21st Century Screening Assessment of Pesticides – A Regulatory View

1. 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. Managing Chemical Risks • 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 National Pesticide Program Gateway to Market • ~1,100 active ingredients & 19,000 products • Reevaluate existing pesticides on a regular schedule

3. Managing Chemical Risks Common Challenges • 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

4. Managing Chemical Risks Strategic Direction Transition toward new integrative & predictive 21st century techniques, to increase efficiency and effectiveness of testing & assessment 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

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

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

9. 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 8

10. 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 9

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

12. 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. 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. 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 13

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

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

23. (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. 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/) • Consistent with EDSTAC & SAB/SAP recommendations

25. 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