1. 1 Endocrine Disrupting Chemicals Major Areas of Controversy James C. Lamb, Ph.D., DABT, ATS Alexandria, VA

2. 2 Outline  Endocrinology 101  Endocrine Disruption History  Definition of an EDC  Examples of Controversies  Non-monotonic Dose Response Curves  Policy reports by various organizations (eg., WHO)  EU regulatory policy  Conclusions

3. 3 Hormones  Chemical messengers that affect  Growth  Reproduction  Behavior  Migration  Many other functions Estradiol-17β Source: www.3dchem.com/imagesofmolecules/Estradiol.jpg.

4. 4 Sources and Targets of Hormones  Brain  Thyroid  Gonads  Pancreas  Adrenal glands  Every part of the body is a target of one or more hormones  EDCs work in various ways

5. 5 Hormones and Endocrine Disruption  Hormones are chemical messengers  Move from organ A to B with a biological purpose and control  Endocrine disruptor is "an exogenous substance which causes adverse effects in an organism, or its progeny, subsequent to changes in the endocrine system.“ Weybridge Conference (1996)  Many possible chemical modes of action are implicated in the definition

6. 6 Evolution of the EDC Issue  Diethylstilbestrol  Exposures in the 1950s, effects in the 1970s  Human effects  Mouse model  Environmental effects of various substances  “Wingspread” and other conferences and books on the hypothesis (1992 term “Endocrine Disruptor” invented) Are we at risk of harm from environmental exposures to EDCs?

7. 7 Endocrine Disrupting Chemicals How did this come about?  Children whose mothers took DES in 50’s-70’s  NIEHS – program on “environmental estrogens” in the 1970s to present  1992 the term Endocrine Disruptor is invented  FQPA 1996 led to current EPA testing of pesticides and drinking water contaminants for endocrine activity Now national and international policy and scientific issues on EDCs…  Complicated scientific and regulatory issues

8. 8 Altered Function of Endocrine System Altered Function of Endocrine System Exposure Contributes to Adverse Effect Exposure Contributes to Adverse Effect Endocrine-Mediated Mode-of-action 8 EDC

9. 9 Dose Response Curves  Three common dose response curves  Linear  Non-monotonic  Sigmoidal

10. 10 Cytotoxicity  Often seen and seldom meaningful NMDR  A response occurs, but the target cell, organ or organism is overcome by toxicity at a higher level  Less relevant to EDCs than other MOAs (lose 45% of the 80 chemicals evaluated) Danish Centre on Endocrine Disrupters, 2013 80 substances cited by Vandenberg et al., 2012

11. 11 2002 report World Health Organization (WHO) and International Programme on Chemical Safety (IPCS) Early 2013 report World Health Organization (WHO) and United Nations Environment Programme (UNEP)

12. 12  Thousands of publications  Improved surveillance of exposure and effects  Advances in lab and field testing  Increased application of advance methodologies to looks at initiating events  New endpoints and pathways  Wider engagement of the scientific community

13. 13  Reviewed described process and methods  Compared to 2002 report  Evaluated all chapters to identify common strengths and weaknesses  Identified key issues and concerns  Select examples of unsupported claims  Not a comprehensive assessment or re-evaluation  Manuscript accepted in Reg Tox Pharm  Open Access (Lamb et al., 2014; reference at end)

14. 14  Not an objective, state-of-the-science review  Not an update of WHO-IPSC 2002 report  Causation is often inferred – not established  Controversial topics are poorly addressed

15. 15  Focused on one or two elements of definition of endocrine disruptor  No systematic process for assessing causation  Did not adopt framework from 2002 report  “best professional judgment”  Separate discussion of exposure  Biological plausibility and MOA of causal relationship cannot be addressed

16. 16 Spot the Differences…

17. 17 Spot the Differences…

18. 18 Summary for Decision-Makers WHO-UNEP 2012 State-of-the-Science Review EndometriosisDevelopmental exposure “now hypothesized” to contribute to risk Autoimmune thyroid disease“it is possible that EDCs play an important role in the development of these [autoimmune] diseases” Heart disease/hypertensionNo data provided on specific EDCs Alzheimer disease and Parkinson disease Diseases not even mentioned in main report

19. 19 Recent NTP Study on BPA  Conducted by FDA/NCTR  Two papers published in Toxicological Sciences  Part of a $32 million NTP/NIEHS investigation into BPA called CLARITY that has been discussed since 2008  Withering criticism as soon as the paper was released  Similar process with an EPA study on BPA  Two contrasting versions in the press http://www.motherjones.com/environment/2014/03/scientists-slam-fda-study-bpa http://www.forbes.com/sites/trevorbutterworth/2014/04/09/bpa-the-scientists-the-scare-the-100-million-dollar-surge/

20. 20 Conclusions  Natural and synthetic chemicals can have hormonal activity  All elements of the definition of an EDC (endocrine MOA, altered function, adversity) must be considered  Exposure is also critical  Public reaction is highly susceptible to those misinterpreting the data  Substantial differences around the world in how regulators respond

21. 21 PREPARED BY: James C. Lamb IV a, Paolo Boffetta b, Warren G. Foster c, Julie E. Goodman d, Karyn L. Hentz a, Lorenz R. Rhomberg d, Jane Staveley a, Gerard Swaen e, Glen Van Der Kraak f, Amy L. Williams a a Exponent; b Icahn School of Medicine at Mount Sinai; c McMaster University; d Gradient; e Exponent/Maastricht University; f University of Guelph This independent review has been commissioned by joint funding from: American Chemistry Council (ACC) CropLife America (CLA), CropLife Canada (CLC) and Croplife International (CLI) European Chemistry Industry Council (Cefic) European Crop Protection Association (ECPA) In press, available online in Regulatory Pharmacology and Toxicology