Re-analysis of Ranch Hand study supports reverse causation hypothesis between dioxin and diabetes

A dose-response relationship between serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) and adult diabetes risk has been reported among U.S. Vietnam veterans in the Ranch Hand (RH) cohort. We examine the hypothesis that diabetes progression leads to higher serum dioxin (reverse causation) rather than higher serum dioxin leading to diabetes (causation) across the longitudinal medical monitoring data on these airmen. Lipid-adjusted serum dioxin levels and clinical parameters relating to diabetes progression were examined. Potential confounding due to age, race, diabetes family history, serum total lipid, and body mass index (BMI) was accounted for. The similar incidence of diabetes in RH and Comparison veterans, along with generally similar incidence trends with dioxin decile and lipid decile despite the large differential in serum dioxin, is evidence consistent with reverse causation. Of 135 RH diabetics with at least two dioxin measurements, 32.6% had a temporary serum dioxin increase more than a decade after Vietnam tour and another 22.2% had an interval of unusually slow half-life (>15.5 years); these diabetes-related changes shifted more diabetics into the higher dioxin deciles. Further, the increased diabetes odds ratio among the generally younger RH veterans in the highest dioxin decile is associated with a higher incidence of adult obesity in this RH subgroup, both at tour of duty and decades later. Change in serum dioxin levels is likely due to diabetes progression or poor control and is not independently related to serum dioxin concentrations. In summary, the data from the Ranch Hand studies does not indicate that dioxin increases adult diabetes risk.