13


Other Chronic Health Outcomes

Chapter Overview

Based on new evidence and a review of prior studies, the committee for Update 2012 did not find any new significant associations between the relevant exposures and adverse chronic health outcomes other than those addressed in earlier chapters. Current evidence supports the findings of earlier studies that:

•  No other adverse outcomes had sufficient evidence of an association with the chemicals of interest.

•  No other adverse outcomes had limited or suggestive evidence of an association with the chemicals of interest.

•  There is inadequate or insufficient evidence to determine whether there is an association between the chemicals of interest and respiratory disorders, gastrointestinal and digestive diseases (including liver toxicity), adverse effects on thyroid homeostasis, eye problems, or bone conditions.

In previous updates that considered short-term adverse outcomes (see Appendix B), committees found

•  There is sufficient evidence of an association between the chemicals of interest and chloracne.

•  There is limited or suggestive evidence of an association between the chemicals of interest with early onset peripheral neuropathy and porpohyria cutanea tarda.



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13 Other Chronic Health Outcomes Chapter Overview Based on new evidence and a review of prior studies, the committee for Update 2012 did not find any new significant associations between the relevant exposures and adverse chronic health outcomes other than those addressed in earlier chap- ters. Current evidence supports the findings of earlier studies that: • No other adverse outcomes had sufficient evidence of an association with the chemicals of interest. • No other adverse outcomes had limited or suggestive evidence of an as- sociation with the chemicals of interest. • There is inadequate or insufficient evidence to determine whether there is an association between the chemicals of interest and respiratory dis- orders, gastrointestinal and digestive diseases (including liver toxicity), adverse effects on thyroid homeostasis, eye problems, or bone conditions. In previous updates that considered short-term adverse outcomes (see Appendix B), committees found • There is sufficient evidence of an association between the chemicals of interest and chloracne. • There is limited or suggestive evidence of an association between the chemicals of interest with early onset peripheral neuropathy and porpo- hyria cutanea tarda. 879

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880 VETERANS AND AGENT ORANGE: UPDATE 2012 This chapter discusses data on the possible association between expo- sure to the herbicides used in Vietnam—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-­ trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachloro­dibenzo-p-dioxin (TCDD), picloram, and cacodylic acid and several noncancer health outcomes: respiratory disorders, gastrointestinal and digestive diseases (including liver toxicity), adverse effects on thyroid homeo- stasis, eye problems, and bone conditions. The committee also considers results of studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like chemicals to be informative if they were reported in terms of TCDD toxic equiva- lents (TEQs) or concentrations of specific congeners. While all studies reporting TEQs based on PCBs were reviewed, those studies that reported TEQs based only on mono-ortho PCBs (which are PCBs 105, 114, 118, 123, 156, 157, 167, and 189) were given very limited consideration since mono-ortho PCBs typically contribute less than 10% to total TEQs, based on the World Health Organization (WHO) revised toxicity equivalency factors (TEFs) of 2005 (La Rocca et al., 2008; van den Berg et al., 2006). In previous updates, chloracne and porphyria cutanea tarda were considered with the chronic noncancer conditions. They are accepted as being associated with dioxin exposure, but when they occur it happens within a matter of months of the exposure. In Update 2010, the two health outcomes were 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 disorders. 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 Medi- cine 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 are not revisiting a previously studied population, design information is summarized with the results; design information on other studies can be found in Chapter 6. A synopsis of toxicologic and clinical information related to the biologic plausibility that the chemicals of interest (COIs) 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 regard- ing the strength of the evidence that supports an association with the COIs. The categories of association and the committee’s approach to categorizing 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

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OTHER CHRONIC HEALTH OUTCOMES 881 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 pulmonary 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 do 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 often misclassified on death certificates. Grouping vari- ous respiratory diseases for analysis, unless they all are associated with a given 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 is often inconsistent. In par- ticular, when a person had 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 combines pneumonia, influenza, and other diseases with COPD and asthma. The committee notes that an association between the group of all noncancerous respiratory diseases with any of the COIs would be too nonspecific to be clinically meaningful; at most, such a pattern would be an indication that within this broad classification the

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882 VETERANS AND AGENT ORANGE: UPDATE 2012 incidence of some particular disease entity might be affected by an exposure to a COI. 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 COIs and the respiratory disorders speci- fied above. Additional information available to the committees responsible for Veterans and Agent Orange: Update 1996 (IOM, 1996) and Update 1998 (IOM, 1999) did not change that finding. Update 2000 (IOM, 2001) drew attention to findings in the Seveso cohort that suggested a higher mortality from noncancerous 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 COIs and respiratory disorders. Additional information available to the com- mittee responsible for Update 2002 (IOM, 2003) did not change that finding. Update 2004 (IOM, 2005) included a new cross-sectional study of people who lived 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 confounding in that history of tobacco use was not accounted for adequately. 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 (AFHS) (Ketchum and Michalek, 2005), and in two Australian studies of Vietnam veterans (ADVA, 2005b,c). In contrast, in the US Army Chemical Corps (ACC) cohort of Vietnam veterans, Kang et al. (2006) found that the prevalence of self-reported noncancer- ous 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 parts per trillion (ppt). In addition, Update 2006 addressed new studies of potentially exposed oc-

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OTHER CHRONIC HEALTH OUTCOMES 883 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 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 Update 2008 (IOM, 2009) concerning morbidity from particular self-reported respiratory health problems: analyses concerning wheeze (Hoppin et al., 2006b), asthma (Hoppin et al., 2008), “farmer’s lung” or hypersensitivity pneumonitis (Hoppin et al., 2007a), and chronic bronchitis (Hoppin et al., 2007b; Valcin et al., 2007). The 25-year followup of mortality in the Seveso population through 2001 (Consonni et al., 2008) was also considered in Update 2008; again there was some increase in mortality from COPD as had been seen in the earlier mortality followup re- viewed in Update 2000. New literature considered in Update 2010 raised considerable concern that a pattern of COPD might be coming into focus. Cypel and Kang (2010) reported cause-specific mortality through 2005 in an ACC cohort of deployed and non- deployed Vietnam-era veterans and in a subset of the original deployed ACC veterans who reported in a morbidity study whether they had sprayed herbicide (Kang et al., 2006). Cypel and Kang (2010) reported a statistically significant ex- cess mortality from COPD (RR = 4.82, 95% confidence interval [CI] 1.10–21.18) when comparing the deployed and nondeployed groups. A similar pattern in the deployed ACC veterans was observed when they were compared with the US male population (SMR = 1.62, 95% CI 0.99–2.51). When the subgroups of deployed ACC veterans who had and had not reported spraying herbicides were compared, the sprayers had an elevated risk for death due to the less specific category of “noncancerous respiratory system disease” (RR = 2.24, 95% CI 0.42–11.83); this was the only one of these comparisons able to control for self- reported herbicide exposure, body-mass index, and smoking status. Deaths due to CODP were lower in non-deployed ACC veterans relative to males in the US population (standardized mortality ratio [SMR] = 0.3, 95% CI 0.04–1.07); this is noteworthy because the prevalence of smoking in the nondeployed ACC veterans was about twice that in men in the US population (Kang et al., 2006). Publica- tions evaluated in Update 2010 that studied industrial cohorts did not report on COPD but did not find increased mortality from noncancerous respiratory dis- eases overall (Boers et al., 2010; Collins et al., 2009a,b; McBride et al., 2009a). In the AHS cohort, Hoppin et al. (2009) did not find increased morbidity from asthma associated with 2,4-D or 2,4,5-T use; Slager et al. (2009) found current use of 2,4-D to be associated with an increase in current rhinitis. Table 13-1 summarizes the results of the relevant studies.

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884 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 13-1  Selected Epidemiologic Studies—Noncancer Respiratory Disease (Shaded Entries Are New Information for This Update) Exposure of Interest/Estimated Exposed Relative Risk Study Population Casesa (95% CI)a Reference VIETNAM VETERANS US Vietnam Veterans US Air Force Health Study—Ranch Hand All COIs veterans vs SEA veterans (unless otherwise noted) Mortality Through 1999—Ranch Hand personnel (n 8 1.2 (0.6–2.5) Ketchum and =1,262) vs SEA veterans (19,078) (respiratory Michalek, disease, ICD-9 460–519) 2005 US VA Cohort of Army Chemical Corps— All COIs Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 nondeployed) serving during Vietnam era (07/01/1965–03/28/1973) Incidence—Self-reported respiratory disease diagnosed by doctor CATI survey of stratified sample: 1,499 Kang et al., deployed (795 with TCDD measured) vs 1,428 2006 nondeployed (102 with TCDD measured) Deployed vs nondeployed 267 1.4 (1.1–1.8) Sprayed herbicides in Vietnam (n = 662) vs 140 1.6 (1.2–2.1) never (n = 811) Mortality—respiratory disease Through 2005 Cypel and Deployed veterans (2,872) vs nondeployed Kang, 2010 (2,737) Respiratory system disease 32 vs 8 2.2 (1.0–4.9) Pneumonia, 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) Through 1991 (respiratory system disease) 11 vs 2 2.6 (0.5–12.2) Dalager and Kang, 1997 US CDC Vietnam Experience Study—Cross- All COIs sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed Incidence Physical health— ORs from pulmonary- CDC, 1988 function tests (case definition: ≥ 80% predicted value) FEV1 254 0.9 (0.7–1.1)

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OTHER CHRONIC HEALTH OUTCOMES 885 TABLE 13-1  Noncancer Respiratory Disease, continued Exposure of Interest/Estimated Exposed Relative Risk Study Population Casesa (95% CI)a Reference FVC 177 1.0 (0.8–1.3) FEV1/FVC 152 1.0 (0.8–1.3) Mortality 1965–2000 (noncancerous respiratory 20 0.8 (0.5–1.5) Boehmer et mortality, ICD-9 460–519) al., 2004 US VA Proportionate Mortality Study—sample All COIs of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973 1965–1988 Watanabe Army, deployed (n = 27,596) vs 648 0.8 (p < 0.05) and Kang, nondeployed (n = 31,757) 1996 Marine Corps, deployed (n = 6,237) vs 111 0.7 (p < 0.05) nondeployed (n = 5,040) US VA Study of Male Vietnam Veterans All COIs Wounded in Combat Mortality through December 1991 Bullman and Noncancerous respiratory mortality (ICD-9 43 0.9 (0.7–1.2) Kang, 1996 460–519) US VA Cohort of Monozygotic All COIs Twins—Vietnam-era Incidence of respiratory conditions, deployed Eisen et al., vs undeployed 1991 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) State Studies of US Vietnam Veterans 923 White male Vietnam veterans with Anderson et Wisconsin death certificate (1968–1978) vs al., 1986 proportions for Vietnam-era veterans (mortality from noncancerous respiratory disease, ICD-8 460–519) Vietnam veterans vs expected deaths calculated 10 from proportions for: Nonveterans 0.5 (0.3–0.8) All veterans 0.8 (0.4–1.5) Vietnam-era veterans 1.0 (0.5–1.8) International Vietnam-Veteran Studies Australian Vietnam Veterans—58,077 men All COIs and 153 women served on land or in Vietnamese waters during 5/23/1962–7/1/1973 vs Australian population Mortality All branches, return–2001 ADVA, Respiratory system disease 239 0.8 (0.7–0.9) 2005b continued

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886 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 13-1  Noncancer Respiratory Disease, continued Exposure of Interest/Estimated Exposed Relative Risk Study Population Casesa (95% CI)a Reference COPD 128 0.9 (0.7–1.0) Navy Respiratory system disease 50 0.8 (0.6–1.0) COPD 28 0.9 (0.6–1.3) Army Respiratory system disease 162 0.8 (0.7–0.9) COPD 81 0.9 (0.7–1.0) Air Force Respiratory system disease 28 0.6 (0.4–0.9) COPD 18 0.8 (0.4–1.2) 1980–1994 CDVA, Noncancerous respiratory mortality (ICD-9 1997a 460–519) 1964–1979 3 0.1 (0.0–0.3) 1980–1994 92 0.9 (0.7–1.1) Chronic obstructive airways disease 47 0.9 (0.7–1.2) (ICD-9 460–496) Sample of 1,000 Male Australian Vietnam All COIs Veterans—prevalence 450 interviewed 2005–2006 vs respondents to O’Toole et 2004–2005 national survey al., 2009 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, allergic rhinitis nr 1.2 (0.96–1.4) Chronic sinusitis nr 1.7 (1.5–2.0) Other diseases of respiratory system nr 15.4 (11.7–19.1) 641 interviewed 1990–1993 vs respondents to O’Toole et 1989–1990 national survey al., 1996 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) Australian Conscripted Army National Service All COIs (18,940 deployed vs 24,642 nondeployed) Mortality 1966–2001 ADVA, Respiratory diseases 18 1.1 (0.6–2.2) 2005c COPD 8 1.0 (0.3–2.8) 1982–1994 CDVA, 1965–1982 2 2.6 (0.2–30.0) 1997b 1982–1994 6 0.9 (0.3–2.7)

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OTHER CHRONIC HEALTH OUTCOMES 887 TABLE 13-1  Noncancer Respiratory Disease, continued Exposure of Interest/Estimated Exposed Relative Risk Study Population Casesa (95% CI)a Reference OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates Mortality 1939–1992 Phenoxy Kogevinas et herbicides, al., 1997 chlorophenols 21,863 exposed workers Men 252 0.8 (0.7–0.9) Women 7 1.1 (0.4–2.2) British MCPA Plant—Production 1947–1982 (n MCPA = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort) Mortality through 1983 (noncancerous 93 0.6 (0.5–0.8) Coggon et respiratory diseases, ICD-9 460–519) al., 1986 British Production Workers at 4 plants Dioxins, but Coggon et (included in IARC cohort) TCDD unlikely; al., 1991 MCPA Mortality 1963–1985 (noncancerous 8 0.7 (0.3–1.3) respiratory diseases, ICD-9 460–519) Dutch production workers in Plant A and Dioxins; 2,4-D, Plant B, combined (Plant A, 1,020 workers; 2,4-DP; 2,4,5- Plant B, 1,036 workers) (in IARC cohort) T; 2,4,5-TCP MCPA; MCPP Mortality 1955–2006 (diseases of the 52 1.0 (0.8–1.2) Boers et al., respiratory system) 2012 Dutch production workers in Plant A (549 Dioxins, 2,4,5-T, men exposed during production 1955–1985; 594 2,4,5-TCP unexposed) (in IARC cohort) Mortality 1955–2006 (HRs for lagged TCDD Boers et al., plasma levels) 2012 Diseases of the respiratory system 31 1.0 (0.8–1.3) Mortality 1955–2006 19 vs 12 1.0 (0.4–2.3) Boers et al., 2010 Dutch production workers in Plant B (414 2,4-D; MCPA; men exposed during production 1965–1986; 723 MCPP; highly unexposed) (in IARC cohort) chlorinated dioxins unlikely continued

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888 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 13-1  Noncancer Respiratory Disease, continued Exposure of Interest/Estimated Exposed Relative Risk Study Population Casesa (95% CI)a Reference Mortality 1965–2006 6 vs 15 0.5 (0.2–1.2) Boers et al., German Production Workers at Bayer Plant Dioxins; 2010 in Uerdingen (135 men working > 1 month in 2,4,5-TCP 1951–1976) (in IARC cohort as of 1997) and women—no results Mortality 1951–1992 (ICD-9 460–519) 2 0.9 (0.1–3.1) Becher et al., 1996 German Production Workers at Bayer Plant Dioxins; 2,4-D; in Dormagen (520 men working > 1 month in 2,4,5-T; MCPA; 1965–1989) (in IARC cohort as of 1997) and MCPP; 2,4-DP women—no results Mortality 1965–1989 (ICD-9 460–519) 0 0.0 Becher et al., 1996 German Production Workers at BASF Dioxins; 2,4-D; Ludwigshafen Plant (680 men working > 1 2,4,5-T; MCPA; month in 1957–1987) (in IARC cohort as of MCPP; 2,4-DP 1997) and women—no results Mortality 1956–1989 (ICD-9 460–519) 4 0.6 (0.2–1.6) Becher et al., 1996 BASF Cleanup Workers from 1953 accident Focus on TCDD (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC) Incidence Through 1989 (n = 158 men exposed Zober et al., within 1 yr of accident vs 161 other BASF 1994 employees 1953–1969) All noncancerous respiratory diseases nr 33.7/31.0 (p = (ICD-9 460–419) 0.22) Upper respiratory tract infections nr 12.0/9.0 (p = (ICD-9 460–478) 0.00) Pneumonia, 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) Mortality 1953–1992 (noncancerous respiratory) 1 0.1 (0.0–0.8) Ott and Zober, 1996 German Production Workers at Boehringer– Dioxins; 2,4,5- Ingelheim Plant in Hamburg (1,144 men T; 2,5-DCP; working > 1 month in 1952–1984; generation 2,4,5-TCP of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)

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OTHER CHRONIC HEALTH OUTCOMES 889 TABLE 13-1  Noncancer Respiratory Disease, continued Exposure of Interest/Estimated Exposed Relative Risk Study Population Casesa (95% CI)a Reference Mortality 1952–2007 (ICD-9 codes 460–519) 33 0.6 (0.4–0.9) Manuwald et Men 25 0.6 (0.4–0.9) al., 2012 Women 8 0.7 (0.3–1.4) Mortalilty 1952–1989 (ICD-9 460–519) 10 0.5 (0.3–1.0) Becher et al., 1996 New Zealand Phenoxy Herbicide Production Dioxins; 2,4-D; Workers and Sprayers (1,599 men and women 2,4,5-T; MCPA; working any time in 1969–1988 at Dow plant in MCPB; 2,4,5- New Plymouth) (in IARC cohort) TCP; Picloram Mortality 1969–2004 McBride et Ever-exposed workers 12 0.8 (0.4–1.4) al., 2009a Never-exposed workers 2 0.4 (0.0–1.5) Production Workers (713 men and 100 women worked > 1 month in 1969–1984) Mortality 1969–2000 9 0.9 (0.4–1.8) ’t Mannetje et al., 2005 Sprayers (697 men and 2 women on register of New Zealand applicators, 1973–1984) Mortality 1973–2000 6 0.7 (0.2–1.2) ’t Mannetje et al., 2005 NIOSH Mortality Cohort (12 US plants, 5,172 Dioxins, phenoxy male production and maintenance workers 1942– herbicides 1984) (included in IARC cohort as of 1997) Through 1993 (noncancerous respiratory, 86 0.9 (0.7–1.1) Steenland et ICD-9 460–519) al., 1999 Monsanto workers (n = 240) involved Suskind and in 2,4,5-T production (1948–1969) and Hertzberg, 163 unexposed workers, results of clinical 1984 examination July 1979—morbidity “Abnormal” outcome on pulmonary- functions tests: FEV1 (< 80% predicted) 32 2.81 (p = 0.02) FVC (< 80% predicted) 35 2.25 (p = 0.03) FEV1/FVC (< 70%) 32 2.97 (p = 0.01) FEF25–75 (< 80% predicted) 47 1.86 (p = 0.05) All Dow TCP-Exposed Workers (TCP 2,4,5-T; production 1942–1979 or 2,4,5-T production 2,4,5-TCP 1948–1982 in Midland, Michigan) (in IARC and NIOSH cohorts) 1942–2003 (n = 1,615) 44 0.8 (0.6–1.0) Collins et al., 2009a continued

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OTHER CHRONIC HEALTH OUTCOMES 925 Although men have much higher baseline BMD than women have, they seem to have a similar fracture risk for a given BMD (Lash et al., 2009). Sex is an important risk factor for osteoporosis; about 56% of post­ enopausal m women have decreased BMD, and 6% have osteoporosis (CDC, 2002). Data on the effects of aging on bone loss in women are well known, but many health care providers and patients are less familiar with the prevalence and effects of bone changes in older men (Orwoll et al., 2010). Individual patients have genetic and acquired risks of osteoporosis, and 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 BMD include use of long-acting benzodiazepine or anticonvulsant drugs, previous hyperthyroidism, excessive caffeine intake, and standing for 4 hours a day or less (Lash et al., 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 PCDFs who developed irregular calcifications of their skulls (Miller, 1985) and reports of accidental organochlorine poisoning that resulted in osteoporosis (Cripps et al., 1984; Gocmen et al., 1989). However; the epidemiologic studies of the association between environmental exposures to organochlorine compounds and bone disorder have been inconsistent. Summary of Previous Updates Update 2010 was the first VAO update that reviewed studies of the associa- tion between exposures to the COIs and decrease in BMD. Results from Hodgson et al. (2008) motivated the inclusion of this health outcome. They studied the relationship between environmental exposures and BMD in a set of 325 members of the Osteoporosis Cadmium as a Risk Factor (OSCAR) cohort who were at least 60 years old. Forearm BMD was measured, and blood samples were analyzed for the five dioxin-like mono-ortho PCB congeners (PCB 105, 118, 156, 157, and 167) and TEQs calculated. In men, PCB 118 had a marginally significant negative association with BMD, but the TEQ for all five dioxin-like mono-ortho PCBs did not show an association. In women, PCB 118 alone and the TEQ for all five dioxin-like mono-ortho PCBs were positively associated with BMD (slope 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) was treated as a binary variable in an adjusted logistic model, there was a significant association with PCB 118 in men, but none of the measured compounds (also including non- dioxin-like PCBs 138, 153, and 180) was predictive in women.

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926 VETERANS AND AGENT ORANGE: UPDATE 2012 Update of the Epidemiologic Literature Vietnam-Veteran and Case-Control Studies No Vietnam veteran or case-control studies of exposure to the COIs and BMD or osteoporosis have been published since Update 2010. Occupational Studies The recent update of the AHS (Waggoner et al., 2011) reported an inverse association of death with musculoskeletal and connective tissue diseases. This category is difficult to interpret and may be subject to a healthy-worker effect bias. The AHS has been generating valuable information on the COIs for a num- ber of years, but these results, like those in Alavanja et al. (2005) and Blair et al. (2005), are not herbicide-specific and so are not regarded as being fully informa- tive for the committee’s task. Environmental Studies Cho et al. (2011) recently reported that persistent organic pollutants can interact biologically with fat mass and lean mass and affect BMD. The study involved the NHANES population (2,769 participants). Biologic Plausibility Animal studies suggest that TCDD may have some influence on bone forma- tion and maintenance. It is known that TCDD can induce chondrocyte apoptosis in culture, which could be an initial event leading to cartilage degradation as observed in arthritis (Yang and Lee, 2010); Lee and Yang (2012) recently dem- onstrated that this is mediated by reactive oxygen species. In addition, TCDD exposure via the dam’s milk impaired bone mineralization during postnatal development in mice because of a reduction in osteoblastic activity as a re- sult of TCDD-induced up-regulation in the active form of vitamin D in serum (Nishimura et al., 2009). TCDD altered osteogenesis (bone formation) in an in vitro osteoblast model and led to alterations in proteins associated with cytoskel- eton organization and biogenesis, a decrease in the expression of calcium-binding proteins, and a decrease in osteoblast calcium deposition (Carpi et al., 2009). In adult rats, TCDD exposure reduced trabecular bone cross-sectional area, but significantly increased total BMD; it was further noted that TCDD decreased expression of the bone-formation marker procollagen type I N-terminal propep- tide and increased expression of the bone-resorption marker carboxy-terminal collagen cross-link, suggesting a net loss of bone tissue (Lind et al., 2009). It is also known that exposure to polyaromatic hydrocarbons (such as those in tobacco

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OTHER CHRONIC HEALTH OUTCOMES 927 smoke) can affect bone health, and some of these alterations have been shown to be mediated, at least in part by the AHR. That implies that TCDD may alter or modify the effects (Kung et al., 2012; Yan et al., 2011). Synthesis The small amount of available epidemiologic information on possible ad- verse effects of exposure to the COIs on bone structure is based entirely on dioxin-like mono-ortho PCBs, which contribute a small percentage to total TEQs based on all dioxin-like PCBs. The findings of Hodgson et al. (2008) do not constitute a strong or consistent pattern. The alteration in BMD associated with persistent pollutants in the NHANES participants suggests that additional studies of this affect are warranted. Conclusion There is inadequate or insufficient evidence of an association between ex- posure to the COIs and clinical or overt adverse effects of osteoporosis or loss of BMD. 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. 2000. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1997 Followup 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 Followup 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. 1  Throughout this report, the same alphabetic indicator after year of publication is used consistently for a given reference when there are multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicators in order of citation in a given chapter is not followed.

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