Veterans and Agent Orange Update 2014 (2016) / Chapter Skim
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13 Other Chronic Health Outcomes
13 Other Chronic Health Outcomes
Pages 841-902
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From page 841... ...
In previous updates that considered short-term adverse outcomes (see Appendix B) , the committees found: • There is sufficient evidence of an association between the COIs and chloracne.
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From page 842... ...
and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) , picloram, and cacodylic acid -- and several non- ancer health outcomes: respiratory disorders, gastrointestinal and diges c tive disease (including liver toxicity)
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From page 843... ...
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 non-Vietnam veterans (Kang et al., 2006; McKinney et al., 1997)
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From page 844... ...
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)
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From page 845... ...
. Publications evaluated in Update 2010 that studied industrial cohorts did not report on COPD specifically but did not find increased mortality from non-cancerous respiratory diseases overall (Boers et al., 2010; Collins et al., 2009a,c; McBride et al., 2009a)
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From page 846... ...
(2012) using serum measurements from a subcohort of 187 workers to construct a model of TCDD exposure, but no association of TCDD exposure with respiratory diseases was observed.
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From page 847... ...
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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From page 848... ...
US VA Study of Male Vietnam Veterans All COIs Wounded in Combat Mortality through December 1991 Bullman and Non-cancerous respiratory mortality (ICD-9 43 0.9 (0.7–1.2)
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From page 849... ...
vs et al., proportions for Vietnam-era veterans (mortality 1986a,b from non-cancerous respiratory disease, ICD-8 460–519) Vietnam veterans vs expected deaths calculated 10 from proportions for: Non-veterans 0.5 (0.3–0.8)
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From page 850... ...
COPD 18 0.8 (0.5–1.2) Korean Vietnam Veterans Health Study -- All COIs entire population categorized with high exposure (n = 85,809)
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From page 851... ...
Mortality through 1983 (non-cancerous 93 0.6 (0.5–0.8) Coggon respiratory diseases, ICD-9 460–519)
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From page 852... ...
TCDD unlikely; et al., 1991 MCPA Mortality 1963–1985 (non-cancerous 8 0.7 (0.3–1.3) respiratory diseases, ICD-9 460–519)
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From page 853... ...
All non-cancerous respiratory diseases nr 33.7/31.0 (p = (ICD-9 460–419)
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From page 854... ...
and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL) Respiratory disorders (ICD-9 460–466, 470–478, 480–487, 490–519)
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From page 855... ...
4 1.3 (0.4–3.3) Preliminary NIOSH Cross-Sectional Medical Study -- workers in production of sodium trichlorophenol, 2,4,5-T ester contaminated with TCDD -- morbidity Chronic bronchitis and COPD 2 nr Sweeney et al., 1997/98 ORs for increase in 1 ppt of serum TCDD Calvert compared to unexposed workers et al., 1991 Chronic bronchitis nr 0.5 (0.1–2.6)
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From page 856... ...
Prevalence of chronic bronchitis at 0.9 (0.7–1.1) Valcin et al., enrollment in nonsmoking farm women (n = 2007 21,541)
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From page 857... ...
women) US Department of Agriculture Workers -- Herbicides nested case-control study of white men dying 1970–1979 of non-cancerous respiratory diseases (ICD-8 460–519)
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From page 858... ...
Zone R 74 1.2 (0.9–1.5) 15-yr follow-up to 1991 -- women Bertazzi Respiratory disease (460–519)
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From page 859... ...
Chronic bronchitis By history 40.5% vs 11.0% (p < 0.0001) Diagnosed by physician 13.1% vs 12.0% ns Other International Environmental Studies JAPAN 2,253 Japanese from general population not Total Serum Nakamoto occupationally exposed to dioxins, aged 15–76 TEQ et al., 2013 yrs in 2002–2008, Asthma (40 cases in men; 53 cases in 93 women)
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From page 860... ...
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; CDC, US Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; COPD, chronic obstructive pulmonary disease; EOI, Exposure Opportunity Index; FEF25-75, 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, 8th revision; ICD-9, International Classification of Diseases, 9th revision; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)
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From page 861... ...
that assessed relationships between adverse respiratory outcomes and various agricultural risk factors with exposure characterizations that are not informative for this report. Environmental Studies In a cross-sectional study of 1,063 men and 1,201 women living throughout Japan (who had not been occupationally exposed to dioxins)
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From page 862... ...
. Acute non-cancerous respiratory disorders, including pneumonia and other respiratory infections, can also be increased in frequency and severity when the normal defense mechanisms of the lower respiratory tract are compromised.
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From page 863... ...
Synthesis Non-Cancerous Respiratory Disease (Without Further Specification) Results of the studies of mortality from non-cancerous respiratory diseases reported in Update 2008 and earlier VAO reports (ADVA, 2005b,c; Anderson et
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From page 864... ...
and several new environmental and occupational studies, but no additional data convincingly contributed consistent evidence of either enhanced mortality or an increased risk associated with exposures to the COIs for specific or nonspecific nonmalignant respiratory diseases. The committee does not believe that scientific conclusions (other than that the evidence is inadequate)
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From page 865... ...
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 service in the ACC, as of 1991, the deployed ACC veterans had a non-significant adjusted RR of 2.59 for death due to non-cancerous respiratory diseases compared with their non-deployed peers (Dalager and Kang, 1997)
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From page 866... ...
International Vietnam-Veteran Studies Australian Vietnam Veterans -- 58,077 men and All COIs 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population
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From page 867... ...
COPD 18 0.8 (0.5–1.2) Korean Vietnam Veterans Health Study -- entire All COIs population categorized with high exposure (n = 85,809)
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From page 868... ...
Incidence Through 1989 (n = 158 men exposed within 1 Zober yr of accident vs 161 other BASF employees et al., 1994 1953–1969) All non-cancerous respiratory diseases nr 33.7/31.0 (p = (ICD-9 460–419)
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From page 869... ...
53 0.7 (0.3–2.2) Preliminary NIOSH Cross-sectional Medical Study -- workers in production of sodium trichlorophenol, 2,4,5-T ester contaminated with TCDD -- morbidity Chronic bronchitis and COPD 2 nr Sweeney et al., 1997/98 ORs for increase in 1 ppt of serum TCDD Calvert compared to unexposed workers et al., 1991 Chronic bronchitis nr 0.5 (0.1–2.6)
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From page 870... ...
8 1.0 (0.5–2.2) 1989a NOTE: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; COPD, chronic obstructive pulmonary disease; EOI, Exposure Opportunity Index; FEF25-75, 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-9, International Classification of Diseases, 9th revision; MOS, months of service; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; OR, odds ratio; PCP, pentachlorophenol; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; VA, US Department of Veterans Affairs.
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From page 871... ...
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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From page 872... ...
were indeed COPD cases; among the non-deployed 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 an 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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From page 873... ...
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. GASTROINTESTINAL AND DIGESTIVE DISEASEs, INCLUDING LIVER TOXICITY This section discusses a variety of conditions specified by ICD-9 520–579 or ICD-10 K00–K95: diseases of the esophagus, stomach, intestines, rectum, liver, and pancreas.
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From page 874... ...
The only regularly reported abnormality in liver function associated with TCDD exposure in humans is an increase in GGT. Estimated serum activity of that enzyme is a sensitive indicator of a variety of conditions, including alcohol and drug hepato toxicity, infiltrative lesions of the liver, parenchymal liver disease, and biliary tract obstruction.
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From page 875... ...
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. An evaluation of the effects of herbicide and TCDD exposure on non-cancer 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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From page 876... ...
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. However, mortality studies of the Ranch Hand cohort have not found increased mortality related to gastrointestinal or liver disease (Ketchum and Michalek, 2005)
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From page 877... ...
For liver disease, there was a small but statistically significant elevation in the prevalence of liver cirrhosis (OR = 1.08, 95% CI 1.01–1.16) and a significant log-linear relationship between an exposure opportunity score and the odds of having cirrhosis (p = 0.007)
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From page 878... ...
Changes in the serum concentrations of liver enzymes are biomarkers of liver toxicity, and their magnitudes correlate with the degree of liver damage. The 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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From page 879... ...
Thus, the animal data do not support a plausible link between herbicide exposure and gastro intestinal toxicity in Vietnam veterans. Synthesis Prior to this update there was little convincing evidence of liver toxicity associated with exposure to the COIs.
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From page 880... ...
(2013a) examined the prevalence of self-reported diseases from a postal survey of 114,562 Korean Vietnam veterans with respect to their perceived herbicide exposure as assessed by a six-item questionnaire.
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From page 881... ...
Environmental Studies In a cross-sectional study of 1,063 men and 1,201 women living throughout Japan (who had not been occupationally exposed to dioxins) , 47 cases of kidney disease (not otherwise characterized)
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From page 882... ...
The few findings on this health outcome reviewed by the current committee do not present any coherent pattern of an association between exposure to the COIs and kidney disorders. Conclusion The committee found that these first epidemiologic results addressing kidney disease in relation to exposure to the COIs constituted inadequate or insufficient evidence of an association between nonmalignant kidney diseases and exposure to the herbicides sprayed in Vietnam.
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From page 883... ...
. Both conditions are diagnosed on the basis of blood concentrations of thyroid hormones, TSH, and other proteins (antithyroid antibodies)
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From page 884... ...
(2010) also published negative results for an association between phenoxyherbicide exposures and self-reported history of physician-diagnosed thyroid disease in women in the AHS.
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From page 885... ...
Update of the Scientific Literature Several new epidemiologic studies of occupational or environmental exposure to the COIs or of Vietnam veterans and effects on thyroid homeostasis have been published since Update 2012. Mass media coverage of conference presentations in 2010 created an expectation of results from a study of Graves disease, an autoimmune hyperthyroid condition.
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From page 886... ...
O'Toole et al., respondents to 2004–2005 national 2009 survey (disorders of the thyroid gland) Korean Vietnam Veterans Health All COIs Study -- entire population categorized with high exposure (n = 42,421)
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From page 887... ...
(48 vs 92) OCCUPATIONAL -- INDUSTRIAL IARC Phenoxy Herbicide Cohort -- Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying)
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From page 888... ...
T4 vs estimated serum TCDD level 32 Normal = 0.045– 2.125 µg/ml Based on local levels 0.1 Based on individual sampling LDs –0.0 Based on back extrapolation –0.0 T3 vs estimated serum TCDD level 32 Normal = 0.9–1.9 µg/ml Based on local levels –0.1 Based on individual sampling LDs –0.4 (p < 0.05) Based on back extrapolation –0.5 (p < 0.01)
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From page 889... ...
Self-reported hypothyroid disease (n = 461) Self-reported 2,4-D exposure 392 1.4 (1.0–1.8)
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From page 890... ...
T4 –2.19 (p < 0.05) T3 –0.01 Women 87 TSH 0.04 T4 0.04 T3 –0.01 Cross-sectional examination of serum 150 dl compounds Foster et al., from pregnant women attending 2005 Canadian prenatal diagnosis clinic TSH correlation coefficient ns (value nr)
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From page 891... ...
Quartile 4 0.7 (0.3–1.9) p-trend = 0.32 Yusho patients exposed in 1968 during 16 PCDDs, PCDFs, Nagayama et al., Yusho incident; blood collection from dl PCBS 2001 participants 1996 and 1997 TSH correlation coefficient 0.01 (p = 0.97)
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From page 892... ...
892 VETERANS AND AGENT ORANGE: UPDATE 2014 TABLE 13-3 Thyroid Homeostasis, continued Exposure of Exposed Interest/Reported Study Population Casesa Resultsa Reference KOREA -- 105 pregnant Korean women dl mono-ortho Kim et al., 2013 provided blood samples the day before PCB 118 delivery β (95% CI)
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From page 893... ...
propionic acid; CATI, computer-assisted telephone interviewing; CI, confidence interval; COI, chemical of interest; dl, dioxin-like; dL, deciliter; EOI, Exposure Opportunity Index; HR, hazard ratio; IARC, International Agency for Research on Cancer; LD, level of detection; ml, m illiliter; NHANES, National Health and Nutrition Examination Survey; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; ns, nonsignificant; PCB, polychlorinated b iphenyls; PCDD, polychlorinated dibenzo-p-dioxins; PCDD/Fs, chlorinated ioxins and furans d combined; PCDF, polychlorinated dibenzofurans; ppt, parts per trillion; SE, standard rror; SEA, e Southeast Asia; RH, Ranch Hand; T3, triiodothyronine; T4, tetraiodothyronine; TCDD, tetra hloro c dibenzo-p-dioxin; TEQ, (total) toxic equivalent; TSH, thyroid stimulating hormone.
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From page 894... ...
. None of the phenoxy herbicides was found to be related to having histories of other thyroid diseases.
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From page 895... ...
(2014) studied steroid hormone levels in the serum and saliva and dioxin concentrations in the breast milk of lactating Vietnamese women living in a so-called "Agent Orange hot spot" (n = 51)
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From page 896... ...
Biologic Plausibility The influence of TCDD on thyroid-hormone homeostasis has been measured in numerous animal studies, and exposure has been associated with changes in serum concentrations of T4, T3, and TSH. In most studies, TCDD exposure is associated with a hypothyroid state, including reduced circulating T3 and T4 and increased TSH, especially after chronic exposure.
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From page 897... ...
Because of the consistent observations of exposures to the COIs being related to perturbations of thyroid function, and to clinical hypothyroidism in particular, the committee considered the body of epidemiologic data, in combination with strong biologic plausibility, to represent limited or suggestive evidence. New data from the Korean Vietnam Veterans Health Study suggest that adrenal and possibly pituitary function may also be affected by exposure to DLCs supporting some older literature data.
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From page 898... ...
On the basis of the evidence reviewed, Update 2010 concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and eye conditions. In Update 2012, the committee noted that no epidemiologic studies of exposure to the COIs and eye problems had been published since Update 2010, and they concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and eye conditions.
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From page 899... ...
Synthesis Since Update 2012, no additional epidemiologic results have supported the increase in risk of several eye conditions in the Australian Vietnam veterans reported by O'Toole et al.
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From page 900... ...
. However, epidemiologic studies of the association between environmental exposures to organochlorine compounds and bone disorders have had inconsistent results.
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From page 901... ...
The study did not support the hypothesis that postnatal TCDD exposure adversely affects adult bone health. There were two cross-sectional studies recently published addressing the association of exposure to DLCs and bone quality in residents of Canada's northern regions who are known to be exposed to these compounds as a result of their diet, which includes marine mammals and predatory fish (Paunescu et al., 2013a,b)
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From page 902... ...
. In adult rats, TCDD exposure reduced trabecular bone cross-sectional area, but significantly increased total BMD; it was further noted that TCDD decreased the expression of the bone-formation marker procollagen type I N-terminal propeptide and increased the 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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