1. Director, Office of Health Assessment & Translation
NTP Workshop: Role of Environmental Chemicals in the Development of Diabetes and Obesity January 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
Arsenic
Persistent organic pollutants (POPs)
Bisphenol A (BPA)
Pesticides
Organotins
Phthalates
Maternal Smoking
Nicotine

3.
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 adipocyte differentation, 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