Veterans and Agent Orange Update 2004 (2005) / Chapter Skim
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9 Other Health Effects
9 Other Health Effects
Pages 436-490
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From page 436... ...
. Each section ends with the Veterans and Agent Orange: Update 2004 committee's conclusions regarding the strength of the evidence from epidemiologic studies, biologic plausibility, and evidence regarding Vietnam veterans.
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From page 437... ...
Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committee responsible for Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as VAO; IOM, 1994) determined there was sufficient evidence of an association between exposure to at least one compound of interest and chloracne.
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From page 438... ...
(2003) conducted a cross-sectional study of Korean veterans who served in Vietnam to determine what adverse health effects might be associated with service in Vietnam and, by inference, attributable to exposure to Agent Orange.
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Reviews of the relevant studies are found in the earlier reports. Update of the Scientific Literature No relevant occupational or environmental studies have been published since Update 2002.
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From page 440... ...
Although PCT has been seen after exposure to TCDD in industrial settings, Vietnam veterans enrolled in the Ranch Hand study have not exhibited symptoms suggestive of the disorder. Conclusions Strength of Evidence from Epidemiologic Studies On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to at least one compound of interest and PCT.
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From page 441... ...
For those reasons, cigarette-smoking is 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 (McKinney et al., 1997)
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Exposed residents reported greater frequency of chronic bronchitis by history (17.8% versus 5.7%, p < 0.0001) and asthma by history (40.5% versus 11.0%, p < 0.0001)
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Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and the respiratory disorders specified above, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk. IMMUNE SYSTEM DISORDERS The immune system defends the body against infection by viruses, bacteria, and other disease-producing microorganisms (pathogens)
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From page 444... ...
In this case, the immune system mistakenly attacks the body's own cells and tissues as if they were foreign. The autoimmune reaction in multiple sclerosis is directed against the myelin sheath of the nervous system; in Crohn's disease, the gut is the target of attack; in type 1 diabetes mellitus, the insulin-producing cells of the pancreas are destroyed by the immune response.
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From page 445... ...
Environmental Studies In a new study about Seveso, Italy, Baccarelli et al.
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Study subjects were classified into three groups, based on self-reported Agent Orange exposure history and health status. A veteran patient group (N = 24)
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. In contrast, Korean Vietnam veterans had increased rather than decreased IgE concentrations in plasma -- independent of health status (Kim H-A et al., 2003)
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From page 448... ...
Chapter 3 discusses recent toxicologic studies that demonstrate the immunotoxic effects of the compounds of interest. Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and immune system disorders, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.
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From page 449... ...
That review focused on information published after the deliberations of the Update 1998 committee, and it resulted in the report Veterans and Agent Orange: Herbicide/ Dioxin Exposure and Type 2 Diabetes (IOM, 2000)
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(2003) analyzed data from the Ranch Hand study to address a question of methodology: Is the association between serum TCDD concentration and diabetes incidence attributable to some characteristic that affects both diabetes and TCDD elimination rate?
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Studies Reviewed in VAO Sweeney et al., 1992 NIOSH production workers 26 1.6 (0.93.0) Henneberger et al., 1989 Paper and pulp workers 9 1.4 (0.72.7)
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Studies Reviewed in Update 2002 Masley et al., 2000 Population based survey in Saskatchewan 28 * Studies Reviewed in Update 2000 Bertazzi et al., 2001 Seveso residents -- 20-year follow-up Zone A females 2 1.3 (0.35.1)
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92 NS Rate of TCDD elimination and time to onset of diabetes (proportional hazards model) 92 NS Studies Reviewed in Update 2000 AFHS, 2000b Air Force Ranch Hand veterans and (Numerous analyses comparisons discussed in the text of Herbicide/Dioxin Exposure and Type 2 Diabetes)
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From page 454... ...
predictor of incidence of diabetes in the subset of Ranch Hand veterans. The data suggest that the association between serum TCDD and diabetes is not simply attributable to a factor that causes diabetes and slows elimination of TCDD.
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(2003) provide additional support for a causal relationship between TCDD exposure and the development of diabetes by demonstrating in data from the Ranch Hand study that the association is not an artifact of differences in the elimination rate of TCDD.
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From page 456... ...
Nevertheless, until appropriate animal models are developed to show the etiology and pathogenesis of diabetes, confirmation of TCDD's ability to induce diabetes in animals will remain elusive. Increased Risk of Disease Among Vietnam Veterans Although there are data to suggest an association between exposure to the chemicals of interest and type 2 diabetes, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.
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From page 457... ...
OTHER HEALTH EFFECTS 457 LIPID AND LIPOPROTEIN DISORDERS Plasma lipid (notably cholesterol) concentrations have been shown to predict cardiovascular disease and are considered fundamental to the underlying atherosclerotic process (Kuller and Orchard, 1988)
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458 VETERANS AND AGENT ORANGE: UPDATE 2004 Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002 The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and lipid and lipoprotein disorders. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding.
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OTHER HEALTH EFFECTS 459 (which had a range from undetectable to 14 pg/g, with a median of 1.6 pg/g)
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in which the highest level of the parameter was measured and serum 2,3,7,8-TCDD level in 1966 Cholesterol r = 0.78; p = 0.01 Triglycerides r = 0.66; p = 0.02 Studies Reviewed in Update 2002 Kitamura et al., 2000 Workers exposed to PCDD at a municipal waste incinerator- elevated cholesterol 8 6.1, p = 0.02 Studies Reviewed in Update 1998 Calvert et al., 1996 Workers (N = 273) exposed to 2,4,5-T and derivatives vs matched referents (N = 259)
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OTHER HEALTH EFFECTS 461 TABLE 9-2 Continued Estimated Study Exposed Relative Risk Reference Population Casesa (95% CI) a Ott and Zober, 1996 Production workers exposed to TCDD 42 Cholesterol NSEb Triglycerides NSEb HDL cholesterol Increased; p = 0.05b Studies Reviewed in VAO Martin, 1984 Production workers exposed to TCDD Workers without chloracne 53 Cholesterol Increased; p < 0.005b Triglycerides Increased; p < 0.005b HDL cholesterol NSEb Workers with chloracne 39 Cholesterol Increased; p < 0.05b Triglycerides Increased; p < 0.01b HDL cholesterol NSEb Moses et al., 1984 TCP and 2,4,5-T production workers 118 Cholesterol NSEc Triglycerides NSEc Suskind and Hertzberg, TCP production workers 204 1984 Cholesterol NSEb Triglycerides NSEb HDL cholesterol NSEb May, 1982 TCP production workers 94 Cholesterol NSEb Triglycerides NSEb Pazderova-Vejlupkova TCP and 2,4,5-T production et al., 1981 workers 55 Cholesterol NSEb Triglycerides Increased VLDL; p = 0.01b ENVIRONMENTAL Studies Reviewed in VAO Assennato et al., 1989 Seveso Zone A subjects who 193 developed chloracne Cholesterol NSEb Triglycerides NSEb continues
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O'Toole et al., 1996 Australian Vietnam veterans, compared with the Australian population 20 Cholesterol 3.0 (1.34.7) Studies reviewed in VAO AFHS, 1991 Air Force Ranch Hand veterans 283304f Serum dioxin analysis (1987 exam data)
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eComparing mean dioxin across lipid groups. fNumber of exposed Ranch Hand with "high" lipid values.
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Some blood groups are associated with increased risk of duodenal ulcer, and HLA-B5 antigen appears to be increased among white males with duodenal ulcer. Cigarette-smoking also has been linked to duodenal ulcer prevalence and mortality.
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OTHER HEALTH EFFECTS 465 orders. The relative sensitivity and specificity of those enzymes for diagnosing liver disease vary, and several tests can be required for diagnosis.
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Clinical experience suggests that medical history and physical examination are undependable diagnostic tools for some ailments, so incidence data are more problematic. The strong interdependence among the characteristics of a given person (weight and laboratory indexes of hepatic function and health)
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Standardized mortality ratios (SMRs) were calculated
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(2003) reported the results of a cross-sectional study of exposure to Agent Orange and the prevalence of a large number of health outcomes in Korean veterans who had served in Vietnam.
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The age-adjusted probability value for the difference in prevalence of hypertension was 0.01; among the Vietnam veterans, the prevalence of hypertension did not vary by quartile of Agent Orange exposure index (p = 0.90)
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This difference is not the result of confounding by important risk factors for hypertension, and the Vietnam veterans did have higher serum TCDD concentrations than did the comparison veterans. Ischemic heart disease was not diagnosed in any of the non-Vietnam veterans, but it was found in Vietnam veterans and was most prevalent among veterans in the highest quartile of the Agent Orange exposure index.
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Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and circulatory disorders, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk. AL AMYLOIDOSIS Amyloidosis (ICD-9 code 277.3)
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. AL amyloidosis can occur in the setting of other diseases that are associated with exposure to compounds of interest, such as multiple myeloma and B-cell lymphomas.
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and the amyloidosis was regarded as occurring only secondary to chronic skin lesions. Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and AL amyloidosis, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.
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Both were small and showed elevated odds ratios, but for both the confidence intervals were very wide and included 1.0. Relevant studies reviewed earlier and in this update are summarized in Table 9-3.
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endometriosis across serum Serum TCDD >100 ppt: TCDD concentrations 9 exposed cases; OR = 2.1 (90% CI, 0.58.0) Studies Reviewed in Update 2002 Pauwels et al., Patients undergoing infertility 6 exposed cases; OR = 4.6 (95% CI, 2001 treatment in Belgium; compared 0.543.6)
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The research included an assessment of the association between serum dioxin concentration and the prevalence of endometriosis. Self-administered questionnaires identified 10 cases of endometriosis in 142 females responding.
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Synthesis None of the three studies discussed in this report demonstrated an increased risk for endometriosis with exposure to dioxin or dioxin-like compounds. Those results are consistent with the two casecontrol studies reviewed previously (IOM, 2003)
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From page 478... ...
Because some animal data and the sparse human data support the biologic plausibility of an association between TCDD exposure and endometriosis, the investigations should continue. Increased Risk of Disease Among Vietnam Veterans The lack of data on the association between exposure to the chemicals of interest and endometriosis, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.
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From page 479... ...
OTHER HEALTH EFFECTS 479 physiology both as a constituent of thyroid hormones and as a regulator of glandular function. Control of circulating concentrations of those hormones is regulated primarily by a negative-feedback pathway that involves three organs: the thyroid, which produces thyroid hormones, and the pituitary and hypothalamus, which help maintain optimal T3 and T4 concentrations.
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From page 480... ...
. In a repeated-measures linear regression adjusted for age, race, and military occupation, the low-exposure and high-exposure Ranch Hands had TSH significantly higher than did the comparison population, and the trend test showed a significant linear increase over the comparison and background-, low-, and high-exposure groups (p = 0.002)
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SUMMARY On the basis of the occupational, environmental, and veterans' studies reviewed, the committee reached one of four conclusions about the strength of the evidence regarding an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and each of the health effects discussed in this chapter. As explained in Chapter 2, the conclusions reflect the committee's judgment that if an association between exposure and an outcome exists, it would be found in a large, well-designed epidemiologic study in which exposure to herbicides or TCDD was sufficiently high, well-characterized, and appropriately measured on
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From page 482... ...
For Update 1996, Update 1998, Update 2000, and Update 2002, the committees determined there was limited or suggestive evidence of an association between exposure to at least one compound of interest and porphyria cutanea tarda. The scientific literature continues to support the classification of this disorder in the category of limited or suggestive evidence.
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OTHER HEALTH EFFECTS 483 Health Outcomes with Inadequate or Insufficient Evidence to Determine Association The scientific data on many of the health effects reviewed by the committee were inadequate or insufficient to determine an association between exposure to the compounds of interest and the health outcome. For the health effects in this category, the available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of association.
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From page 484... ...
Liver toxicity is species specific; 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's effects mediate non-cancer endpoints is not clear.
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OTHER HEALTH EFFECTS 485 immunity, also could be affected by TCDD. The function and commitment patterns of hematopoietic stem cells may also be affected by TCDD.
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Volume 2: Female Vietnam Veterans Survey and Community Compari son Outcomes. Canberra: Department of Veterans' Affairs.
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1997. Serum dioxin and diabetes mellitus in veterans of Operation Ranch Hand.
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2003. Diabetes mellitus and 2,3,7,8-tetrachlorodibenzo-p dioxin elimination in veterans of Operation Ranch Hand.
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2001. Dioxin and diabetes mellitus: an analysis of combined NIOSH and Ranch Hand data.
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1998. Exposure to dioxin and nonneoplastic mor tality in the expanded IARC international cohort study of phenoxy herbicide and chlorophenol production workers and sprayers.
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