1. Office of Research and Development National Center for Computational Toxicology April 6, 2010 Exposure-Based Chemical Prioritization Workshop: Exploring Opportunities for Collaboration RTP, NC April 6, 2010 Robert Kavlock, Director National Center for Computational Toxicology Exposure Prioritization for Computational Toxicology

2. Office of Research and Development National Center for Computational Toxicology “ … to integrate modern computing and information technology with molecular biology to improve Agency prioritization of data requirements and risk assessment of chemicals” www.epa.gov/ncct Providing Decision Support Tools for High-Throughput Screening, Risk Assessment and Risk Management

3. Office of Research and Development National Center for Computational Toxicology 2 Too Many Chemicals Too Little Data (%) 9900 Managing Chemical Risks: Faster Science for Better Decisions

4. Office of Research and Development National Center for Computational Toxicology 3 Human Relevance/ Cost/Complexity Throughput/ Simplicity High-Throughput Screening Assays 10s-100s/yr 10s-100s/day 1000s/day 10,000s- 100,000s/day LTSHTSMTSuHTS batch testing of chemicals for pharmacological/toxicological endpoints using automated liquid handling, detectors, and data acquisition Gene-expression

5. Office of Research and Development National Center for Computational Toxicology 44 ToxCast TM Background Addresses chemical screening and prioritization needs for pesticidal inerts, anti-microbials, CCLs, HPVs and MPVs Comprehensive use of HTS technologies to generate biological fingerprints and predictive signatures Done in Phases (Concept, Expansion and Practice) ~$20k per chemical Committed to stakeholder involvement and transparency Communities of Practice- Chemical Prioritization; Exposure Release of all data upon peer review publication

6. Office of Research and Development National Center for Computational Toxicology Phase I to Phase II and Tox21 Phase IPhase IITox21 Actives272120700 Inerts241001000 Antimicrobials33100500 HPV351701300 MPV7601500 Green460500 PCCL73150500 Nano0400 Pharma01502500 Consumer/Foo d additives001500 Total30970010000

7. Office of Research and Development National Center for Computational Toxicology Phase I ToxCast In Vitro Bioactivity 828 of 199,680 Assay-Chemical Pairs had AC50s of less than 1µM : Assay-Chemical Hit Assays ToxCast_320 Chemicals Cell Free HTS Multiplexed TF HumanBioMap HCS qNPAs Cytotox/XMEs Impedance Genotoxicity Novascreen(Knudsen et al, submitted) Attagene(Martin et al, in press) Bioseek(Houck et al, JBS, 2009) Cellumen(Houck et al, In prep) CellzDirect(Rotroffet al, JTEH in press) Solidus (Ryan et al, In prep) ACEA (Judson et al, In prep) Gentronix(Knight et al, RT, 2009) Judson et al, EHP (2010)

8. Office of Research and Development National Center for Computational Toxicology 77 HE HE HE HE HE HE HE HE HE HE HE HE Low exposure potential High exposure potential HE HE HE ToxCast Hazard Prediction Intelligent, Targeted Testing The Future State: Using Hazard and Exposure Information for Prioritizing Testing and Monitoring Human Biomonitoring ToxCast Low Hazard Prediction Low Priority for Bioactivity Profiling ToxCast targets Lower Priority for Testing and Monitoring

9. Office of Research and Development National Center for Computational Toxicology 8 Disclaimer Although this work was reviewed by EPA and approved for presentation, it may not necessarily reflect official Agency policy.