EXECUTIVE SUMMARY

Strength of Evidence in Epidemiologic Studies

Based on the scientific evidence reviewed in this report as well as the cumulative findings of research reviewed in the previous Veterans and Agent Or ange reports, 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. This is a change in classification from previous Veterans and Agent Orange reports, which found inadequate/insufficient evidence to determine whether an association existed. ³

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. 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. Two studies of a TCDD-exposed cohort of workers at 12 U.S. plants found positive but non-statistically significant associations between measures of exposure and notations of diabetes on death certificates. The fourth study, which examined workers in 12 countries who produced or sprayed phenoxy herbicides and chlorophenols, reported an elevated relative risk of mortality from diabetes in exposed workers versus non-exposed referents. Studies reviewed in previous Veterans and Agent Orange reports show an inconsistent but weakly positive association between 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 National Institute for Occupational Safety and Health (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. However, the survey of male Australian veterans of Vietnam did find a statistically significant excess of self-reported diabetes—2,391 cases were reported when 1,780 were expected. The Ranch Hand comparison group and NIOSH studies each 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 showed nearly identical diabetes incidence in Ranch Hand veterans and the matched comparison group. Despite this negative finding, the study is considered suggestive because dose–response relationships between dioxin levels and diabetes incidence were observed in several other analyses of the Ranch Hand veterans and comparison group that controlled for confounding variables.

Although some of the risk estimates in the studies examined by the committee are not statistically significant and, individually, studies can be faulted for various methodological reasons, the accumulation of positive evidence is suggestive. 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.

Biologic Plausibility

Animal, laboratory, and human data reviewed in Update 1998 provide reasonable evidence that exposure to dioxin could affect Type 2 diabetes risk in humans. TCDD's associations with altered triglyceride and high-density lipoprotein (HDL) concentrations are generally consistent with a diabetes effect because these are the hallmarks of altered lipid metabolism in the disease and fatty acid metabolism, insulin resistance, and glucose metabolism are closely linked. However, it is not at present known whether or not such associations are indicative of a causal pathway from dioxin exposure to Type 2 diabetes. Other observed effects include alteration of glucose transport in a variety of cells, modulation of protein kinase C activity, reduction in adipose tissue lipoprotein lipase in guinea pigs, hypertriglyceridemia in rabbits, and down-regulation of low-density lipoprotein receptors on the plasma membrane in guinea pig hepatocytes.

Three recent studies of humans add to that evidence by reporting a compensatory metabolic relation between dioxin and insulin regulation in Air Force Health Study (AFHS) participants, an apparent association between serum dioxin levels and fasting glucose levels among nondiabetic AFHS comparison group members with less than 10 parts per trillion (ppt) serum dioxin, and an elevated incidence of hyperinsulinemia among a group of nondiabetics with serum TCDD levels greater than 15 ppt. These studies, however, have methodologic limitations—primarily, inadequate measures of individual characteristics such as percentage of body fat at the time of exposure—that prevent more definitive conclusions from being drawn.

Footnotes

1

Also referred to as Type II diabetes, diabetes mellitus, non-insulin-dependent diabetes mellitus, and adult-onset diabetes.

2

2,3,7,8-Tetrachlorodibenzo-p-dioxin, commonly referred to as TCDD or “dioxin,” was an unintentional contaminant of one of the herbicides used in Vietnam.

3

The categories of association mentioned here were established in the original (1994) Veterans and Agent Orange report and have been used in all subsequent reports. A complete list of categories is contained in the “Organization and Framework” section of this report.