneous collection of clinical entities with differing constellations of causes and clinical presentations. That heterogeneity may lead to the masking of important health effects if not all the disease entities are related to the exposure of interest. Furthermore, the fact of service in Vietnam says little about exposures to the chemicals of interest. Therefore, the findings cannot be considered to be either contradictory or confirmatory of the hypothesis that Agent Orange expo- sure increases the occurrence of a specific circulatory disease. Occupational Studies  Peclová and colleagues (2007) assessed vascular func- tion in men who were occupationally exposed to very high concentrations of TCDD while working in the Spolana plant in Noeratovice, Czech Republic, in 1965–1968. In 2004, the authors examined 15 of the exposed workers. Of the 15, nine had hypertension and five had a history of heart attack. The 15 workers were compared with 14 healthy male health-care workers who had no history of occupational exposure to TCDD. Compared with the controls, the exposed workers had lower skin microvascular reactivity in response to a flow-mediated or thermal stimulus. The data are difficult to interpret with respect to the health effects of TCDD. It is unclear how the case series was selected, so the degree to which the participants are representative of all still-living workers, especially with respect to chronic-disease burden, is unclear. Because the exposed group had a large number of metabolic and comorbid conditions of which the control group was largely free, the effects of disease could not be separated from the effects of TCDD. Finally, the relationship between microvascular reactivity and thermal reactivity and clinical cardiovascular events is unclear. Flow-mediated

624 VETERANS AND AGENT ORANGE: UPDATE 2008 reactivity of brachial arteries can predict clinical disease (Yeboah et al., 2007), but the predictive value of the particular measures used in this study has not been demonstrated. Environmental Studies  Ha et al. (2007) reported on the cross-sectional as- sociation between prevalent CVD and blood concentrations of PCDDs, PCDFs, dioxin-like PCBs, non–dioxin-like PCBs, and organochlorine pesticides in the 1999–2002 NHANES. Within these categories, they presented results on specific chemicals whose concentrations were above the analytic method’s lower detec- tion limit in at least 60% of the sample. For each substance, the prevalence of CVD in the lowest quartile was used as the referent for each of the higher quar- tiles. Participants were classified as having CVD if they reported a physician’s diagnosis of coronary heart disease, angina, heart attack, or stroke. Participants who had diabetes were excluded from the analysis. There were 108 cases of CVD in the 899 persons included in the analysis. Results were reported separately for men and women. In men, although the CVD risk for each quartile was elevated compared to the lowest for PCDDs, dioxin-like PCBs, and non-dioxin like PCBs, none of the associations was statistically significant. In women, for dioxin-like PCBs, non–dioxin-like PCBs, and organochlorine pesticides, the adjusted ORs contrasting the prevalence of CVD between those with serum concentrations in the top quartile and those in the lowest quartile were 5.0 (95% CI 1.2–20.4), 3.8 (95% CI 1.1–2.8), and 4.0 (95% CI 1.0–17.1), respectively, and there were sig- nificant trends over quartiles (p < 0.01, p = 0.02, and p = 0.03, respectively), but the CVD risk associated with the highest quartile of PCDD concentrations was not significant (OR = 2.0, 95% CI 0.7–6.4) and the PCDFs showed no elevation in risk. The authors also presented data on the three specific TCDDs that were used to form the composite TCDD score (1,2,3,6,7,8-HxCDD, 1,2,3,4,6,7,8-HpCDD, and 1,2,3,4,6,7,8,9-OCDD); in both men and women, there was a dose–response relationship between CVD prevalence and HxCDD (p = 0.04 for both sexes), but not HpCDD or OCDD. Individual PCBs were examined only in women; three of five dioxin-like PCBs, three of six non–dioxin-like PCBs, and three of four organochlorine pesticides showed dose–response associations with CVD prevalence. It is intriguing that the PCDD with the strongest dioxin activity was associated with CVD prevalence. However, as discussed above in reference to the articles by Lee DH et al. (2007c) and Everett et al. (2007), the lack of measured concentrations and the lack of specific effects diminish the value of the data in clarifying the role of Agent Orange in CVD risk. Consonni and colleagues (2008) reported several circulatory-mortality out- comes in their analysis of 25-year mortality in the Seveso cohort. In addition to hypertension deaths, they examined deaths from chronic rheumatic heart disease, ischemic heart disease, and cerebrovascular disease, all of which are in the ICD-9 rubric of circulatory disease. Compared with residents of surrounding localities, residents of the most highly exposed zone (Zone A) had increased mortality from

OTHER HEALTH EFFECTS 625 chronic rheumatic heart disease (RR = 5.7, 95% CI 1.8–18.0) but not from isch- emic heart disease (RR = 0.9, 95% CI 0.5–1.4) or cerebrovascular disease (pri- marily stroke; RR = 0.9, 95% CI 0.5–1.6). Residents of the intermediate-exposure zone (Zone B) showed only a borderline increase in cerebrovascular disease (RR = 1.2, 95% CI 1.0–1.5), and residents of the least exposed zone (Zone R) had an higher rate of cerebrovascular disease (RR = 1.1, 95% CI 1.0–1.2) and a borderline increase in the rate of ischemic heart disease (RR = 1.06, 95% CI 0.98–1.14). The authors examined mortality patterns by 5-year intervals after the accidental dioxin release, combining deaths from all circulatory diseases. The increase in risk in Zone A was restricted to the first 10 years of follow-up. For residents of Zone B, there was no postaccident interval in which risk was significantly increased. For residents of Zone R, all intervals showed an increase in risk except for the period 15–19 years after the incident but the associations were significant only in the periods 0–4 years and 10–14 years after the incident. However, the precision of the estimates is such that data are consistent with a small increase in risk in all study intervals. Goncharov et al. (2008) investigated associations of PCBs and pesticides with serum lipids and self-reported cardiovascular disease in 335 adult Akwesasne Mohawks. The authors used factor analysis to create a latent variable represent- ing PCB concentrations and found that it was related to CVD prevalence but that the association was confounded by age and either confounded by or mediated by serum lipid concentrations. The congeners examined included PCBs with and without dioxin-like activity, and all were associated to a similar extent with the latent variable. The detailed statistical modeling effort does not have direct utility in interpreting health risks associated with Agent Orange exposure. Other Reviewed Studies  Wang et al. (2008) reported on the 24-year follow-up of the Yucheng cohort in Taiwan. The cohort was exposed to high concentrations of PCBs and PCDFs (some congeners of both have dioxin-like activity) through contaminated rice oil. A nonexposed referent population was matched on age, sex, and neighborhood. In both men and women, there was no association be- tween being in the Yucheng cohort and having CVD. The study also contrasted the lifetime prevalence of several medical conditions on the basis of whether the Yucheng cohort members had a history of chloracne. The risk of CVD was not higher in men (OR = 0.9, 95% CI 0.4–2.2) who had chloracne than in co- hort members who did not, but it was significantly higher in women who had chloracne than in women who did not (OR = 3.0, 95% CI 1.5–8.6); the rate in women who had chloracne vs the referent population would be more extreme. The results of the study were not reported in terms of dioxin-like activity, so they do not contribute directly to the evidence on Vietnam veterans; however, in light of the well-known association between chloracne and AHR activation and dioxin-like activity, they are consistent with an association between exposure to the chemicals of interest and CVD in women.

626 VETERANS AND AGENT ORANGE: UPDATE 2008 Biologic Plausibility It is well established that the vasculature is a target of TCDD toxicity, which leads to significant increases in oxidative stress and induces major changes in expression of genes that regulate numerous signaling pathways (Puga et al., 2004). There is also growing evidence from a variety of experimental models that TCDD induces or promotes CVD in adult animals. For example, chronic ex- posure of the ApoE knockout mouse to TCDD increased the incidence, severity, and progression of atherosclerotic plaques (Dalton et al., 2001), and rats chroni- cally exposed to TCDD exhibited significant arterial remodeling characterized by endothelial-cell hypertrophy, extensive smooth-muscle cell proliferation, and inflammation (Jokinen et al., 2003). The rats also had dose-related increase in cardiomyopathy. Other studies have shown that TCDD exposure increased myo- cardial fibrosis (Riecke et al., 2002) and led to cardiac hypertrophy and alteration in control of heart rhythm (Lin et al., 2001; Thackaberry et al., 2005a,b). In one study, acute exposure of mice to a relatively high dose of TCDD significantly increased the release of vasoconstricting eicosanoids and induced hypertension (Dalton et al., 2001). Similarly, constitutive activation of the AHR results in disruption of cardiovascular homeostasis, as shown in expression of a consti- tutively active AHR in transgenic mice that develop an age-progressive cardiac hypertrophy (Brunnberg et al., 2006). The data show that activation of the AHR, endogenously or by xenobiotics, induces cardiovascular injury and leads to CVD in animal models. Recently, the role of the AHR in normal cardiovascular function in adult ani- mals has been established with studies of AHR-null mice. The animals develop hypertension, cardiac hypertrophy, and reduction in cardiac function with age; hence, the AHR has a role in cardiovascular function (Lund et al., 2003, 2005, 2006, 2008; Thackaberry et al., 2003; Vasquez et al., 2003). That both the sus- tained activation of the AHR by TCDD and the genetic deletion of the AHR result in cardiovascular disease suggests that the AHR acts to maintain the physiologic balance of the cardiovascular system and that either its excessive activation or its insufficient activation disrupts this homeostasis. An additional study in the literature reviewed supports the view that AHR activation may play a role in vascular disease and presumably in ischemic heart disease. The fact that the AHR appears to modulate blood pressure, depending on the partial pressure of oxygen (Lund et al., 2008), is evidence of the relevance of this process to the development of hypertension. Ichihara et al. (2007) found that AHR-null mice had greater vascular endothelial growth factor (VEGF) activity and angiogenesis than wild-type control C57BL/6 mice in a femoral-artery oc- clusion model. The theory is that the AHR binds to the AHR nuclear translocator (ARNT) protein and this leads to a decrease in the physiologic response to isch- emia and hypoxia and then to the induction of hypoxia-inducible factor 1-alpha, binding to ARNT, and activation of VEGF. Thus, there seems to be a consistent

OTHER HEALTH EFFECTS 627 effect of AHR and presumably of TCDD on signaling pathways that are known risk factors for ischemic heart disease. Direct evidence of a vascular effect of TCDD on liver endothelial cells and sinusoids was reported in primates 4 years after subcutaneous injection of TCDD (Korenaga et al., 2007); there was no mention of cardiovascular effects. The committee believes that the risk factors for ischemic heart disease make it difficult to separate the antiangiogenic effects of TCDD from the glucose and lipid metabolic effects that lead to an increase in atherosclerosis, a known risk factor for ischemic heart disease. TCDD and the related PCB-77 were found to increase adipocyte differentiation and adipokine production in 3T3-L1 adipocytes (Arsenescu et al., 2008); the investigators also found that AHR-null mice and ApoE-null C57/BL/6 mice demonstrated an increase in body weight, serum dyslipidemia, and augmented atherosclerosis. In human vascular endo- thelial cells, Dabir et al. (2008) found that glucose activates an AHR-associated thrombospondin-1 signaling pathway that is known to have antiangiogenic and proatherosclerotic activities. Finally, AHR-null mice have been shown to have increased angiotensin II production, which leads to hypertension (Lund et al., 2003); the literature reviewed showed that this may be associated with alpha1D- adrenoreceptor expression (Villalobos-Molina et al., 2008). Thus, on the basis of animal models, there appear to be several overlapping and potentially contribut- ing pathways that may interlink AHR activation, TCDD effects, and CVD. Synthesis In this section, the committee synthesizes information on circulatory dis- orders from the new studies described above and reconsiders studies that were reviewed in previous updates. Because circulatory diseases constitute a broad group of diverse conditions, hypertension and ischemic heart disease are dis- cussed separately from other circulatory diseases so that the new studies can be adequately synthesized and integrated with the earlier studies. Hypertension Hypertension, typically defined as blood pressure above 140/90 mmHg, affects more than 70 million adult Americans and is a major risk factor for coro- nary heart disease, myocardial infarction, stroke, and heart and renal failure. The major quantifiable risk factors for hypertension are well established and include age, race, BMI or percentage body fat, and diabetes; the strongest conclusions regarding a potential increase in the incidence of hypertension come from studies that have controlled for these risk factors. The committee responsible for Update 2006 judged that there was limited or suggestive evidence that Agent Orange exposure is associated with hypertension. The studies published since Update 2006 are consistent with that conclusion.

628 VETERANS AND AGENT ORANGE: UPDATE 2008 The data from the NHANES are broadly consistent with the effect. The NHANES is cross-sectional and so is prone to selection biases that may distort the association between exposure and disease. There is also a concern that re- ported associations are not limited to compounds that have dioxin-like activity or are not in strict correspondence with TEFs. For example, in the analyses by Everett et al. (2008a,b), the data from 1999–2002 yielded the strongest associa- tion for the chemicals with the greatest dioxin-like activity (PCB-126, TEF = 0.1) and showed statistically significant associations with four non–dioxin-like PCBs; when the more extensive data from 1999–2004 were used, however, the increase in risks associated with the four non–dioxin-like PCBs were no longer significant, but the theoretically less potent PCB-118 (TEF = 0.0001) now had the strongest association (although the 95% CIs did remain effectively equivalent). The new data from Karouna-Renier et al. (2007) are from a small survey of a problem- atic sample, so the association is difficult to interpret. The increased lifetime prevalence of hypertension in women in the Yucheng cohort who had chloracne provides support of the link between doxin-like compounds and hypertension, but the support is diminished by the failure to observe an association in men. There is no clear explanation of the sex difference in the findings, but men may have a lower threshold for the development of hypertension. It is important that those who had chloracne were compared with other (presumably) less exposed persons, not with a nonexposed reference cohort. The cohort experienced a good deal of loss to follow-up, so selection bias cannot be ruled out as a potential ex- planation of the disparate results. The data from Consonni et al. (2008) also are generally supportive, although there was little ability to control for potentially important confounders. Furthermore, the association was between exposure zone and deaths from hypertension. In the United States, hypertension, although very prevalent, is fairly rarely identified as an underlying cause of death. Most often, deaths associated with hypertension are ascribed to clinical conditions caused by hypertension (such as stroke).Thus, the degree of correspondence between death from hypertension and the occurrence of hypertension in the exposed populations is unclear. Ischemic Heart Disease Circulatory diseases comprise a group of diverse conditions—of which hy- pertension, coronary heart disease, and stroke are the most prevalent—that ac- count for 75% of deaths from circulatory diseases in the United States. The major quantifiable risk factors for circulatory diseases are similar to those for hyperten- sion and include age, race, smoking, serum cholesterol, BMI or percentage of body fat, and diabetes. The committee responsible for Update 2006 was divided on the weight to be given to the weaknesses of the heart-disease studies and thus remained divided

OTHER HEALTH EFFECTS 629 as to whether the evidence related to exposure to the chemicals of interest and ischemic heart disease (ICD-9 410–414) was adequately informative to advance this health outcome from the “inadequate or insufficient” category into the “lim- ited or suggestive” category. The additional data since Update 2006 are from Ha et al. (2007) on the NHANES data and from Consonni et al. (2008) on the update of the Seveso experience. The interpretation of the NHANES data is complicated by the same factors that compromise the interpretation of the data with respect to hypertension (for example, the data are from a cross-sectional survey). There seems to be a some- what more specific effect of dioxin-related compounds and CVD prevalence than the relationships seen for hypertension. Furthermore, the association persisted after statistical adjustment for a large number of potential confounding risk fac- tors for which the information necessary for adjustment is generally not available in other dioxin-exposed populations. The data on the Seveso incident do not show a dose–response pattern be- tween residence and mortality from ischemic heart disease in that the residential zone with the lowest exposure was the only zone that had a statistically signifi- cant increase in mortality. However, the increase was slight (10% excess), and there is a potential for unmeasured confounders to account for it. Consonni et al. (2008) also reported an association with cerebrovascular-disease mortality in the intermediate-exposure and low-exposure zones. The imprecision of the effect estimate for the high-exposure zone was such that the results from that zone do not rule out a small to moderate increase in mortality. Again, the overall mortal- ity increase is small (10–20%) and important confounders were not measured, so the Seveso data do not constitute a firm finding regarding dioxins’ role in the risk of stroke. In light of the inability of the committee responsible for Update 2006 to reach a consensus, the present committee revisited the entire body of evidence on TCDD exposure and heart disease. More confidence was given to studies that were most rigorously conducted, focused specifically on the chemicals of con- cern, compared Vietnam veterans with nondeployed era veterans, had individual and reliable measures of exposure that permitted evaluation of dose–response relationships, and so on. Evidence of a dose–response relationship is especially helpful in the interpretation of epidemiologic data. In the context of the TCDD literature, that is reflected in studies in which the disease experience of people whose exposure to TCDD or related compounds (documented in terms of serum concentrations) was compared with that of people whose exposure was similarly documented to have been low. In situations where several alternative analyses were presented, the information from the analyses that had the greatest specificity in the dose–response relationship was given more weight. Nine studies provided such information (AFHS, 2005; Calvert et al., 1998; Consonni et al., 2008; Flesch-Janys, 1995; Ha et al., 2007; Hooiveld et al., 1998; Kang et al., 2006;

630 VETERANS AND AGENT ORANGE: UPDATE 2008 Steenland et al., 1999; Vena et al., 1998; these studies are shaded in Table 9-5). The International Agency for Research on Cancer cohort (Vena et al., 1998) is composed of several occupational cohorts that have been studied individually and includes three that are also considered individually here because of their information on serum TCDD: the American NIOSH cohort (Steenland et al., 1999), a German cohort (Flesch-Janys, 1995), and a Dutch cohort (Hooiveld et al., 1998). Six of the reports show strong and statistically significant associa- tions with ischemic heart disease (ORs or RRs ranging from 1.4 to 2.8). The studies include Agent Orange sprayers, occupationally exposed populations, and environmentally exposed populations, and they were either prevalence surveys or mortality follow-up studies. Because of small numbers, the studies that did not report statistically significant associations did not rule out modest increases in ischemic heart disease in those with the strongest evidence of exposure. The committee was impressed by the fact that the studies with the best dose informa- tion all showed evidence of risk increases in the highest exposure categories. Each of the studies has potential limitations. For example, the cross-sectional surveys typically have better measurements of potential confounders, but their design allows for important selection biases. The mortality studies are longitudi- nal, but fatal cases may not represent all incident cases, so there was a potential for bias in outcome ascertainment. The mortality studies also had little data on potential disease confounders. However, for a potential confounder to explain an observed association completely, the strength of its association with the outcome of interest must be greater than that observed for the exposure under consider- ation (Rothman and Greenland, 1998). The strongest potential confounder is age, but this was controlled for in most of the mortality studies. BMI is an important potential uncontrolled confounder, but its association with CVD mortality is not strong enough to explain away the high RRs. Although serum dioxin-like chemi- cals tend to increase with age and BMI in the general population, one would anticipate that half-life decay of the extreme occupational doses would exceed the accumulation attributable to continuing background exposure. Cigarette- smoking is a risk factor for CVD, but for it to be a confounder there would have to be a very strong correlation between smoking and dioxin exposure, which is extremely unlikely to have been the situation in every study. Empirical research also indicates that confounding by smoking could not explain RRs above 1.4 (Siemiatycki et al., 1988). Previous committees have found that there is limited or suggestive evidence of an association between Agent Orange and both diabetes and hypertension, and the present committee concurs in those conclusions. The present committee con- siders that both conditions are strong risk factors for ischemic heart disease, and many epidemiologic studies show a dose–response relationship between dioxin and ischemic heart disease. Finally, toxicologic data support the biologic plausibility of an association between TCDD exposure and vascular disease.

OTHER HEALTH EFFECTS 631 Other Circulatory Disease Data from Consonni et al. (2008) indicate a relationship between residence in a locality with high dioxin exposure and mortality from chronic rheumatic heart disease. The basis of the association is unclear. Given that this is a single finding from a study of disease mortality rather than incidence and that it lacked control for potentially important confounders, there is little basis for a conclusion regarding an effect of Agent Orange on this outcome. Conclusion After extensive deliberation regarding the strengths and weaknesses of the new evidence and evidence from studies reviewed in previous VAO reports, the present committee deemed that the strengths of the evidence related to hyperten- sion outweighed the weaknesses and concluded that there is limited or sugges- tive evidence of an association between exposure to the chemicals of interest and hypertension (ICD-9 401–405) but that chance, bias, and confounding could not be ruled out. After consideration of the relative strengths and weaknesses of the evidence regarding the chemicals of interest and ischemic heart disease (ICD-9 410–414), which includes a number of studies that showed a strong dose–response relationship and that had good toxicologic data demonstrating biologic plausibility, the committee judged that the evidence was adequately informative to advance this health outcome from the “inadequate or insufficient” category into the “limited or suggestive” category, again acknowledging that bias and confounding could not be ruled out. For all other types of circulatory disease, the committee found that the evidence is inadequate or insufficient to determine whether there is an association with exposure to the chemicals of interest. THYROID HOMEOSTASIS Clinical disruptions of thyroid function include various disorders grouped in ICD-9 242.8 and 246.8. The thyroid gland secretes the hormones thyroxine (T4) and triiodothyronine (T3), which stimulate and help to regulate metabolism throughout the body. The thyroid also secretes calcitonin, a hormone that controls calcium concentration in the blood and storage of calcium in bones. Secretion of T4 and T3 is under the control of thyroid-stimulating hormone (TSH), which is secreted by the anterior pituitary gland. Iodine operates in thyroid physiology both as a constituent of thyroid hormones and as a regulator of glandular func- tion. Concentrations of those circulating hormones are regulated primarily by a negative-feedback pathway that involves three organs: the thyroid, the pituitary, and the hypothalamus. In the hypothalamus–pituitary–thyroid feedback scheme, the hypothalamus releases thyrotropin-releasing hormone (TRH), which stimu- lates the pituitary to produce TSH, which triggers the thyroid to produce T4 and

632 VETERANS AND AGENT ORANGE: UPDATE 2008 T3. Cells in the hypothalamus and pituitary respond to concentrations of circu- lating T4 and T3. When T4 and T3 are low, the pituitary is stimulated to deliver more TSH to the thyroid, which increases T4 and T3 output. When circulating T4 and T3 are high, they signal to reduce the output of TRH and TSH. This negative- feedback loop maintains hormone homeostasis. Disruption of thyroid homeostasis can be stimulatory (hyperthyroidism) or suppressive (hypothyroidism). Both conditions are diagnosed on the basis of blood concentrations of thyroid hormones, TSH, and other proteins (antithyroid antibodies). The prevalence of thyroid dysfunction in adults in the general popu- lation ranges from 1% to 10%, depending on the group, the testing setting, sex, age, method of assessment, and the presence of conditions that affect thyroid function. People with subclinical (biochemical) conditions may or may not show other evidence (signs or symptoms) of thyroid dysfunction. In hypothyroidism, the body lacks sufficient thyroid hormone. Overt hy- pothyroidism is seen as a high serum concentration of TSH and a low serum concentration of free T4. Subclinical hypothyroidism is defined as a high serum concentration of TSH and a normal serum concentration of free T4. People who have hypothyroidism typically have symptoms of low metabolism. Studies consistently show that subclinical hypothyroidism is common and occurs more frequently in women than in men (Canaris et al., 2000; Hollowell et al., 2002; Sawin et al., 1985). In the Framingham study, for example, among 2,139 people 60 years old or older, 14% of women and 6% of men had subclinical hypothy- roidism (Sawin et al., 1985). Subclinical hypothyroidism is a risk factor for overt hypothyroidism. Studies have reported an association of hypothyroidism with a wide variety of other conditions. The term hyperthyroidism may involve any disease that results in overabun- dance of thyroid hormone. Clinical or overt hyperthyroidism is characterized as a low serum concentration of TSH and high serum concentration of free T4. Subclinical hyperthyroidism is defined as a low serum concentration of TSH and a normal serum concentration of free T4. The prevalence of subclinical hyper- thyroidism was estimated at about 1% in men and 1.5% in women over 60 years old (Helfand and Redfern, 1998). Conditions associated with hyperthyroidism include Graves disease and diffuse toxic goiter. Like hypothyroidism, hyperthy- roidism is more common in women than in men, and, although it occurs at all ages, it is most likely to occur in people more than 15 years old. A form of hyper- thyroidism called neonatal Graves disease occurs in infants born to mothers who have Graves disease. Occult hyperthyroidism may occur in patients more than 65 years old and is characterized by a distinct lack of typical symptoms. It is important to distinguish between potential effects on adults and effects that may occur during development. In adults, the thyroid is able, within reason, to compensate for mild or moderate disruption (such as that caused by hyper- plasia or goiter). In contrast, the fetus is highly sensitive to alterations in thyroid hormones, and alterations in thyroid homeostasis can hamper the development of

OTHER HEALTH EFFECTS 633 many organ systems, including the nervous and reproductive systems. Both adult and developmental outcomes are considered here. Summary of Previous Updates The thyrotoxic potential of the chemicals of interest was addressed first in Update 2002 (IOM, 2003). Although several studies have found an association between dioxin-like congeners and markers of thyroid homeostasis, there have been no studies that document an increased risk of thyroid disease in veterans of the Vietnam War. The committee responsible for Update 2002 concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and adverse effects on thyroid homeostasis in Vietnam veterans. The committee responsible for Update 2004 concurred. The committee responsible for Update 2006 reviewed several environmen- tal studies of the relationship between exposure to dioxin-like compounds and thyroid function. Bloom et al. (2006) found a significant inverse relationship between the sum of dioxin-like compounds and the concentration of free T4 in anglers in New York state, but no association between the sum of dioxin-like compounds and TSH. Significant associations were not found in patients with Yusho disease (Nagayama et al., 2001) or women undergoing amniocentesis (Foster et al., 2005). The committee responsible for Update 2006 noted that the functional importance of those changes remained unclear because adaptive capac- ity could be adequate to accommodate them, it retained the previous committees’ conclusion that there was inadequate or insufficient evidence of an association. Update of the Scientific Literature No Vietnam-veteran or occupational studies concerning the chemicals of interest and thyroid homeostasis have been published since Update 2006. Environmental Studies Four studies of environmental exposure to PCB congeners and thyroid func- tion in adults have been published since Update 2006. Abdelouahab et al. (2008) reported on a cross-sectional investigation of T3, T4, and TSH in relation to several serum dioxin-like compounds in adult freshwater-fish consumers in two Canadian communities. Fish consumption was measured by self-report. The relationships between fish consumption and serum compound concentrations were adjusted for age, sex, smoking, alcohol consump- tion, medications, and total lipid concentrations. Analyses were performed with levels of compounds adjusted and unadjusted for lipid concentration to take into account potential TH effects on blood lipid mobilization. Thyroid hormones

634 VETERANS AND AGENT ORANGE: UPDATE 2008 were within the normal ranges, and biomarkers of exposure were low compared with those in other reports on fish consumers. Non-ortho-substituted (dioxin- like) PCBs (PCB-105, -118, -128, -138, and -170) were among the compounds analyzed. In women, a negative association was found between PCB-138 con- centrations and T3, but no association was observed between all dioxin-like congeners combined and T3 or T4. No relationships were observed between any of the chemicals, including the dioxin-like compounds and T4. In men, serum T4 was reported to be inversely related to PCB-138 and dioxin-like congeners (p < 0.05). A positive relationship was found between dioxin-like congeners and TSH (p < 0.001). In men, serum TSH was highest among those in the highest 50th percentile for dioxin-like PCB congeners. No associations with T3 were observed in men. Serum concentration of the dioxin-like congeners ranged from the 25th percentile of lipids at 200 ng/g to a maximum value of 2,810 ng/g. Although those results are based on the sum of dioxin-like compounds, and not TCDD specifically, they augment information that dioxin-like chemicals are associated with changes in some measures of thyroid function, although not to an extent that result in clinically abnormal concentrations of the hormones. A second study of adults without thyroid disease in the 1999–2002 NHANES examined the association of dioxin-like TEQs with T4 and TSH (Turyk et al., 2007). PCB, PCDD, and PCDF congeners were examined separately in the serum of a nationally representative sample of the US population. TEFs for each PCDD, PCDF, and coplanar PCD and mono-ortho PCB congener were multiplied by the congener’s concentration and summed to calculate total TEQs. The total T4 was negatively associated with the serum dioxin-like TEQs in a dose-dependent fash- ion; associations were stronger in women than in men. In women, mean T4 was 8.2 µg/dL, and T4 concentrations averaged 0.75 µg/dL lower (95% CI 0.04–1.46) in women in the highest quintile of TEQ exposure than in women in the lowest quintiles. Effects were stronger in people over 60 years old. The committee reviewed two reports concerning thyroid function in adults in the polluted district of Michalovce in East Slovakia compared with neighbor- ing, nonpolluted communities (Langer et al., 2007a,b). Adults were examined for serum TSH, T4, T3, antithyroperoxidase antibodies, and 15 PCBs that included five dioxin-like coplanar congeners. In neither report, however, were the analyses broken out for the dioxin-like congeners alone. In a study of PCB exposures during pregnancy and thyroid function, Chevrier et al. (2008) measured the dioxin-like congeners PCB-118, -156, -157, -167, -180, and -189 among 34 PCBs measured in samples collected from 334 pregnant women living in Salinas Valley, California. PCB-118 and PCB-156 were among the 19 congeners detected in more than 75% of the study partici- pants. After adjustment for demographic covariates, there was no association be- tween concentrations of those two dioxin-like PCB congeners and free T4, total T4, or TSH concentrations.

OTHER HEALTH EFFECTS 635 Biologic Plausibility TCDD has been demonstrated to affect concentrations of T4, T3, and TSH in experimental animals, but the effects appear to be species-dependent, and they lack consistency in demonstrating either definite hyperthyroidism or hypothyroid- ism 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 showed follicular-cell hyperplasia and hypertrophy of thyroid follicles. TCDD influences the metabolism of thyroid hormones and TSH. Notably, the study by Nishimura et al. (2005) confirmed that induction of the glucuronyl transferase UGT1A6, thought to be involved in the reduction in serum thyroid hormone in mice, depends on the AHR. Thus, some dioxin-like PCB congeners (such as PCB-77) can be metabolized to hydroxy derivatives that more closely resemble the structure of T4 and displace it from thyroid-binding proteins, such as transthyretin—a mechanism not likely with TCDD. Not all mechanisms by which chemicals might affect thyroid homeostasis are understood, and dioxin may act on thyroid function via different mechanisms. Synthesis Numerous animal experiments and several epidemiologic studies have shown that TCDD and dioxin-like compounds appear to exert some influence on thyroid homeostasis. An occupational study (Johnson et al., 2001) showed an inverse relationship between TCDD concentrations and T3 and TSH concentrations. 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 workers exposed to TCDD in an industrial incident and reported that thyroid disease was increased (p < 0.05) in the exposed population. Other epidemiologic studies have found inverse relationships between dioxin-like com- pounds and thyroid function after environmental exposures (Bloom et al., 2006). In the AFHS study considered in Update 2004, Pavuk et al. (2003) reported a trend toward an increasing concentration of TSH that was not accompanied by changes in circulating T4 or T3 in Vietnam veterans. There was no evidence of changes in clinical thyroid disease. Although the overall assessment of the stud- ies to date suggests some variation in thyroid hormone concentrations in relation to TCDD exposure, the functional importance of those changes remains unclear because adaptive capacity should be adequate to accommodate them. Conclusions There is inadequate or insufficient evidence of an association between expo- sure to the chemicals of interest and clinical or overt adverse effects on thyroid

636 VETERANS AND AGENT ORANGE: UPDATE 2008 homeostasis. Some effects have been observed in humans, but the functional im- portance of the changes reported in the studies reviewed remains unclear because adaptive capacity could be adequate to accommodate them. SUMMARY On the basis of the occupational, environmental, and veterans studies re- viewed and in light of information concerning biologic plausibility, the commit- tee reached one of four conclusions about the strength of the evidence regarding an association between exposure to the chemicals of interest and each of the health outcomes discussed in this chapter. In categorizing diseases according to the strength of the evidence, the committee applied the same criteria (discussed in Chapter 2) that were used in VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006. 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 conclusions are based on statistical association. 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 were free of bias and confounding and that showed an association that was consistent in magnitude and direction as sufficient to con- clude that there is an association. The committees responsible for VAO, Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 concluded that there was sufficient evidence of an association between exposure to at least one chemical of interest and chloracne. The scientific literature continues to support the clas- sification 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 inclusion in this category. Health Outcomes with Limited or Suggestive Evidence of an Association For this category, the evidence must suggest an association between exposure and outcome, although it can be limited because chance, bias, or confounding could not be ruled out with confidence. The committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 concluded that there was limited or suggestive evidence of an association between exposure to at least one chemi- cal of interest and porphyria cutanea tarda. The scientific literature continues to

OTHER HEALTH EFFECTS 637 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 Type 2 Diabetes concluded that there was limited or suggestive evidence of an association between exposure to at least one chemical of interest and type 2 diabetes; the committees responsible for Update 2000, Update 2002, Update 2004, and Update 2006 reached the same conclusion. New evidence re- viewed by the present committee continues to support that conclusion. The committee for Update 2006 added the cardiovascular condition hyper- tension to the list of health outcomes in the category of limited or suggestive evidence. The present committee reached consensus that another cardiovascular outcome, ischemic heart disease, belonged in this category. Health Outcomes with Inadequate or Insufficient Evidence to Determine Whether There Is an Association The scientific data on many of the health outcomes reviewed by the present committee were inadequate or insufficient to determine whether there is an as- sociation between exposure to the chemicals of interest and the outcomes. For the health outcomes 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. Some studies failed to control for confounding or used 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 (except as qualified above); endometriosis; and disorders of thyroid homeostasis. 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, Update 2002, Update 2004, and Update 2006 concluded that none of the health outcomes discussed in this chapter had limited or suggestive evidence of no association with exposure to the chemicals of interest. The most recent scien- tific evidence continues to support that conclusion.

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From 1962 to 1971, the U.S. military sprayed herbicides over Vietnam to strip the thick jungle canopy that could conceal opposition forces, to destroy crops that those forces might depend on, and to clear tall grasses and bushes from the perimeters of U.S. base camps and outlying fire-support bases.

In response to concerns and continuing uncertainty about the long-term health effects of the sprayed herbicides on Vietnam veterans, Veterans and Agent Orange provides a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange and other herbicides used in Vietnam. The 2008 report is the eighth volume in this series of biennial updates. It will be of interest to policy makers and physicians in the federal government, veterans and their families, veterans' organizations, researchers, and health professionals.

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