1. WILLIAM JORDAN DEPUTY DIRECTOR, OFFICE OF PESTICIDE PROGRAMS UNITED STATES ENVIRONMENTAL PROTECTION AGENCY US EPA Regulation of Endocrine Disrupting Chemicals 2015 Regulatory Conference ECPA-ECCA 1

2. Overview US and international developments on endocrine disruptors policy: do opportunities for cooperation exist? Pesticide Regulation in the US US EPA’s Current Endocrine Disruptor Screening Program (EDSP) Future Directions for the EDSP Concluding Thoughts 2

3. Pesticide Regulation in the US 3

4. What is a Pesticide? 4  In the US, a pesticide is defined as any substance or mixture of substances intended for preventing, destroying, repelling, or mitigating any pest. Examples: insecticidesrodenticides fungicidesplant growth regulators herbicides antimicrobials microbials biochemicals

5. Federal Food Drug And Cosmetic Act (FFDCA) Tolerance) *MRLs (Tolerance) Established *Maximum Residue Level Reasonable Certainty of No Harm (Risk only) Products Registered Periodic Reevaluation No Unreasonable Adverse Effects (Risk/Benefit) Federal Insecticide Fungicide And Rodenticide Act (FIFRA ) U. S. Pesticide Laws 5

6. Human Health Risk Assessment for Pesticides (1) 6 EPA follows the National Academy of Sciences (NAS) four-step risk assessment paradigm*: *From the National Research Council’s Risk Assessment in the Federal Government: Managing the Process, 1983.

7. Human Health Risk Assessment for Pesticides (2) “Hazard” is a type of adverse effect; Hazard identification – what are the possible toxic effects “Dose–response” refers the relationship between a dose of a pesticide and the occurrence of an adverse effect; at what dose(s) are the possible effects seen? “Exposure” is the level of contact of a pesticidal substance “Risk” refers to the likelihood of an adverse effect; risk takes account of hazard, dose-response, and exposure 7

8. Data Requirements to Support Pesticide Registration & MRLs Typically EPA requires over 100 studies for a new pesticide: Human Hazard Studies: multiple endpoints (all organ systems and functions); durations (acute – chronic); lifestages (fetus – adult); routes (oral, dermal, inhalation) Ecological Toxicity Studies: multiple species (birds, fish, insects, invertebrates, plants) Human Exposure Studies: occupational (handlers, workers); bystanders; residential activities Environmental Exposure Studies: hydrolysis, photodegradation, solubility, leaching, volatility, aerobic and anaerobic metabolism 8

9. Risks to Humans Assessed for Multiple Pathways and Routes of Exposure 15 Oral exposure  Food supply  Drinking water  Incidental ingestion Dermal exposure  Applying pesticide  Harvesting crops  Spray drift  Turf contact Inhalation exposure  Applying pesticide  Bystander

10. US EPA’s Current Endocrine Disruptor Screening Program 10

11. 1996 Legislative Mandates Slide 11 of X 1996 Federal Food, Drug and Cosmetic Act, section 408(p) Requires the U. S. EPA to develop a screening program using appropriate validated test systems and other scientifically relevant methods to determine whether pesticide chemicals may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effect as the Administrator may designate. 1996 Safe Drinking Water Act Amendments, section 1457 Testing of chemical substances that may be found in sources of drinking water, if substantial human populations may be exposed.

12. EDSP Chronology 12 1996 FFDCA and SDWA 1998 EDSTAC recommendations 1999 EPA established the EDSP 2008 Validated eleven Tier 1 screening assays 2009 Initial test orders for Tier 1 assays 2011 EDSP21 Work plan 2012 EDSP Comprehensive Mgmt Plan 1999-2014 Scientific Advisory Panel Reviews

13. Public Engagement for EDSP EDSP established and implemented with robust public engagement:  The Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) of 1996-1998  Endocrine Disruptor Methods Validation Advisory Committee (2004)  Public comments on policy papers and management plans  Public reports to Congress and Pesticide Program Dialogue Committee  EPA’s FIFRA Scientific Advisory Panel  EPA website: http://www.epa.gov/scipoly/oscpendo/index.htmhttp://www.epa.gov/scipoly/oscpendo/index.htm 13

14. 1998 Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) Slide 14 of X EDSTAC Key Recommendations: Expand Protection to Include Human Health and Wildlife Include Estrogen, Androgen and Thyroid Pathways Prioritization based on exposure and high throughput screening [HTS] for bioactivity Develop a Two-Tiered Screening and Testing Program: bioactivity and adversity

15. EDSTAC Tiered Testing Approach EDSTAC recommended a two-tiered approach Tier 1 battery (in vitro and in vivo assays) To identify substances that have the potential to interact with the estrogen, androgen, or thyroid hormone systems Tier 2 testing (multigenerational tests) To identify, and establish a dose-response relationship for any adverse effects that might result from the interactions identified through the Tier 1 assays 15

16. EDSP Prioritization, Screening & Testing Relies on: Monitoring data OSRI Relies on: EDSP Tier 1 data OSRI Relies on: EDSP Tier 2 data OSRI UNEP Advisory Group MeetingDecember 12, 2014Slide 16 of 24 16

17. Tier 1 Screening Assays: Bioactivity 17

18. Tier 2 Test Methods: Adversity  Rat: Two-generation rat reproduction test (OECD TG 416) Rat: Extended F1-Generation (OECD TG 443)  Fish: Medaka Multi-generation Toxicity Test (MMT) and Medaka Reproduction Test (MRT) methods  Frog: characterize perturbations of normal development and growth – Xenopus Laevis  Bird: determine long-term effects of maternal transfer and in ovo exposure – Japanese Quail M F 18

19. EDSP Tier 1 Data Review: Current Pace 19 2009- 2010 EDSP Issued Initial Tier 1 Test Orders on 67 chemicals 2012-2013 Tier 1 Data Submitted to the Agency on 52 chemicals 2014-2015 Agency Completes 52 Tier 1 Data Reviews and WOE Determinations

20. Future Direction for U.S. Endocrine Disruptor Screening Program 20

21. EDSP Universe of Chemicals 21 Chemical ListNumber of Compounds Conventional Active Ingredients838 Antimicrobial Active Ingredients324 Biological Pesticide Active Ingredients287 Non Food Use Inert Ingredients2,211 Food Use Inert Ingredients1,536 Fragrances used as Inert Ingredients1,529 Safe Drinking Water Act Chemicals3,616 TOTAL10,341

22. EDSP Chemical Universe 10,000 chemicals (FIFRA & SDWA) EDSP List 2 107 Chemicals EDSP List 1 67 Chemicals  Based on current pace it could take decades to screen all 10,000 chemicals in EDSP Universe  Use compuational toxicology to rapidly screen chemicals for potential bioactivity and exposure  Implement a strategic approach to prioritize chemicals for targeted screening Evolution of EDSP 22

23. Use of HTS / Computational Toxicology Methodologies: Objectives 1. Prioritize chemicals for further EDSP screening and testing based on estimated bioactivity 2. Contribute to the weight of evidence evaluation of a chemical’s potential bioactivity 3. Substitute for specific endpoints in the EDSP Tier 1 battery UNEP Advisory Group MeetingDecember 12, 2014Slide 23 of 24 23

24. ToxCast High Throughput Screening (HTS) Detect agonist and antagonist activities  18 Estrogen receptor assays  9 Androgen receptor assays  3 Thyroid receptor assays http://www.epa.gov/ncct/toxcast/ 24

25. Example: Estrogen Agonism IDAssay NameSourceGeneSpeciesType A1NVS bovine ERNovascreenESR1Bos taurus Receptor Binding A2NVS human ERNovascreenESR1 Homo sapiens Receptor Binding A3NVS mouse ERaNovascreenEsr1 Mus musculus Receptor Binding A4OT ERa-ERa (8 h)Odyssey TheraESR1 Homo sapiensDimerization A5OT ERa-ERa (24 h)Odyssey TheraESR1 Homo sapiensDimerization A6OT ERa-ERb (8 h)Odyssey Thera ESR1, ESR2 Homo sapiensDimerization A7OT ERa-ERb (24 h)Odyssey Thera ESR1, ESR2 Homo sapiensDimerization A8OT ERb-ERb (8 h)Odyssey TheraESR2 Homo sapiensDimerization A9OT ERb-ERb (24 h)Odyssey TheraESR2 Homo sapiensDimerization A10 OT GFP ERa-ERE (2 h)Odyssey TheraESR1, ERE Homo sapiensDNA Binding A11 OT GFP ERa-ERE (8 h)Odyssey TheraESR1, ERE Homo sapiensDNA Binding A12ATG ERa (TRANS)AttageneESR1 Homo sapiens RNA Reporter Gene A13ATG ERE (CIS)AttageneESR1 Homo sapiens RNA Reporter Gene A14 Tox21 ERa BLA Agonist ratioNCGCESR1 Homo sapiensReporter Gene A15 Tox21 ERa LUC BG1 AgonistNCGCESR1 Homo sapiensReporter Gene A16ACEA T47D (80 h)ACEAESR1 Homo sapiensProliferation 25

26. Proposed Methodological Approach Use computational tools to model ER bioactivity 16 ToxCast assays relevant to agonist pathway  Model AUC for R1 (agonist) and R2 (antagonist) activities UNEP Advisory Group MeetingDecember 12, 2014Slide 26 of 24 26

27. Scientific Confidence Needed To Use any New Assay Are reference chemicals that include a range of structures and potencies accurately detected?  Step 1: Does CompTox accurately identify chemicals with demonstrated in vitro bioactivities?  Step 2: Does CompTox accurately identify chemicals with demonstrated in vivo bioactivities? 27

28. Step 1: In Vitro Estrogen-Active Chemicals 40 reference chemicals selected for recognized in vitro ER activity and include: Range of structures Range of potencies Strong: AC50 < 0.0001 μM Moderate: AC50 < 0.1 μM Weak: AC50 < 1 μM Very Weak: all other actives Peer Reviewed OECD ICCVAM http://ntp.niehs.nih.gov/pubhealth/evalatm/i ccvam/test-method-evaluations/endocrine- disruptors/in-vitro-assay- review/brd/index.html 28

29. Step 1: ToxCast results vs. reference chemical results Reference Chemicals ToxCastPOSNEG POS360 NEG210 Overall concordance ~90% (36/40) 29

30. Step 2: In vivo Estrogen-Active Chemicals Comparison of ToxCast results for chemicals with recognized in vivo ER activity Leverage existing in vivo data  Systematic literature search of publically available (e.g. PubMed) Uterotrophic studies  Review published studies for QC and consistency with EPA (890.1600) guideline  6 minimum criteria to establish methodological consistency  Two independent reviewers evaluate studies based on criteria  All 6 criteria must be met to consider a study “guideline-like” 30

31. Step 2: ToxCast results vs. Uterotrophic results Uterotrophic ToxCastPOSNEG POS438 NEG632 Overall concordance ~84% (75/89) 31

32. Integrated Bioactivity-Exposure Ranking: Objective Prioritize chemicals for further EDSP screening and testing based on rank of ER bioactivity and estimated exposure UNEP Advisory Group MeetingDecember 12, 2014Slide 32 of 24 32

33. Proposed Method Bioactivity ToxCast Bioactivity ToxCast Exposure ExpoCast Exposure ExpoCast HTTK Integrated Bioactivity Exposure Ranking (IBER) Integrated Bioactivity Exposure Ranking (IBER) Prioritization Screening Some or All EDSP Tier 1 Assays Some or All EDSP Tier 1 Assays Testing Some or All EDSP Tier 2 Assays UNEP Advisory Group MeetingDecember 12, 2014Slide 33 of 24 33

34. Integrated Bioactivity-Exposure Ranking 34

35. FIFRA Scientific Advisory Panel Peer Reviews http://www.epa.gov/scipoly/sap/index.htm http://www.epa.gov/scipoly/sap/index.htm  Prioritizing the Universe of Endocrine Disruptor Screening Program (EDSP) Chemicals Using Computational Toxicology Tools (January 2013)  http://www.regulations.gov (Search under EPA docket number: EPA-HQ-OPP-2012-0818) http://www.regulations.gov  Endocrine Disruptor Screening Program (EDSP) Tier 1 Screening Assays and Battery Performance (May 2013)  http://www.regulations.gov (Search under EPA docket number:EPA-HQ-OPP-2013-0075) http://www.regulations.gov  Endocrine Disruptor Screening Program (EDSP) Tier 2 Ecotoxicity Tests (June 2013)  http://www.regulations.gov (Search under EPA docket number:EPA-HQ-OPP-2013-0182) http://www.regulations.gov  Weight-of-Evidence: Evaluating Results of EDSP Tier 1 Screening (July 2013)  http://www.regulations.gov (Search under EPA docket number: EPA-HQ-OPP-2013-0230) http://www.regulations.gov  New High Throughput Methods To Estimate Chemical Exposure (July 2014)  http://www.regulations.gov (Search under EPA docket number: EPA-HQ-OPP-2014-0331) http://www.regulations.gov  Endocrine Activity and Exposure-based Prioritization and Screening (December 2014)  http://www.regulations.gov (Search under EPA docket ID: EPA-HQ-OPP-2014-0614) http://www.regulations.gov 35

36. EDSP Prioritization, Screening & Testing Relies on: QSARs ToxCast/ExpoC ast Monitoring data OSRI Relies on: QSARs ToxCast EDSP Tier 1 data OSRI Relies on: EDSP Tier 2 data OSRI UNEP Advisory Group MeetingDecember 12, 2014Slide 36 of 24 36

37. Concluding Thoughts 37

38. US Views on EC Roadmap for EDs The United States expressed concerns that the options provided in the EC’s Roadmap for defining criteria for identifying endocrine disruptors, specifically as it relates to plant protection products, does not appear to take into account risk from exposure in its approach, and may impose unnecessary and burdensome restrictions, that do not benefit public health or environmental protection. Further, implementation of an EU policy that removes the requirement for conducting a full risk assessment, [as required by the WTO], is likely to have severe implications for EU imports of U.S. agricultural goods and plant protection products which serve an important public health objective by controlling pests and diseases. 38

39. YES! Are There Opportunities for EU-US Collaboration for ED Chemicals? 39