Prioritizing the Toxicity Testing of Environmental Chemicals at EPA

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Josephine Lindsey
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1 Prioritizing the Toxicity Testing of Environmental s at EPA George Gray, Ph.D. Assistant Administrator

2 Ranking and Prioritizing s Ranking for further testing Identify compounds of greatest concern Focus testing efforts Ranking for decision making Challenge of consistent methods vs. chemical specific information Differential uncertainty 1

3 ToxCast TM Addresses the Critical Need for Prioritization Too Many s Too High a Cost Pesticides HPV Actives Inerts DW Cancer ReproTox DevTox NeuroTox ImmunoTox $20M 2 IUR (5375) HPV (3548) HPV Challenge (1973) Pesticides (3448) Pesticides (Actives Supported) (1082) Pesticide (Food Use Actives) (336) AntiMicrobial (754) AntiMicrobial (Food Use) (26) Inerts (3305) Inerts (List 1) (8) Inerts (List 2) (96) Toxic Release Inventory (563) CCL (41)

4 ToxCast Merges HTS and Genomics Technologies with Traditional Toxicology Quantitative Biology (HTS) Toxicogenomics ToxCast Toxicology Systems Biology 3

5 4

6 High-Throughput Screening Assays batch testing of chemicals for pharmacological/toxicological endpoints using automated liquid handling, detectors, and data acquisition LTS MTS HTS uhts Gene-expression 1000s/day 10s-100s/yr 10s-100s/day 10,000s- 100,000s/day Human Relevance/ Cost/Complexity Throughput/ Simplicity 5

7 ToxCast TM will identify classifiers or signatures from HTS, HCS and genomics assays to predict hazard $20K Cancer ReproTox DevTox NeuroTox ImmunoTox and prioritize further testing of chemicals. 6

8 Examples of ToxCast Assays Biochemical Target Profiling High Content Cytotoxicity Assessment Transcription Factor Activity Profiling Gene Expression Profiling by Microarray and PCR 7

9 Pesticides as Proof of Concept ~800 Registered in the United States Wealth of Toxicological Information (~$19m) Developmental, reproductive, chronic, etc Represent broad range of chemistries Azoles, carbamates, pyrethroids, triazines, etc. Designed with biological activity in mind Receptor binding, enzyme inhibition, cytoskeletal, etc. 8

10 340 Candidate s for ToxCast Phase pesticidal active ingredients with complete animal toxicity datasets - 7 metabolites 6 pesticidal inerts 17 industrial chemicals - 16 HPV (11 HPVchallenge) 9

11 Correlating HTS to Toxicity CellularAssays Profile Matching Physical chemical properties Biochemical Assays Genomic Signatures Toxicology Endpoints 10

12 Finding Tests For Toxicity - Classification Goal: Find classifiers that accurately predict endpoints Use all available data ToxCast TM & public sources HTS, HCS, genomics, physicochemical properties, calculated properties Properties of an ideal classifier Accurate (low false positive & false negative rates) Inexpensive and easy to measure for new chemicals Easy to interpret provides biological insight ToxCast TM 11

13 Difficult Issues (the usual suspects) Endpoint data Extent to which concentration-response information is acquired (versus use of only single concentration) Ability to detect protoxicants Solubility How many assays are needed? How many assays are affordable? Ability to cover many mechanisms of toxicity 12

14 Phased Development of ToxCast Phase I Proof of Concept: derivation of first-generation ToxCast signatures based on known toxicity of 300 pesticide actives Phase II: Expansion and validation of ToxCast signatures with >1000 additional chemicals, most with partially characterized toxicity. Phase III: Application to thousands of environmental chemicals. Delivering affordable, science-based system for categorizing chemicals Increasing confidence as database grows Identify potential mechanisms of action Refine and reduce use of animals in hazard identification and risk assessment ToxCast ToxCast Assays Assays NO Hazard ToxCast Further Prediction Database Screening And YES Testing No Further Testing Prioritize HIGH Office of Research and LOW Development MEDIUM Programs OPP- inerts, antimicrobials OPPT- HPV, TRI, IUR OSCP- EDC OW- CCL 13

15 Phased Development of ToxCast Phase Number of s Purpose I >300 Training and Cross-Validation II >1000 Validation and Prediction III thousands Prediction and Prioritization ToxCast ToxCast Assays Assays NO ToxCast Database No Further Testing LOW Hazard Prediction YES Prioritize MEDIUM HIGH Further Screening And Testing 14

16 Roles for ToxCast TM in Prioritization and Risk Assessment Risk Assessment Hazard Dose Response Exposure Assessment ID Mode of Action Mechanism of Action Mode of Action Mechanism of Action Genotox Carc. Non-genotox Carc. ReproTox DevTox NeuroTox ToxCast TM ToxCast TM 15

17 Summary Prioritization for testing is important goal for EPA ToxCast is structured approach to developing a prioritization tool using modern biological and information management approaches Still need solid data on endpoints and analytic tools to inform decisions 16

18 Thank You! 17

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