Veterans and Agent Orange Update 1998 (1999) / Chapter Skim
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11 Other Health Effects
11 Other Health Effects
Pages 478-530
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From page 478... ...
(IOM, 1994) and Veterans and Agent Orange: Update 1996 (henceforth called Update 1996)
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Summary of VAO and Update 1996 Chloracne has been linked to TCDD exposure in numerous epidemiologic studies of occupationally and environmentally exposed populations. The data on Vietnam veterans potentially exposed to Agent Orange and other herbicides are .
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A more thorough discussion of biologic plausibility with respect to exposure to TCDD or herbicides and chloracne is contained in Chapter 3; a summary is presented in the conclusion to this chapter. PORPHYRIA CUTANEA TARDA Background Porphyria cutanea tarda (PCT)
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From page 481... ...
Porphyrin levels did not differ between exposed and unexposed workers, and there was no significant relationship between urinary porphyrin levels and serum TCDD levels. Taken together, the studies reviewed did not support the hypothesis that TCDD caused disturbances in home metabolism in humans, even at the relatively
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From page 482... ...
Conclusions Strength of Evidence in Epidemiologic Studies There is limited/suggestive evidence of an association between exposure to the herbicides considered in this report and porphyria cutanea tarda. Evidence regarding the association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components.
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and 95 percent confidence intervals (95% CIs) were calculated using West German mortality rates by five-year age and calendar intervals.
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, as part of a larger study of Dow chemical manufacturing workers exposed to the higher chlorinated dioxins. The study cohort was assembled from company records, starting with a cohort of 2,192 workers ever employed in a department with potential PCDD exposure between 1937 and 1980.
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From page 485... ...
Data were obtained on 641 veterans from the Australian Bureau of Statistics Health Interview Survey 1989-90, and illness rates were compared to the age- and sexmatched Australian population. They observed no significant increase in overall respiratory system disease among veterans; the relative risk (RR)
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Additional research, with adequate information on cigarette smoking and other risk factors for respiratory disease, is required to adequately assess the potential association between respiratory disease and herbicide or TCDD exposure. Conclusions Strength of Evidence in Epidemiologic Studies There is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides and mortality from respiratory diseases; symptoms or history of respiratory illnesses, such as chronic bronchitis, bronchitis, asthma, pleurisy, pneumonia, tuberculosis, and respiratory conditions; abnormalities on lung or thorax physical examination; pulmonary function test results; and chest radiographs.
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, and exposure to immunosuppressive agents (Paul, 1993~. Immune suppression can also occur in patients with autoimmune disease (discussed below)
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Summary of VAO and Update 1996 The effects of herbicide exposure on the level of several immune parameters were presented in studies reviewed in VAO and Update 1996. The data are divided into two categories: immune suppression and immune enhancement.
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From page 489... ...
Vietnam veterans compared with non-Vietnam veterans had a slightly elevated proportionate mortality ratio from infectious and parasitic diseases (PMR = 1.6, CI 1.2-2.1, N= 56~. The study, however, did not distinguish Vietnam veterans exposed to Agent Orange from those with no known exposure.
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From page 490... ...
No evidence was found of increased upper or lower respiratory tract symptoms or altered antibody production to mumps, measles, or rubella in relation to PCB or TCDD exposure. Although there were small differences in the Tcell, B-cell, and NK-cell populations between high- and low-exposed infants, all values were within the normal range.
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One study was reported of autoimmunity following TCDD exposure. Chinh et al.
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hepatic glucose overproduction. Although the relative contributions of these features are controversial, it is generally accepted that the main factors for increased risk of Type II diabetes include age (with older individuals at higher risk)
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The insulin receptor itself, insulin receptor tyrosine kinase activity, insulin receptor substrate proteins, insulin-regulated glucose transporters, enhanced protein kinase C (PKC) activity, tumor necrosis factored, red (ras associated with diabetes)
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of 117 2,4,5-T production workers with chloracne compared to 109 without, 1020+ years after mixed accidental and chronic TCDD exposure (Moses et al., 1984~. Two mortality studies provide further negative data.
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(AFHS, 1984~. Reporting data using lipid-adjusted serum TCDD levels as a measure of exposure from the same cohort study, the Ranch Hand Study (AFHS, 1991)
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The prevalence of diabetes mellitus by 1995 was 13.2 percent in the comparison group and increased from 9.5 percent to 17.2 percent to 20.1 percent across the three Ranch Hand exposure categories. There was a statistically significant increase of the prevalence of the highest-exposure category relative to the comparison group (RR 1.5, 95% CI 1.2-2.0~.
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From page 499... ...
Although the availability of serum dioxin levels enables a better measure of exposure and a focus on the risks of the low- and high-exposed groups is understandable, Ranch Hands as a group do not have an increased risk of diabetes: Comparison group Ranch Hands (all groups)
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However, the increased risk reported for the highest exposure groups suggests dose-responsiveness in both the Ranch Hand and the NIOSH studies. On the other hand, the much higher serum TCDD levels in the exposed groups in the NIOSH (Sweeney et al., 1996, 1997)
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A different possibility, namely that obesity is a mediator of TCDD-enhanced diabetes risk, has not been formally addressed in the analyses to date. This possibility remains open but difficult to explore as obesity or percent body fat measures at the time of initial Vietnam service would be needed along with equally precise TCDD exposure measures.
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At this time, questions concerning case definition and full control for obesity and other confounders (in the Ranch Hand study) preclude determining whether or not an association exists between herbicide exposure and diabetes in these studies.
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Increased Risk of Disease Among Vietnam Veterans Currently, it is uncertain whether any increased risk of diabetes has been experienced by Vietnam veterans exposed to herbicides. Although the most recent Ranch Hand study report suggests that those with the highest exposure may experience an increased risk (up to 50 percent)
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in those with chloracne. In a detailed analysis of lipid values from a mixed accidentally and chronically exposed cohort of 2,4,5-T and TCP production workers from a plant in Nitro, West Virginia, no differences were noted 10-30 years after exposure in mean total HDL and LDL cholesterol and triglyceride levels for those exposed
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using serum (lipid weight-adjusted) dioxin analyses as a measure of exposure, revealed low-order but significant correlations between HDL cholesterol and dioxin level (r = -0.14 for Ranch Hands and r = -0.10 for comparisons)
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higher HDL cholesterol compared to nonexposed controls. The German Cancer Research Center, reporting on employees from six West German chemical plants found no apparent effect of TCDD on lipid metabolism (don Benner et al., 1994~.
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Increased Risk of Disease Among Vietnam Veterans Ranch Hand study data (AFHS, 1991) suggest that lipid and lipoprotein concentrations of Ranch Hands and comparison subjects do not differ overall, although significant correlation between HDL cholesterol (negative)
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Peptic ulcer disease is characterized as gastric ulcer or duodenal ulcer, depending on the anatomic site of origin. Peptic ulcer disease occurs when the corrosive action of gastric acid and pepsin exceeds the normal mucosal defense mechanisms protecting against ulceration.
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Cirrhosis of the liver is the most commonly reported liver disease outcome in epidemiologic studies of herbicide and/or TCDD exposure. Pathologically, cirrhosis reflects irreversible chronic injury of the liver, with extensive scarring and resultant loss of liver function.
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These metabolic "adaptations" to chemical exposure have been seen in industrial workers as well as Ranch Hand veterans. Results from studies relating liver enzyme measurements or the diagnosis of chronic liver disease to serum TCDD levels or clinical indices of dioxin exposure (e.g., chloracne)
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(1996) examined mortality in a cohort of workers exposed to pentachlorophenol, as part of a larger study of Dow chemical manufacturing workers exposed to the higher chlorinated dioxins.
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Data were obtained on 641 veterans from the Australian Bureau of Statistics Health Interview Survey 1989-90, and illness rates were compared to the age- and sexmatched Australian population. Ulcer disease (RR 2.7, 99% CI 1.7-3.8)
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, there was strong evidence that excess alcohol consumption was the etiology for the cirrhosis. Additional research, with adequate information on alcohol consumption and other risk factors for gastrointestinal disease, is required to adequately assess the potential association between gastrointestinal disease and herbicide or TCDD exposure.
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However, the Air Force Health Study (AFHS, 1991) reported associations between serum TCDD and both diabetes and blood lipids, suggesting a reason to examine coronary artery disease in subjects exposed to dioxins because of the possible association between risk factors for coronary artery disease and serum TCDD level.
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, with an RR of 2.0 (95% CI 1.2-3.3) among men in the highest docile of estimated TCDD exposure.
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(1996) examined mortality in a cohort of workers exposed to PCP, as part of a larger study of Dow chemical manufacturing workers exposed to the higher chlorinated dioxins.
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The ongoing study of Ranch Hand veterans (AFHS, 1996) , reported causespecific mortality among 1,261 Ranch Hand personnel compared to 19,080 Air Force veterans from the same era who did not handle herbicides.
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Additional research, with adequate information on the numerous risk factors for circulatory disease, is required to adequately assess the potential association between circulatory disease and herbicide or TCDD exposure. Further research on the potential relationships between TCDD exposure and diabetes or lipid abnormalities may also shed further light on any potential relationships to circulatory diseases.
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The committee also regarded evidence from several small studies that are free from bias and confounding, and that show an association that is consistent in magnitude and direction, as sufficient evidence for an association. Health Outcomes with Limited/Suggestive Evidence of Association In Update 1996, the committee found limited/suggestive evidence of an association between herbicide/dioxin exposure and porphyria cutanea tarda.
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From page 521... ...
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, diabetes, lipid and lipoprotein disorders, gastrointestinal diseases, digestive diseases, liver toxicity, and circulatory disorders. Health Outcomes with Limited/Suggestive Evidence of No Association In VAO and Update 1996, the committee did not find any evidence to conclude that there is limited/suggestive evidence of no association between the health effects discussed in this chapter and exposure to TCDD or herbicides.
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From page 523... ...
Mice and rats are susceptible to TCDD-induced liver toxicity, but guinea pigs and hamsters are not. It is possible that liver toxicity is associated with susceptibility to liver cancer, but the extent to which TCDD effects mediate noncancer end points is not clear.
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Other studies provide evidence that 2,4-D binds covalently to hepatic proteins and lipids; the molecular basis of this interaction and its biologic consequences are unknown. The potential immunotoxicity of the herbicides used in Vietnam has been studied to only a very limited extent.
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From page 525... ...
Research on biological mechanisms is burgeoning, and subsequent Veterans and Agent Orange updates may have more and better information on which to base conclusions. Increased Risk of Disease Among Vietnam Veterans Under the Agent Orange Act of 1991, the committee is asked to determine (to the extent that available scientific data permit meaningful determinations)
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workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. American Journal of Industrial Medicine 25:559-571.
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From page 527... ...
1997. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins.
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1984. Lipid abnormalities in workers exposed to dioxin.
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From page 529... ...
1996. Review and update of the results of the NIOSH medical study of workers exposed to chemicals contaminated with 2,3,7,8-tetrachlorodibenzodioxin.
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From page 530... ...
1980. WHO Expert Committee on Diabetes Mellitus (Tech.
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