11

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 several noncancer health outcomes: respiratory disorders, immune-system disorders, diabetes, lipid and lipoprotein disorders, gastrointestinal and digestive disease (including liver toxicity), circulatory disorders, and adverse effects on thyroid homeostasis. The committee also considers studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like chemicals informative if their results were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners.

In previous updates, chloracne and porphyria cutanea tarda (PCT) were considered along with these chronic noncancer conditions. These are conditions that are quite well accepted to be associated with dioxin exposure, but when they occur this happens within a matter of months of the exposure. In this update these two health outcomes have been moved to an appendix on short-term effects along with transient early-onset peripheral neuropathy, which had previously been discussed in the chapter on neurologic disorder.

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 environmental). For articles that report on only a single health outcome and that are not revisiting a previously studied population, design information is summarized



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11 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: respiratory disorders, immune-system disorders, diabetes, lipid and lipoprotein disorders, gastrointestinal and digestive disease (including liver toxicity), circulatory disorders, and adverse effects on thyroid homeostasis. The committee also considers studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like chemicals informative if their results were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners. In previous updates, chloracne and porphyria cutanea tarda (PCT) were considered along with these chronic noncancer conditions. These are conditions that are quite well accepted to be associated with dioxin exposure, but when they occur this happens within a matter of months of the exposure. In this update these two health outcomes have been moved to an appendix on short-term effects along with transient early-onset peripheral neuropathy, which had previously been dis - cussed in the chapter on neurologic disorder. 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 708

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709 OTHER HEALTH EFFECTS 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. RESPIRATORY DISORDERS For the purposes of this report, noncancerous respiratory disorders comprise acute and chronic lung diseases other than cancer. Acute noncancerous 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 noncancerous 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 noncancerous 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 (Kang et al., 2006; 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 vari- ous respiratory diseases for analysis, unless they all are associated with a given

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710 VETERANS AND AGENT ORANGE: UPDATE 2010 exposure, will lead to attenuation of the estimates of relative risk (RR) and to a diminution of statistical power. Moreover, diagnosis of the primary cause of death from respiratory and cardiovascular diseases (CVDs) is often inconsistent. In particular, when persons have both conditions 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 are small, so investigators group deaths from all noncancerous respiratory diseases into one category that combined pneumonia, influenza, and other diseases with COPD and asthma. The committee notes that an association for the grouping of all noncancerous respiratory diseases with any of the chemicals of interest would be too nonspecific to be clinically meaningful; at most, such a pattern would be an indication that within this broad classifica - tion some particular disease entity might be impacted by an exposure of interest. 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) concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and the respiratory disorders specified above. Additional information available to the committees re - sponsible for Veterans and Agent Orange: Update 1996 (IOM, 1996) and Update 1998 (IOM, 1999) did not change that finding. Veterans and Agent Orange: Update 2000 (IOM, 2001) drew attention to findings on the Seveso cohort that suggested a higher mortality from noncancer- ous 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 noncancerous respiratory disorders, particularly COPD, in people exposed to TCDD, the observation was tentative and the information insufficient to determine whether there is an association between exposures to the chemicals of interest and respiratory disorders. Addi - tional information available to the committee responsible for Veterans and Agent Orange: Update 2002 (IOM, 2003) did not change that finding. Veterans and Agent Orange: Update 2004 (IOM, 2005) 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 “nonexposed” control group, the committee

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711 OTHER HEALTH EFFECTS concluded that selection bias and recall bias limited the utility of the results and that there was a possibility of confounding in that history of tobacco use was not accounted for adequately. Veterans and Agent Orange: Update 2006 (IOM, 2007) 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 Vietnam Experience Study (Boehmer et al., 2004), in the Air Force Health Study (Ketchum and Michalek, 2005), and in two Australian 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 noncancerous respiratory problems diagnosed by a doctor was significantly increased by about 40–60%, although no differences in the preva - lence 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). There was also an AHS analysis (Hoppin et al., 2006a) of specific pesticide exposures and the self-reported prevalence of wheeze that showed an association with “current” exposure to 2,4-D. Several additional new AHS publications were reviewed in Veterans and Agent Orange: Update 2008 (IOM, 2009) concerning morbidity from particular self-reported respiratory health problems: another analysis concerning wheeze (Hoppin et al., 2006b), asthma (Hoppin et al., 2008), “farmer’s lung” or hypersen- sitivity pneumonitis (Hoppin et al., 2007a), and chronic bronchitis (Hoppin et al., 2007b; Valcin et al., 2007). The 25-year follow-up of the mortality of the Seveso population through 2001 (Consonni et al., 2008) was also considered in Update 2008; again there was some elevation in mortality from COPD as had been seen in the earlier mortality follow-up reviewed in Update 2000. Table 11-1 summarizes the results of the relevant studies. Update of the Epidemiologic Literature Vietnam-Veteran Studies The Army Chemical Corps (ACC) cohort is of particular interest because the members deployed to Vietnam had potential exposure to the chemicals of interest second only to that of the Ranch Hand veterans. Cypel and Kang (2010) reported the cause-specific mortality through 2005 in ACC veterans who served in Vietnam between July 1, 1965–March 28, 1973 (n = 2,872) and ACC veterans

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712 VETERANS AND AGENT ORANGE: UPDATE 2010 TABLE 11-1 Selected Epidemiologic Studies—Noncancerous Respiratory Disease Exposure of Interest/ Exposed Estimated Risk Casesa (95% CI)a Reference Study Population VIETNAM VETERANS US Air Force Health Study—Ranch Hand veterans vs SEA veterans All COIs Ketchum and Rand Hand personnel (n = 1,262) vs SEA Michalek, veterans (19,078)—respiratory disease (ICD-9 2005 460–519) Mortality through 1999 8 1.2 (0.6–2.5) AFHS, 1996 Mortality through 1993 2 0.5 (0.1–1.6) US VA Cohort of Army Chemical Corps All COIs Cypel and Deployed veterans (2,872) vs nondeployed Kang, 2010 (2,737)—mortality through 2005 Respiratory system disease 32 vs 8 2.2 (1.0–4.9) Pneumonia and influenza 12 vs 6 1.3 (0.5–3.6) COPD 20 vs 2 4.8 (1.1–21.2) ACC deployed men in Kang et al. (2006) reported sprayed herbicide vs did not spray Respiratory system disease 8 2.2 (0.4–11.8) Pulmonary disease (COPD) 6 3.6 (0.4–32.1) Kang et al., Self-reported morbidity 1999—noncancerous 2006 respiratory problems diagnosed by doctor Deployed (n = 1,499) vs nondeployed (n = 267 1.4 (1.1–1.8) 1,428) Sprayed herbicides in Vietnam vs never 140 1.6 (1.2–2.1) Dalager and Mortality through 1991 Kang, 1997 Respiratory system disease 11 vs 2 2.6 (0.5–12.2) US CDC Vietnam Experience Study All COIs Boehmer Vietnam Experience Cohort et al., 2004 Noncancerous respiratory mortality (ICD-9 20 0.8 (0.5–1.5) 460–519) 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) US VA Mortality Study of Army and Marine Veterans (ground troops All COIs serving July 4, 1965–March 1, 1973) Watanabe Mortality of US Vietnam veterans who and Kang, died during 1965–1988, PMR analysis of 1996 noncancerous respiratory mortality (ICD-8 460–519) 0.8 (p < 0.05) Army 648 0.7 (p < 0.05) Marine Corps 111

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713 OTHER HEALTH EFFECTS TABLE 11-1 Noncancerous Respiratory Disease, continued Exposure of Interest/ Exposed Estimated Risk Casesa (95% CI)a Reference Study Population US VA Cohort of Monozygotic Twins All COIs Eisen et al., Incidence in deployed vs nondeployed 1991 monozygotic 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) Other US VA Vietnam Veteran Studies All COIs Bullman and Male Vietnam veterans who were wounded in Kang, 1996 combat vs US population Noncancerous respiratory mortality (ICD 9 43 0.9 (0.7–1.2) 460–519) State Studies of US Vietnam Veterans All COIs Anderson White males with Wisconsin death certificate et al., 1986 (1968–1978), mortality from noncancerous respiratory disease (ICD-8 460–519) Vietnam veterans vs expected deaths calculated from proportions for: 10 Nonveterans 0.5 (0.3–0.8) All veterans 0.8 (0.4–1.5) Vietnam-era veterans 1.0 (0.5–1.8) Australian Vietnam Veterans vs Australian Population All COIs ADVA, Third Australian Vietnam Veterans Mortality 2005b Study Deployed veterans vs Australian population All branches Respiratory system diseases 239 0.8 (0.7–0.9) COPD 128 0.9 (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 0.9 (0.7–1.0) Air Force Respiratory system diseases 28 0.6 (0.4–0.9) COPD 18 0.8 (0.4–1.2) CDVA, Mortality of male Australian Vietnam veterans 1997a vs Australian population Noncancerous 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) 47 0.9 (0.7–1.2) continued

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714 VETERANS AND AGENT ORANGE: UPDATE 2010 TABLE 11-1 Noncancerous Respiratory Disease, continued Exposure of Interest/ Exposed Estimated Risk Casesa (95% CI)a Reference Study Population Australian Conscripted Army National Service (deployed vs All COIs nondeployed) ADVA, Mortality 1966–2001 2005c Respiratory diseases 18 1.1 (0.6–2.2) COPD 8 1.0 (0.3–2.8) CDVA, Mortality from noncancer respiratory disease 1997b 1965–1982 2 2.6 (0.2–30.0) 1982–1994 6 0.9 (0.3–2.7) Australian Army Vietnam Veterans—sample of 1,000 vs Australian All COIs National Health Survey—self-reported chronic conditions Relative Prevalence O’Toole Veterans interviewed 2005–2006 (n = 450) vs et al., 2009 2004–2005 National Survey results Chronic lower respiratory disease nr Bronchitis nr 2.9 (2.2–3.6) Emphysema nr 2.0 (1.3–2.7) Asthma nr 1.3 (1.0–1.6) Hay fever and allergic rhinitis nr 1.2 (0.96–1.4) Chronic sinusitis nr 1.7 (1.5–2.0) Other diseases of the respiratory system nr 15.4 (11.7–19.1) O’Toole Veterans interviewed 1990–1993 (n = 641) vs et al., 1996 1989–1990 National Survey results 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) OCCUPATIONAL IARC Phenoxy Herbicides Cohort (mortality vs national mortality Dioxin, phenoxy rates) herbicides Kogevinas Mortality in international workers producing et al., 1997 or applying phenoxy herbicides, noncancerous respiratory mortality (ICD-9 460–519), 1939–1992 Men 252 0.8 (0.7–0.9) Women 7 1.1 (0.4–2.2) NIOSH Mortality Cohort (12 US plants, production 1942–1984) Dioxin, phenoxy (included in IARC cohort) herbicides Steenland NIOSH mortality study of chemical workers at et al., 1999 12 plants in US exposed to TCDD Noncancerous respiratory mortality (ICD-9 460–519) 86 0.9 (0.7–1.1) Preliminary NIOSH Cross-Sectional Medical Study—workers in Dioxin, phenoxy herbicides production of sodium trichlorophenol, 2,4,5-T ester contaminated with TCDD—morbidity Sweeney Chronic bronchitis and COPD 2 nr et al., 1997/98

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715 OTHER HEALTH EFFECTS TABLE 11-1 Noncancerous Respiratory Disease, continued Exposure of Interest/ Exposed Estimated Risk Casesa (95% CI)a Reference Study Population Calvert Odds ratios for increase in 1 ppt of serum et al., 1991TCDD compared to unexposed workers Chronic bronchitis nr 0.5 (0.1–2.6) COPD nr 1.2 (0.5–2.8) Monsanto Production Workers—Nitro, WV, 2,4,5-T plant Dioxin, phenoxy herbicides Suskind and Cross-sectional study, 1979, comparing exposed Hertzberg, with nonexposed workers for “abnormal” 1984 outcome on pulmonary-functions tests: FEV1 (< 80% predicted) 2.81 (p = 0.02) FVC (< 80% predicted) 2.25 (p = 0.03) FEV1/FVC (< 70%) 2.97 (p = 0.01) FEF25-75 (< 80% predicted) 1.86 (p = 0.05) Dow Chemical Company—Midland, MI (included in IARC and Dioxin, phenoxy NIOSH cohorts) herbicides Collins Mortality 1942–2003—noncancerous et al., 2009a respiratory disease (ICD-10 J00–J99) TCP workers 44 0.8 (0.6–1.0) Collins Mortality 1942–2003—noncancerous et al., 2009b respiratory disease (ICD-10 J00–J99) PCP workers without TCP exposure 19 0.7 (0.4–1.2) Burns et al., Mortality of 2,4-D workers, 1945–1994 2001 Noncancerous respiratory (ICD-8 460–519) 8 0.4 (0.2–0.7) Pneumonia 4 0.6 (0.2–1.4) Ramlow Mortality of PCP workers, 1940–1989 et al., 1996 Noncancerous respiratory mortality (ICD-8 460–519) 14 0.9 (0.5–1.5) Cumulative PCP exposure < 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) BASF Production Workers—German workers exposed to trichlorophenol Dioxin, phenoxy herbicides contaminated with TCDD from 1953 accident (included in IARC cohort) Ott and Noncancerous respiratory mortality through 1 0.1 (0.0–0.8) Zober, 1996 1993 vs West German rates (n = 243 men) Zober et al., Prevalence—cohort (n = 158), reference (n = 1994 161) (illness episodes per 100 person–years, 1953–1989) All noncancerous respiratory diseases (ICD-9 460–519) nr 33.7/31.0 (p = 0.22) Upper respiratory tract infections (ICD-9 460–478) nr 12.0/9.0 (p = 0.00) 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) continued

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716 VETERANS AND AGENT ORANGE: UPDATE 2010 TABLE 11-1 Noncancerous Respiratory Disease, continued Exposure of Interest/ Exposed Estimated Risk Casesa (95% CI)a Reference Study Population Dutch Production Workers (included in IARC cohort) Dioxin, phenoxy herbicides Boers et al., Dutch chlorophenoxy workers 2010 Diseases of the respiratory system Factory A (HR for exposed vs unexposed) 19 vs 12 1.0 (0.4–2.3) Factory B (HR for exposed vs unexposed) 6 vs 15 0.5 (0.2–1.2) German Production Workers (included in IARC cohort) Dioxin, phenoxy herbicides Becher et al., Four German facilites for production 1996 of phenoxy herbicides, chlorophenols, noncancerous 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) New Zealand Production Workers—Dow plant in Plymouth, NZ Dioxin, phenoxy (included in IARC cohort) herbicides McBride Dow trichlorophenol workers in Plymouth, NZ et al., 2009a Ever-exposed workers 12 0.8 (0.4–1.4) ’t Mannetje New Zealand phenoxy herbicide workers, et al., 2005 noncancerous respiratory mortality (ICD-9 480–519) Producers 9 0.9 (0.4–1.8) Sprayers 6 0.7 (0.2–1.2) United Kingdom Production Workers (included in IARC cohort) Dioxin, phenoxy herbicides Coggon Production of phenoxy herbicides, 8 0.7 (0.3–1.3) et al., 1991 chlorophenols in four British plants, mortality from noncancerous respiratory diseases, 1963–1985 Coggon British plant manufacturing MCPA, mortality 93 0.6 (0.5–0.8) et al., 1986 from noncancerous respiratory diseases (ICD-9 460–519), 1947–1983 Agricultural Health Study Herbicides Hoppin US AHS—prevalence at enrollment among et al., 2009 male agricultural workers of: Allergic asthma 2,4,5-T 38 1.4 (1.0–2.2) 2,4-D 110 1.6 (0.9–2.7) Nonallergic asthma 2,4,5-T 88 1.2 (0.9–1.6) 2,4-D 264 1.2 (0.9–1.6) Slager et al., US AHS—commercial pesticide applicators 1,664 2009 Current rhinitis and exposure to: 2,4-D 750 1.3 (1.1–1.6)

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717 OTHER HEALTH EFFECTS TABLE 11-1 Noncancerous Respiratory Disease, continued Exposure of Interest/ Exposed Estimated Risk Casesa (95% CI)a Reference Study Population Hoppin US AHS—prevalence at enrollment among et al., 2008 farm 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 et al., 2007a self-reported farmer’s lung (hypersensitivity pneumonitis) Private applicators exposed to phenoxy 392 1.2 (0.8–1.7) herbicides 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) Valcin et al., US AHS—prevalence at enrollment of chronic 2007 bronchitis in nonsmoking farm women exposed 0.9 (0.7–1.1) to: 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—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) continued

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718 VETERANS AND AGENT ORANGE: UPDATE 2010 TABLE 11-1 Noncancerous Respiratory Disease, continued Exposure of Interest/ Exposed Estimated Risk Casesa (95% CI)a Reference Study Population 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) Commercial applicators with current use of: 2,4-D nr 1.0 (0.7–1.3) Dicamba nr 0.8 (0.6–1.1) 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) Other Agricultural Studies Herbicides Senthilselvan Cross-sectional study of self-reported et al., 1992 prevalence of self-reported asthma (n = 83) Asthmatics vs in male farmers (n = 1,939) in Saskatchewan nonasthmatics (1982–1983) Phenoxyacetic herbicide use 71 85.5% vs 88.5% Herbicide and Pesticide Applicators Herbicides Blair et al., Licensed pesticide applicators, Florida, 1983 noncancerous respiratory diseases, (ICD-8 2 0.9 (nr) 460–519) Analyses by length of licensure ≥ 10 yrs 8 0.6 (nr) 10–19 yrs 8 1.5 (nr) ≥ 20 yrs 4 1.7 (nr) Forestry Workers Herbicides Alavanja PMR study of US Department of Agriculture 80 0.8 (0.6–1.0) et al., 1989 soil, forest conservationists, mortality 1970– 1979 from noncancerous respiratory diseases (ICD-9 460–519) ENVIRONMENTAL Seveso, Italy Residential Cohort TCDD Consonni 25-yr follow-up of Seveso residents—mortality et al., 2008 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) 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)

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748 VETERANS AND AGENT ORANGE: UPDATE 2010 the osteoporosis disease process can be without symptoms for decades. It is well known that hormones, vitamins, and pharmaceuticals can have adverse effects on bone. Drug-induced osteoporosis occurs primarily in postmenopausal women, but premenopausal women and men are also significantly affected. Glucocorticoids are the most common cause of drug-induced osteoporosis (Mazziotti et al., 2010). Other risk factors for loss of bone density include long-acting benzodiazepine or anticonvulsant drug use, previous hyperthyroidism, excessive caffeine intake, and standing 4 or fewer hours per day (Lash, 2009). Several studies have described a link between organochlorine exposure and effects on bone growth, most notably reports of infants exposed in utero to high concentration of PCBs and polychlorinated dibenzofurans developing irregular calcifications of their skull bones (Miller, 1985) and reports of accidental or- ganochlorine poisonings resulting in osteoporosis (Cripps et al., 1984; Gocmen et al., 1989). However; the epidemiological studies of the association between bone disorders and environmental exposures to organochlorine compounds have been inconsistent. Summary of Previous Updates Previous VAO updates have not examined bone density or osteoporosis as a health outcome. This is the first VAO update in which studies examining the association between exposures to the chemicals of interest and decrease in bone density are reviewed. Update of the Scientific Literature No Vietnam-veteran or occupational studies concerning the chemicals of interest and bone density or osteoporosis have been published. Environmental Studies Hodgson et al. (2008) studied the relationship between organochlorine ex- posure and BMD in a subset of 325 members of the Osteoporosis Cadmium as a Risk Factor (OSCAR) cohort who were at least 60 years old. Many of the cohort members lived close to the Baltic coast and may have had PCB exposure from fish consumption and potentially from exposure from a PCB-contaminated river. The cohort contains 1,021 individuals who provided information on employment, residence, smoking, diet, and medical history. Forearm BMD was measured on the distal site of the nondominant forearm with an osteometer using dual energy x-ray absorptiometry. Blood samples were analyzed for total TEQs for five mono- ortho chlorine substituted congeners (PCB 105, 118, 156, 157, and 167) and for the concentration of PCB 118 alone. TEQs for the mono-ortho PCBs ranged from 0.002 to 0.067 pg/mL in men and from 0.003 to 0.053 pg/mL in women. In males,

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749 OTHER HEALTH EFFECTS stepwise multivariate analyses adjusted for age, BMI, and milk consumption found PCB 118 to have a marginally significant negative association with BMD (β = –0.00011, p = 0.079), but TEQ for all five dioxin-like PCBs did not show an association (β = 0.225, p = 0.846). In females, stepwise multivariate analyses adjusted for age, BMI, age at menstruation, and ever-pregnant found PCB 118 alone and TEQ for all five dioxin-like PCBs were positively associated with BMD (β = 0.00008, p = 0.045; β = 1.652, p = 0.057, respectively). When the risk of low BMD (more than 1 standard deviation below the mean value) was treated as a binary variable in a similarly adjusted logistic model, there was a significant association with PCB 118 in men (OR = 1.06, 95% CI 1.01–1.12, p = 0.027), but none of the measured organochlorine compounds (also including non-dioxin-like PCB 138, 153, and 180) were predictive for the women. Biological Plausibility Animal studies suggest that TCDD may have some influence on bone forma- tion and maintenance. For instance, TCDD exposure via the dam’s milk impaired bone mineralization during postnatal development in mice due to a reduction of the osteoblastic activity, which is caused by TCDD-induced up-regulation in the active form of vitamin D in serum (Nishimura et al., 2009). TCDD altered osteo - genesis (bone formation) in an in vitro osteoblast model, producing alterations in proteins associated with cytoskeleton organization and biogenesis and a decrease in the expression of calcium-binding proteins, which decreases osteoblast calcium deposition (Carpi et al., 2009). Synthesis The small amount of epidemiologic information available concerning pos - sible adverse effects on bone structure in association with exposure to the chemi - cals of interest is based almost entirely on a single dioxin-like PCB. The findings of Hodgson et al. (2008) do not constitute a strong or consistent pattern. Conclusion There is inadequate or insufficient evidence of an association between expo - sure to the chemicals of interest and clinical or overt adverse effects of osteopo- rosis or loss of bone mineral density. 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

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750 VETERANS AND AGENT ORANGE: UPDATE 2010 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, Update 2006, and Update 2008. 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. On the basis of the literature, none of the 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. On the basis of the literature, none of the health effects discussed in this chapter satisfy the criteria necessary for inclusion 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 asso- ciation 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 noncancerous respiratory disorders, such as COPD, asthma in isolation, pleurisy, pneumonia, and tuber- culosis; gastrointestinal diseases; digestive diseases; liver toxicity; disorders of thyroid homeostasis; and disorders of the eyes and bones. 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

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751 OTHER HEALTH EFFECTS 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. REFERENCES1 Abdelouahab N, Mergler D, Takser L, Vanier C, St-Jean M, Baldwin M, Spear PA, Chan HM. 2008. Gender differences in the effects of organochlorines, mercury, and lead on thyroid hormone levels in lakeside communities of Quebec (Canada). Environmental Research 107(3):380–392. ADVA (Australian Department of Veterans Affairs). 2005b. The Third Australian Vietnam Veterans Mortality Study 2005. Canberra, Australia: Department of Veterans’ Affairs. ADVA. 2005c. Australian National Service Vietnam Veterans: Mortality and Cancer Incidence 2005. Canberra, Australia: Department of Veterans’ Affairs. AFHS (Air Force Health Study). 1991b. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Mortality Update: 1991. Brooks AFB, TX: Armstrong Laboratory. AL-TR-1991-0132. AFHS. 1996. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Mortality Update 1996. Brooks AFB, TX: Epidemiologic Research Division, Armstrong Laboratory. AL/AO-TR-1996-0068. AFHS. 2000. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1997 Follow-up Examination Results. Brooks AFB, TX: Epidemiologic Research Division, Armstrong Laboratory. AFRL-HE-BR-TR-2000-02. AFHS. 2005. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 2002 Follow-up Examination Results. Brooks AFB, TX: Epidemiologic Research Division, Armstrong Laboratory. AFRL-HE-BR-SR-2005-0003. Alavanja M, Merkle S, Teske J, Eaton B, Reed B. 1989. Mortality among forest and soil conservation- ists. Archives of Environmental Health 44:94–101. Anderson H, Hanrahan L, Jensen M, Laurin D, Yick W, Wiegman P. 1986. Wisconsin Vietnam Veteran Mortality Study: Proportionate Mortality Ratio Study Results. Madison: Wisconsin Division of Health. Becher H, Flesch-Janys D, Kauppinen T, Kogevinas M, Steindorf K, Manz A, Wahrendorf J. 1996. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins. Cancer Causes and Control 7(3):312–321. Bertazzi P, Zocchetti C, Pesatori A, Guercilena S, Sanarico M, Radice L. 1989a. Mortality in an area contaminated by TCDD following an industrial incident. Medicina Del Lavoro 80:316–329. 1 Throughout the report the same alphabetic indicator following year of publication is used con - sistently for the same article when there were multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicator in order of citation in a given chapter is not followed.

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753 OTHER HEALTH EFFECTS Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. 2000. The Colorado thyroid disease prevalence study. Archives of Internal Medicine 160(4):526–534. Carlson E, McCulloch C, Koganti A, Goodwin S, Sutter T, Silkworth J. 2009. Divergent transcrip - tomic responses to aryl hydrocarbon receptor agonists between rat and human primary hepato - cytes. Toxicological Sciences 112(1):257–272. Carpi D, Korkalainen M, Airoldi L, Fanelli R, Hakansson H, Muhonen V, Tuukkanen J, Viluksela M, Pastorelli R. 2009. Dioxin-sensitive proteins in differentiating osteoblasts: Effects on bone formation in vitro. Toxicological Sciences 108(2):330–343. Casarett L, Doull J. 1995. Casarett and Doull’s Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill. CDC (Centers for Disease Control and Prevention). 1988. Centers for Disease Control Vietnam Ex - perience Study. Health status of Vietnam veterans. II: Physical health. Journal of the American Medical Association 259(18):2708–2714. CDC. 2002. National health and nutrition examination survey: Osteoporosis. http://www.cdc.gov/ nchs/data/nhanes/databriefs/osteoporosis.pdf (accessed April 1, 2011). CDVA (Commonwealth Department of Veterans’ Affairs). 1997a. Mortality of Vietnam Veterans: The Veteran Cohort Study. A Report of the 1996 Retrospective Cohort Study of Australian Vietnam Veterans. Canberra, Australia: Department of Veterans’ Affairs. CDVA. 1997b. Mortality of National Service Vietnam Veterans: A Report of the 1996 Retrospective Cohort Study of Australian Vietnam Veterans. Canberra, Australia: Department of Veterans’ Affairs. Celli BR, Halbert, RJ. 2010a. Point: Should we abandon FEV1/FEC < 0.70 to detect airway obstruc- tion? No. Chest 138(5):1037–1039. Celli BR, Halbert, RJ. 2010b. Rebuttal from Drs Celli and Halbert. Chest 138(5):1042–1043. Chevrier J, Eskenazi B, Bradman A, Fenster L, Barr DB. 2007. Associations between prenatal exposure to polychlorinated biphenyls and neonatal thyroid-stimulating hormone levels in a Mexican-American population, Salinas Valley, California. Environmental Health Perspectives 115:1490–1496. Chevrier J, Eskenazi B, Holland N, Bradman A, Barr DB. 2008. Effects of exposure to polychlori - nated biphenyls and organochlorine pesticides on thyroid function during pregnancy. American Journal of Epidemiology 168:298–310. Coggon D, Pannett B, Winter P, Acheson E, Bonsall J. 1986. Mortality of workers exposed to 2-methyl-4-chlorophenoxyacetic acid. Scandinavian Journal of Work, Environment, and Health 12:448–454. Coggon D, Pannett B, Winter P. 1991. Mortality and incidence of cancer at four factories making phenoxy herbicides. British Journal of Industrial Medicine 48:173–178. Collins JJ, Bodner K, Aylward LL, Wilken M, Bodner CM. 2009a. Mortality rates among trichlo - rophenol workers with exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. American Journal of Epidemiology 170(4):501–506. Collins JJ, Bodner K, Aylward LL, Wilken M, Swaen G, Budinsky R, Rowlands C, Bodnar CM. 2009b. Mortality rates among workers exposed to dioxins in the manufacture of pentachloro - phenol. Journal of Occupational and Environmental Medicine 51(10):1212–1219. Collins JJ, Bodner K, Aylward LL. 2010a. Letter to editors. American Journal of Epidemiology 171:129–133. Collins JJ, Bodner K, Aylward LL. 2010b. Three authors reply. American Journal of Epidemiology 171(1):130–131. Consonni D, Pesatori AC, Zocchetti C, Sindaco R, D’Oro LC, Rubagotti M, Bertazzi PA. 2008. Mortality in a population exposed to dioxin after the Seveso, Italy, accident in 1976: 25 years of follow-up. American Journal of Epidemiology 167(7):847–858.

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