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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. 46

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4 OTHER HEALTH EFFECTS 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.,

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48 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.

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49 OTHER HEALTH EFFECTS 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.

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0 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

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1 OTHER HEALTH EFFECTS 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.

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2 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.

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 OTHER HEALTH EFFECTS 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-

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4 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.

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 OTHER HEALTH EFFECTS TABLE 9-1 Selected Epidemiologic Studies—Nonmalignant Respiratory Disease Estimated Exposed Relative Risk Casesa (95% CI)a Reference Study Population 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

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6 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 9-1 Continued Estimated Exposed Relative Risk Casesa (95% CI)a Reference Study Population 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) 0.8 (p < 0.05) Army 648 0.7 (p < 0.05) Marine Corps 111 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)

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