Veterans and Agent Orange Update 2012 (2014) / Chapter Skim
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13 Other Chronic Health Outcomes
13 Other Chronic Health Outcomes
Pages 879-935
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• 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)
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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)
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. 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.
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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.
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. Publications evaluated in Update 2010 that studied industrial cohorts did not report on COPD but did not find increased mortality from noncancerous respiratory diseases overall (Boers et al., 2010; Collins et al., 2009a,b; McBride et al., 2009a)
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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)
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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)
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(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)
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From page 887... ...
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)
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All noncancerous respiratory diseases nr 33.7/31.0 (p = (ICD-9 460–419)
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(included in IARC cohort as of 1997) Through 1993 (noncancerous respiratory, 86 0.9 (0.7–1.1)
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al., 2009b Mortality 1940–1989 (n = 770) Ramlow et Noncancerous respiratory mortality 14 0.9 (0.5–1.5)
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in Saskatchewan Asthmatics vs (1982–1983) nonasthmatics Phenoxyacetic herbicide use 71 85.5% vs 88.5% UNITED STATES US Agricultural Health Study -- prospective Phenoxy study of licensed pesticide sprayers in Iowa herbicides and North Carolina: commercial (n = 4,916 men)
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women) US Department of Agriculture Workers -- Herbicides nested case-control study of white men dying 1970–1979 of noncancerous respiratory diseases (ICD-8 460–519)
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Zone R 74 1.2 (0.9–1.5) 15-yr followup to 1991 -- women Bertazzi et Respiratory disease (ICD-9 460–519)
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NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid; 2,5-DCP, 2,5-dichlorophenol; CATI, computer-assisted telephone interviewing; CI, confidence interval; COI, chemical of interest; COPD, chronic obstructive pulmonary disease; FEF 25–75, forced midexpiratory flow; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD-8, International Classification of Diseases, Eighth Revision; ICD-9, International Classification of Diseases, Ninth Revision; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)
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(2012) reported on the mortality experience of workers in two chlorophenoxy-herbicide plants in the Netherlands by using semi-quantitative measures of TCDD exposure.
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No relationship was found between TCDD exposure and respiratory diseases. Hazard ratios (HRs)
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. Acute noncancerous respiratory disorders, including pneumonia and other respiratory infections, also can be increased in frequency and severity when the normal defense mechanisms of the lower respiratory tract are compromised.
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Synthesis Noncancerous Respiratory Disease (Without Further Specification) Results of the studies of mortality from noncancerous respiratory diseases reported in Update 2008 and earlier VAO reports (ADVA, 2005b,c; Anderson et al., 1986; Becher et al., 1996; Blair et al., 1983, 2005; Boehmer et al., 2004; Bullman and Kang, 1996; Burns et al., 2001; Coggon et al., 1986, 1991; Consonni et al., 2008; Crane et al., 1997a; Ketchum and Michalek, 2005; Kogevinas et al., 1997; Ott and Zober, 1996; Ramlow et al., 1996; Steenland et al., 1999; Svensson et al., 1995; 't Mannetje et al., 2005; Zober et al., 1994)
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Table 13-2 summarizes the findings with the relevant information from previous studies. In an earlier study of mortality in a cohort of Vietnam-era veterans who had served in the ACC, as of 1991, the deployed ACC veterans had a nonsignificant adjusted RR of 2.59 for death due to noncancerous respiratory diseases compared with their nondeployed peers (Dalager and Kang, 1997)
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FEV1/FVC 152 1.0 (0.8–1.3) 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)
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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)
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UNITED STATES US Agricultural Health Study -- prospective Phenoxy study of licensed pesticide sprayers in Iowa herbicides and North Carolina: commercial (n = 4,916 men) , private/farmers (n = 52,395, 97.4% men)
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conducted in 1999–2000 (Kang et al., 2006) found a significant increase in the broader category of self-reported noncancerous respiratory conditions in deployed ACC veterans (OR = 1.41, 95% CI 1.13–1.76)
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The NIOSH cross-sectional study of production workers exposed to TCDD (Calvert et al., 1991) did not show an increase in COPD or chronic bronchitis or in altered pulmonary function measures associated with increased serum TCDD concentration in workers compared with a community-based referent population.
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were indeed COPD cases; among the nondeployed ACC veterans in the morbidity study, there had been only one death from respiratory disease, and it had not been from COPD; and all the respiratory deaths had been in smokers. Conclusions from analysis of COPD mortality in the ACC morbidity-study subset are limited by the very small number of deaths that had occurred by the end of 2005 and by the fact that this subset cannot be considered representative of the entire ACC cohort in that its members were all alive in 1999.
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Conclusion On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence of an association between exposure to the COIs and mortality from all noncancerous respiratory diseases or from COPD specifically. There is also inadequate or insufficient evidence of an association between exposure to the COIs and the prevalence of respiratory diseases, such as wheeze or asthma, COPD, and farmer's lung.
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. Liver Disease Blood tests that reflect liver function are the mainstay of diagnosis of liver disease.
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Conclusions from VAO and Previous Updates Some studies that have been reviewed by previous VAO committees focused on liver enzymes, and others reported specific liver diseases. Evaluation of the effects of herbicide and TCDD exposure on noncancer gastrointestinal ailments is challenging in that clinical experience suggests that medical history and physical examination are undependable diagnostic tools for some ailments, so incidence data are sometimes problematic.
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of some abnormalities in liver enzymes in the Ranch Hand cohort, including decreasing C4 complement as dioxin increased; abnormal triglyceride concentrations also increased as the 1987 dioxin concentration increased. Mortality studies of the Ranch Hand cohort, however, have not found increased mortality related to gastrointestinal or liver disease (Ketchum and Michalek, 2005)
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, there was strong evidence that excess alcohol consumption was the cause of the cirrhosis. The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and gastrointestinal and digestive disease, including liver toxicity.
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Changes in serum concentrations of liver enzymes are biomarkers of liver toxicity, and their magnitude correlates with the degree of liver damage. Exposure of laboratory animals to high doses of 2,4-D, 2,4,5-T, and TCDD is known to cause liver damage.
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Few health-relevant effects of phenoxy herbicides or TCDD on the gastrointestinal tract, even after high exposure, have been reported. Thus, the animal data do not support a plausible link between herbicide exposure and gastrointestinal toxicity in Vietnam veterans.
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THYROID HOMEOSTASIS Clinical disruptions of thyroid function include various disorders grouped in ICD-9 as codes 242.8 and 246.8. The thyroid secretes the hormones thyroxine (T4)
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The report focused on TCDD and maternal thyroid function during pregnancy and therefore is less relevant to the experience of the predominantly male Vietnam veterans. Extensive assessment of endocrine function, including a series of thyroidfunction tests, was carried out in connection with the Operation Ranch Hand study (AFHS, 1991b)
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Prior committees had also noted increasing evidence of an association between exposure to some COIs and changes in markers of thyroid function below the threshold of clinical symptoms, perhaps because of the adaptive capacity of the adult system to accommodate such variation. Several studies of thyroid disease were considered in Update 2010.
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2009 (disorders of the thyroid gland) OCCUPATIONAL -- INDUSTRIAL IARC Phenoxy Herbicide Cohort -- Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying)
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AUSTRALIAN 2,4,5-T in Victoria, 2,4-D; 2,4,5-T Johnson et al., Australia (n = 37) 2001 TSH vs estimated serum TCDD level 32 Normal = 0.3–5.0µIU/ml Based on local levels 0.2 Based on individual sampling LDs –.03 Based on back extrapolation –1.4 (p < 0.05)
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UNITED STATES US Agricultural Health Study -- Phenoxy prospective study of licensed pesticide herbicides sprayers in Iowa and North Carolina: commercial (n = 4,916 men) , private/ farmers (n = 52,395, 97.4% men)
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OTHER CHRONIC HEALTH OUTCOMES 919 TABLE 13-3 Thyroid Homeostasis, continued Exposure of Exposed Interest/Reported Study Population Casesa Resultsa Reference ENVIRONMENTAL National Health and Nutrition Examination 2,4-D Survey NHANES III -- analysis of data from subjects Schreinemachers, with detectable limits of urinary 2,4-D 2010 TSH Detectable 2,4-D 102 1.6 mU/L Non-detectable 2,4-D 625 1.7 mU/L T4 Detectable 2,4-D 102 8.5 µg/dl Non-detectable 2,4-D 625 8.6 µg/dl NHANES (1999–2002, 2001–2002) -- Turyk et al., Associations with TEQs in individuals 2007 without thyroid disease Men (1999–2000)
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PCDD/Fs r = –0.198 (p = 0.21) JAPANESE patients exposed in 1968 16 PCDDs, PCDFs, Nagayama et al., during Yusho incident; blood collection from dl PCBS 2001 participants 1996 and 1997 TSH correlation coefficient 0.01 (p = 0.97)
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T3 ng/dL 92.6/87.5 (56.0–181.0) NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenol; CATI, computerassisted telephone interviewing; CI, confidence interval; COI, chemical of interest; dl, dioxin-like; IARC, International Agency for Research on Cancer; LD, level of detection; NA, not available; NHANES, National Health and Nutrition Examination Survey; nr, no relationship; ns, nonsignificant; PCB, polychlorinated biphenyls; PCDD, polychlorinated dibenzo-p-dioxins; PCDD/Fs, chlorinated dioxins and furans combined; PCDF, polychlorinated dibenzofurans; ppt, parts per trillion; SE, standard error; SEA, Southeast Asia; RH, Ranch Hand; T3, triiodothyronine; T4, tetraiodothyronine; TCDD, tetrachlorodibenzo-p-dioxin; TEQ, (total)
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. Synthesis Numerous animal experiments and several epidemiologic studies have shown that TCDD and dioxin-like chemicals appear to exert some influence on thyroid homeostasis.
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Conclusions There is inadequate or insufficient evidence of an association between exposure to the COIs and clinical or overt adverse effects on thyroid homeostasis. Some effects have been observed in humans, but the functional importance of the changes reported in the studies reviewed remains unclear because adaptive capacity could be adequate to accommodate them.
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Conclusion Given the lack of additional evidence, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and eye conditions. BONE CONDITIONS This section discusses conditions encompassed by ICD-9 code 733.0: osteo porosis, or decreased bone density.
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. However; the epidemiologic studies of the association between environmental exposures to organochlorine compounds and bone disorder have been inconsistent.
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. 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 propeptide and increased expression of the bone-resorption marker carboxy-terminal collagen cross-link, suggesting a net loss of bone tissue (Lind et al., 2009)
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2005b. The Third Australian Vietnam Veterans Mortality Study 2005.
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1996. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins.
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1991. Evaluation of chronic bronchitis, chronic obstructive pulmonary disease, and ventilatory function among workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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2012. Increased plasma thyroid hormone concentrations in LDL receptor deficient mice may be explained by inhibition of aryl hydrocarbon receptor dependent expression of hepatic UDP-glucuronosyltransferases.
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2007b. Pesticide use and chronic bronchitis among farmers in the Agricultural Health Study.
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1997. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins.
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1996. The Australian Vietnam Veterans Health Study: II.
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2009. Rhinitis associated with pesticide exposure among commercial pesticide applicators in the Agricultural Health Study.
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2007. Chronic bronchitis among nonsmoking farm women in the Agricultural Health Study.
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