Kris Thayer, Ph.D. Director, Office of Health Assessment & Translation NIEHS/NTP

1. NTP Workshop: Role of Environmental Chemicals in the Development of Diabetes and ObesityJanuary 11-13, 2011 Kris Thayer, Ph.D. Director, Office of Health Assessment & Translation NIEHS/NTP

2. Overall Goals of Workshop • Evaluate the science associating exposure to certain chemicals or chemical classes with development of diabetes or obesity in humans • Provide input to NTP and NIEHS for development of a research agenda • Bring together diverse expertise including toxicologists, epidemiologists, bio-informaticists, and experts in the pathobiology of disease

3. http://cerhr.niehs.nih.gov/evals/diabetesobesity/ • Plan to publish workshop reports in EHP

4. Charge to Participants • For the individual chemicals or chemical classes • Evaluate strength/weaknesses, consistency, and biological plausibility of findings reported in humans and experimental animals • Identify the most useful and relevant endpoints in experimental animals, in vitro models, and screening systems • Identify data gaps and areas for future evaluation/research • Consider relevant biological targets and pathways for assays for inclusion in the Toxicology in the 21st Century high throughput screening initiative (“Tox21”)

5. Points of General Agreement: Maternal Smoking • Maternal smoking during pregnancy is associated with lower birth weight and later excess weight gains in children • Provides support for plausibility of “obesogen” hypothesis • Animal studies with nicotine reproduce “to a large extent” metabolic changes seen in the children of mothers who smoke • Mechanistic studies suggest biologically plausible associations of nicotine with the disruption of pathways important in obesity and diabetes (e.g., effects on beta cell mass and function) • Many “disease pathways” remain unexplored • Insulin signaling, feeding behavior, peripheral inflammation, insulin resistance, etc.

6. Epidemiological data support an association between maternal smoking and increased risk of obesity in offspring

7. Points of General Agreement: Arsenic • Evidence linking high arsenic exposure (> 150 ppb) with diabetes in humans is “limited to sufficient” • Some support from animal studies • Inhibition of insulin signaling and glucose uptake by adipocytes provides mechanistic support

8. Studies of Arsenic and Diabetes in Regions with High Arsenic Exposures

9. Points of General Agreement: Pesticides/POPs • Using the forest plot generator, identified classes of POPs that should be considered together • Evidence is “sufficient” for an association with diabetes based on collected analyses of cross-sectional, prospective/retrospective, and occupational exposure studies • Included data from NHANES, maternal, and military Veteran exposure studies • Initial data-mining indicates strongest correlations of diabetes with trans-nonachlor, DDE, and dioxins/dioxin-like chemicals including PCBs

10. POPs: Vietnam Veterans and Diabetes

11. DDE and Diabetes

12. Trans-nonachlor and Diabetes

13. Organotins/Phthalates Phthalates and organotins were grouped together because • Both interact with the protein transcription factor PPARγ, which is intimately involved in the regulation of adipocytedifferentation, metabolic syndrome, and insulin sensitivity • Both have a common use as plasticizers in polyvinylchloride (PVC) plastics • There are co-exposures to these two chemical classes

14. Points of General Agreement: Organotins/Phthalates • Human studies are “insufficient” (phthalates) or nonexistent (organotins) for evaluating an association with diabetes or obesity • Animal phthalate data are problematic because of PPARα contribution; relatively few studies on organotins • Recent mechanistic studies show potent effects of trialkyl tins on adipogenesis of adipose-derived stem cells and PPARγ activation • Phthalates activate PPARγ at 1000x lower potency than tins • Mechanistic basis for recommending combination studies from co-occurrence in plastics

15. Conclusions • General support for: • Plausibility of “obesogen” hypothesis • Linkage of type 2 diabetes to certain chemical exposures • Common mechanistic basis for certain chemical classes • Tox 21 approaches identified a number of chemicals of potential interest