CONCLUSIONS

The committee assessed the association between Type 2 diabetes and herbicide or dioxin exposure. The assessment included several papers and reports published after deliberations were completed for the last National Academies report that addressed this topic, Veterans and Agent Orange: Update 1998.

Strength of Evidence in Epidemiologic Studies

Based on material presented in the papers and reports reviewed here, as well as the cumulative findings of research reviewed in Veterans and Agent Orange (1994), Veterans and Agent Orange: Update 1996, and Veterans and Agent Orange: Update 1998, the committee finds that there is limited/suggestive evidence of an association between exposure to the herbicides used in Vietnam or the contaminant dioxin and Type 2 diabetes.

No one paper or study was determinative in reaching this decision. Instead, the committee found that the information accumulated over years of research now meets the definition established for limited/suggestive evidence—that is, evidence is suggestive of an association between herbicides and the outcome, but limited because chance, bias, and confounding could not be ruled out with confidence. In reaching this decision, the committee observed the following:

  • Positive associations are reported in many mortality studies, which may underestimate the incidence of diabetes. Morbidity (the rate of incidence of a disease) is thought to be a more informative end point than mortality (the rate of death) when conducting epidemiologic studies of Type 2 diabetes because the disease is not typically fatal, its known complications may be more likely to be implicated as the underlying cause of death, and reporting of contributory causes of death on death certificates may be spotty. These reasons also lead epidemiologists to suspect that mortality studies may underestimate the incidence of diabetes, although, as Steenland and colleagues (1992) point out, such underreporting might be expected to equally affect the exposed and referent populations and thus wash out the effect. Four mortality studies were reviewed in this report. Individuals living near the site of a 1976 industrial accident involving dioxin were found to have a higher risk of diabetes death than a reference population in all exposure zones where diabetes deaths were recorded (Pesatori et al., 1998). Two studies of a TCDD-exposed cohort of workers at 12 U.S. plants (Steenland et al., 1992, 1999) found positive but non-statistically significant associations between measures of exposure and notations of diabetes on death certificates, although the later paper also found a significant negative trend between diabetes mortality and cumulative TCDD exposure. The fourth study, which examined workers in 12 countries who produced or sprayed phenoxy herbicides and chlorophenols (including some of those investigated by Steenland and colleagues), reported an elevated relative risk of mortality from diabetes in exposed workers versus non-exposed referents (Vena



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VETERANS AND AGENT ORANGE 36 CONCLUSIONS The committee assessed the association between Type 2 diabetes and herbi- cide or dioxin exposure. The assessment included several papers and reports published after deliberations were completed for the last National Academies report that addressed this topic, Veterans and Agent Orange: Update 1998. Strength of Evidence in Epidemiologic Studies Based on material presented in the papers and reports reviewed here, as well as the cumulative findings of research reviewed in Veterans and Agent Orange (1994), Veterans and Agent Orange: Update 1996, and Veterans and Agent Or- ange: Update 1998, the committee finds that there is limited/suggestive evi- dence of an association between exposure to the herbicides used in Vietnam or the contaminant dioxin and Type 2 diabetes. No one paper or study was determinative in reaching this decision. Instead, the committee found that the information accumulated over years of research now meets the definition established for limited/suggestive evidence—that is, evidence is suggestive of an association between herbicides and the outcome, but limited because chance, bias, and confounding could not be ruled out with confidence. In reaching this decision, the committee observed the following: • Positive associations are reported in many mortality studies, which may underestimate the incidence of diabetes. Morbidity (the rate of incidence of a disease) is thought to be a more informative end point than mortality (the rate of death) when conducting epidemiologic studies of Type 2 diabetes because the disease is not typically fatal, its known complications may be more likely to be implicated as the underlying cause of death, and reporting of contributory causes of death on death certificates may be spotty. These reasons also lead epidemiolo- gists to suspect that mortality studies may underestimate the incidence of diabetes, although, as Steenland and colleagues (1992) point out, such underreporting might be expected to equally affect the exposed and referent populations and thus wash out the effect. Four mortality studies were reviewed in this report. Individuals liv- ing near the site of a 1976 industrial accident involving dioxin were found to have a higher risk of diabetes death than a reference population in all exposure zones where diabetes deaths were recorded (Pesatori et al., 1998). Two studies of a TCDD-exposed cohort of workers at 12 U.S. plants (Steenland et al., 1992, 1999) found positive but non-statistically significant associations between measures of exposure and notations of diabetes on death certificates, although the later paper also found a significant negative trend between diabetes mortality and cumulative TCDD exposure. The fourth study, which examined workers in 12 countries who produced or sprayed phenoxy herbicides and chlorophenols (including some of those investigated by Steenland and colleagues), reported an elevated relative risk of mortality from diabetes in exposed workers versus non-exposed referents (Vena

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HERBICIDE/DIOXIN EXPOSURE AND TYPE 2 DIABETES 37 et al., 1998). Earlier studies reviewed in Update 1998, Update 1996, and VAO— and cited in Appendix B—show an inconsistent but weakly positive association be- tween exposure measures and Type 2 diabetes mortality. • Positive associations are reported in most of the morbidity studies identified by the committee. Several studies that used Type 2 diabetes morbidity as an outcome measure have been published since the last Veterans and Agent Orange review: studies of male and female Vietnam veterans from Australia; a NIOSH study of U.S. chemical workers; the Air Force Health Study (Ranch Hand study); and a separate examination of the Ranch Hand comparison group. One of these studies did not show a positive association: the survey of female veterans from Australia indicated 5 self-reported cases of diabetes where 10 were expected (Commonwealth Department of Veterans’ Affairs, 1998b). However, the survey of male Australian veterans of Vietnam (Commonwealth Department of Veterans’ Affairs, 1998a) did find a statistically significant excess of self-reported diabe- tes—2,391 cases were reported when 1,780 were expected. The NIOSH (Calvert et al., 1999) and Ranch Hand comparison group (Longnecker and Michalek, 2000) studies both reported an elevated incidence of diabetes in individuals who had high levels of serum dioxin relative to others examined in that study. The primary analysis in the Air Force Health Study (AFHS, 2000) showed nearly identical dia- betes incidence in Ranch Hand veterans and the matched comparison group. De- spite this negative finding, the study is considered suggestive because dose–re- sponse relationships between dioxin levels and diabetes incidence were observed in several other analyses that controlled for confounding variables. In presently unpublished material provided by AFHS researchers, additional analyses were carried out that support the 2000 report findings (Michalek, 2000b). The commit- tee encourages the researchers to seek publication of these results in a peer- reviewed journal so that they can be fully evaluated. Although some of the risk estimates in the studies examined by the com- mittee are not statistically significant and, individually, studies can be faulted for various methodological reasons, the accumulation of positive evidence is sug- gestive. The committee does not believe that publication bias plays a crucial role in this tendency in the data. Increased Risk of Diabetes Among Vietnam Veterans Presently available data allow for the possibility of an increased risk of Type 2 diabetes in Vietnam veterans. It must be noted, however, that these studies indicate that the increased risk, if any, from herbicide or dioxin exposure appears to be small. The known predictors of diabetes risk—family history, physical inactivity, and obesity—continue to greatly outweigh any suggested increased risk from wartime exposure to herbicides.

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VETERANS AND AGENT ORANGE 38 Biologic Plausibility As discussed in Update 1998,16 animal, laboratory, and human data provide reasonable evidence that TCDD exposure could affect Type 2 diabetes risk in humans. TCDD’s association with triglyceride and high-density lipoprotein (HDL) concentrations suggests a general consistency because these are the hallmarks of altered lipid metabolism in diabetes, since fatty acid metabolism, insulin resistance, and glucose metabolism are closely linked. Other observed effects include alteration of glucose transport in a variety of cells, modulation of protein kinase C (PKC) activity, reduction in adipose tissue lipoprotein lipase in guinea pigs, hypertriglyceridemia in rabbits, and down-regulation of low-density lipoprotein (LDL) receptors on the plasma membrane in guinea pig hepatocytes. Three recent studies of humans reviewed here add to that evidence by re- porting a compensatory metabolic relation between dioxin and insulin regulation in Air Force Health Study participants (Michalek et al., 1999), an apparent asso- ciation between serum dioxin levels and fasting glucose levels among nondia- betic AFHS comparison group members with less than 10 ppt serum dioxin (Longnecker and Michalek, 2000), and an elevated incidence of hyperinsuline- mia among a cohort of nondiabetics with serum TCDD levels greater than 15 ppt (Cranmer et al., 2000). These studies, however, have methodologic limita- tions—primarily, inadequate measures of individual characteristics such as per- centage of body fat at the time of exposure—that prevent more definitive con- clusions from being drawn. REFERENCES ADA (American Diabetes Association). 1997. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20(7):1183. AFHS (Air Force Health Study). 1982. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides: Study Protocol, Initial Report. Brooks AFB, TX: U.S. Air Force (USAF) School of Aerospace Medicine. SAM-TR-82-44. 189 pp. AFHS. 1983. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Baseline Mortality Study Results. Brooks AFB, TX: USAF School of Aerospace Medicine. NTIS AD-A130 793. AFHS. 1984a. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Baseline Morbidity Study Results. Brooks AFB, TX: USAF School of Aerospace Medicine. NTIS AD-A138 340. 362 pp. AFHS. 1984b. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Mortality Update: 1984. Brooks AFB, TX: USAF School of Aerospace Medicine. 16 An overview of the biologic plausibility material addressed in Update 1998 is given in the “Synthesis” section of its diabetes discussion, which is reproduced in Ap- pendix B of this report.

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