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

Abstract

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.

Keywords::

• 2,3,7,8-tetrachlorodibenzo-p-dioxin
• dioxin
• Agent Orange
• reverse causation
• diabetes mellitus type 2
• toxicokinetics
• lipolytic metabolism
• persistent organic pollutant
• body mass index
• obesity
• human epidemiology

Acknowledgments

The authors would like to acknowledge the following individuals who provided technical assistance in prior analyses: Laura F. Scott, Kenneth M. Unice, and Julie N. Robinson, who was formerly a member of the Air Force Health Study team.

Declaration of interest

This work was a collaborative effort among the authors and was funded exclusively by the authors and by ChemRisk, LLC. Each of the authors in the past has performed dioxin research on behalf of private and governmental clients. Some of the authors (BK, DP, MG) have provided expert witness testimony in Congressional hearings or in lawsuits regarding dioxin health effects, but none within the past 3 years. The authors have sole responsibility for the analysis reported and the writing of the paper.

Three of the authors (BK, PS, DP) are currently employed by ChemRisk, LLC, a for-profit environmental consulting firm with headquarters in California. DP participated in peer review of the USEPA Dioxin Reassessment documents in 1987–2002 as a member of the EPA Scientific Advisory Boards evaluating those documents. BK participated in an external peer review panel on the USEPA Dioxin Reassessment documents in 2000. BK and DP have testified as expert witnesses in personal injury and government permitting hearings concerning dioxins up to 2009. The efforts of these three authors on this manuscript since 2009 have been funded entirely by ChemRisk, LLC; no outside parties assisted in creating or editing this manuscript.

Dr. Pavuk worked directly for the Air Force Health Study from 2003–2005 as an epidemiologist/statistician and was the Scientific Director from 2005–2006. He prepared Study briefings for government entities during that time, but has not participated as an expert witness in Congressional hearings or in any litigation related to dioxin or Agent Orange. Dr. Pavuk is currently employed by ATSDR, a U.S. government agency. He has not received any compensation for his work on this manuscript. He also states that this work does not necessarily represent the opinions of his current employer, ATSDR.

Dr. Gough directed the Congressional Office of Technology Assessment’s committee that advised the Department of Veteran Affairs on studies of the health of U.S. Vietnam veterans, including the Air Force Health Study, between about 1980 and 2000. From 1988–2000, he worked at for-profit consulting groups that included research and litigation expert witness testimony on a few occasions, in addition to testimony before Congress on several occasions regarding Vietnam veteran studies. He retired from full time work in 2000, and from part-time consulting in 2005. Dr. Gough received payment from ChemRisk, LLC for earlier research on diabetes and dioxin before 2005, but has not received any compensation for his work on this manuscript that commenced in 2009.