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 reporting a compensatory metabolic relation between dioxin and insulin regulation in Air Force Health Study participants (Michalek et al., 1999), an apparent association between serum dioxin levels and fasting glucose levels among nondiabetic AFHS comparison group members with less than 10 ppt serum dioxin (Longnecker and Michalek, 2000), and an elevated incidence of hyperinsulinemia among a cohort of nondiabetics with serum TCDD levels greater than 15 ppt (Cranmer et al., 2000). 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.

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 Appendix B of this report.



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