1. Office of Pesticide Programs 21st Century Screening Assessment of Pesticides – A Regulatory View Vicki Dellarco, Ph.D. Senior Science Advisor Office of Pesticide Programs US Environmental Protection Agency

2. Office of Pesticide Programs 1 Managing Chemical Risks Gateway to Market National Pesticide Program ~1,100 active ingredients & 19,000 products Reevaluate existing pesticides on a regular schedule Safety evaluations required for human health & ecological risks –FIFRA, FFDCA, FQPA, ESA Risk management decisions apply to –Antimicrobials, biochemical & conventional active ingredients and food-use & non-food use inert ingredients Available information –Varies across chemical programs with extensive requirements for food use, conventional pesticide actives to minimal requirements for non-food use inert ingredients

3. Office of Pesticide Programs 2 Managing Chemical Risks Large Number of Chemicals to Review with Many Possible Adverse Outcomes Finite Resources & Time Science Increasingly Complex & Changing Public Expectation Sound Science, Transparency & Timeliness for Environmental Health Protection Common Challenges

4. Office of Pesticide Programs 3 Animal Testing: Reduce, Refine, Replace 2005 OPPTS-ORD White Paper 2007 NAS Report on Testing in the 21st Century 2009 Agency’s Strategic Plan for Evaluating the Toxicity of Chemicals Use of computational tools is not new to evaluate & assign priorities for follow-up actions Managing Chemical Risks Strategic Direction Transition toward new integrative & predictive 21st century techniques, to increase efficiency and effectiveness of testing & assessment

5. Office of Pesticide Programs NRC 2007 “Toxicity Testing in the 21st Century: A Vision and A Strategy Objective –Foster transformative paradigm shift based largely on increased use of in vitro & in silico systems that will: broader coverage of chemicals, end points, life stages reduce cost & time of testing, increase efficiency & flexibility use fewer animals more robust scientific basis by providing mode of action & dosimetry information

6. Office of Pesticide Programs 5 Current Data Paradigm Cancer Reproductive Toxicity Developmental Toxicity Neurotoxicity KidneyToxicity ImmunoTox in vivo testing $Millions Food Use, Conventional Pesticide Actives: Generates in vivo animal data for all possible outcomes to determine which of all possible effects are relevant.

7. Office of Pesticide Programs 6 Evaluation for Relevant Effects Risk Assessment C 2 Cl 3 Cl C C 2 Cl 3 Cl C OH Cl OH Cl C 2 Cl 3 Cl C C 2 Cl 3 Cl C OH Cl OH Cl Chemical Inventories C 2 Cl 3 ClCl ClCl C ClCl ClCl C ClCl ClCl C ClCl ClCl C ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl OHOH OHOH OHOH ClCl ClCl OHOH ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl OHOH ClCl ClCl C ClCl ClCl OHOH OHOH ClCl ClCl OHOH ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl OHOH OHOH ClCl ClCl OHOH ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl OHOH ClCl ClCl OHOH OHOH OHOH ClCl ClCl OHOH ClCl ClCl OHOH OHOH ClCl ClCl OHOH ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl ClCl OHOH ClCl ClCl OHOH In Vitro Profiling: Molecular interactions, Cellular Responses Existing Knowledge, exposure use, toxicity data, SAR, QSAR Efficient Focused In Vivo Testing Priority Setting Process Research: Learn & Refine

8. Libraries of Toxicological Pathways Receptor/Ligand Interaction Gene Activation Protein Production Gonad Development Altered Hormone Levels Impaired Reproduction Molecular Cellular Organ Individual Chemical 3- D Structure/ Properties Chemical 2-D Structure Structure Mapping Toxicity Pathways to Adverse Outcomes

9. Office of Pesticide Programs 8 Managing Chemical Risks Near Term (≤5 years) Goal –Integrated Approaches to Testing & Assessment “Enhance Tool Box” - Create means to efficiently & credibly predict toxic potency & exposure levels and to focus information needs –Situations e.g., pesticide inerts, certain antimicrobials, metabolites & degradates of pesticide actives Challenge: Assessing Data-Limited Chemicals

10. Office of Pesticide Programs 9 Managing Chemical Risks Long Term (~15 years) –Develop means to move, in a credible & transparent manner to hypothesis & mechanism- driven, risk-based approaches that focus on effects most relevant to risk assessment & risk management “omics” technology in identifying toxicity pathways PDPK modeling Improved human exposure modeling Challenge: Reducing Uncertainty

11. Office of Pesticide Programs Integrated Approaches to Testing & Assessment Existing Knowledge, exposure use, toxicity data, SAR, QSAR In Vitro Profiling: Molecular interactions, Cellular Responses Efficient Focused In Vivo Testing (Q)SAR-Based System to Predict ER Binding Affinity ToxCast HTP Research Program New F1 Extended Reproductive Study Example Activities

12. Office of Pesticide Programs Partnerships Collaborate on development & application of predictive computational models Promote development of common databases Harmonize frameworks/guidance Build a common application tool box –OECD QSAR Tool Box Agencies & International Organizations

13. Office of Pesticide Programs International Partnerships Collaborate on development & application of predictive computational models –OECD Workshop (Dec 07, Wash DC) - Integrative Approaches to Testing & Assessment Build a common application tool box –OECD QSAR Tool Box Harmonize frameworks/guidance

14. Office of Pesticide Programs 13 Stakeholder Engagement Pesticide Program Dialogue Committee (PPDC) – Workgroup on 21st Century Toxicology/New Integrated Testing Strategies –Purpose is to advise on communication & transition Improve understanding of the perspectives of all stakeholders regarding new testing paradigm Ensure input on key science & regulatory products Develop common understanding for use of new tools

15. Office of Pesticide Programs Priority Setting Assay Validation Procedures US EPA EDSP Implementation 14 Selecting chemicals to be screened

16. Office of Pesticide Programs OECD Endocrine Testing & Assessment Conceptual Framework Level 1 - Sorting & prioritizing with existing data and/or (Q)SARs Level 2 - In vitro assays to provide mechanistic data Level 3 - In vivo assays providing data about single endocrine mechanisms & effects Level 4 - In vivo assays providing data about multiple endocrine mechanisms & effects Level 5 - In vivo assays providing data about endocrine & other effects (OECD, 2004)

17. Office of Pesticide Programs USEPA Endocrine Disruptor Screening & Assessment Program Sorting & Prioritizing Chemicals Tier 1 Screening –Data to determine if a chemical has the potential to interact with the estrogen, androgen or thyroid systems Tier 2 Testing –Data to determine if endocrine-mediated adverse effects occur and quantify dose-response Hazard & Risk Assessment (USEPA, 1998)

18. Office of Pesticide Programs Sorting Chemicals for Endocrine Disruptor Screening & Testing: Four Categories Chemicals unlikely to interact with hormone systems (e.g., certain polymers, strong mineral acids/bases) Chemicals without sufficient existing data to determine if Tier 2 testing required Chemicals with sufficient existing data to determine if Tier 2 testing required Chemicals with sufficient data to support a hazard assessment (USEPA, 1998)

19. Office of Pesticide Programs Prioritizing Chemicals for Endocrine Disruptor Screening & Testing Chemicals without sufficient existing data –Considered by the EDSTAC (USEPA 1998) to have the largest number of chemicals and the greatest need for prioritization –EDSTAC (USEPA, 1998) and the SAB/SAP (USEPA, 1999) strongly recommended a prioritization scheme that included an effects & exposure component

20. Office of Pesticide Programs Prioritizing Chemicals for Endocrine Disruptor Tier 1 Screening: Effects EDSTAC (USEPA, 1998) recommended the use of measured or predicted receptor binding and/or transcriptional activation data derived through in vitro assays/High Throughput (HTP) Screening and (Q)SARs, respectively SAB/SAP (USEPA, 1999) concurred; however, concluded that HTP screening and (Q)SARs were not sufficiently developed at that time – encouraged continued research As part of USEPA’s computational toxicology and endocrine disruptor research programs, the Office of Research and Development (ORD), in collaboration with OPP and OSCP, has been developing in vitro assays, HTPs applications & (Q)SARs

21. Office of Pesticide Programs (Q)SAR-Based System to Predict Estrogen Receptor Binding Affinity ORD/OPP Collaborative Effort Application for use in a prioritization scheme in the context of EDSTAC & SAB/SAP recommendations Development focused on chemicals without sufficient existing data to determine if Tier 2 testing required Model’s applicability domain – Structures associated with pesticide inert ingredients & antimicrobial pesticides

22. Adverse Outcome Pathway ER-mediated Reproductive Impairment QSAR focus area Inerts; Antimicrobial Chemicals Receptor Binding ER Binding Liver Cell Protein Expression Vitellogenin (egg protein transported to ovary) Liver Altered proteins(Vtg) & hormones; Gonad Ova-testis; Complete ovary in male Sex reversal; Altered behavior; Repro. In vivo MOLECULAR Target CELLULAR Response TISSUE/ORGAN INDIVIDUAL Skewed Sex Ratios; Yr Class POPULATION In vitro Assay focus area Toxicity Pathway Adverse Outcome Pathway Greater Toxicological Understanding Greater Risk Relevance

23. Office of Pesticide Programs (Q)SAR-Based System to Predict ER Binding Affinity External peer-review by USEPA SAP, August 2009 –http://www.epa.gov/scipoly/sap/meetings/2009/082509meeting. html Development benefited from EDTA VMG-NA and two OECD peer consultations –May, 2008 Structural Alert Workshop http://www.olis.oecd.org/olis/2009doc.nsf/linkto/env-jm- mono(2009)4 –February, 2009 Expert Consultation to Evaluate an Estrogen Receptor Binding Affinity Model for Hazard Identification http://www.olis.oecd.org/olis/2009doc.nsf/linkto/env-jm- mono(2009)33

24. Office of Pesticide Programs Future Prioritization for EDSP Tier 1 Screening Inert ingredients & other chemicals –develop in vitro & in silico tools that are integrated with exposure-based metrics Pesticide active ingredients –current plan is to use EPA’s schedule for re- evaluating registered active ingredients in the Registration Review program (http://www.epa.gov/oppsrrd1/registration_review/)http://www.epa.gov/oppsrrd1/registration_review/ Consistent with EDSTAC & SAB/SAP recommendations

25. Office of Pesticide Programs 24 Enhanced Integrated Testing & Assessment Where we need to be in the near term –Accelerated/enhanced priority setting/screening & focused animal testing Where we would like to be in the long term –Greater reliance on hypothesis & mechanism-based assessments What needs to happen –Collaborative research to develop scientific basis –Partnerships, stakeholder input, peer review, consensus building, staff training, development of new polices, etc