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Exposure Prioritization for Computational Toxicology

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

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Exposure Prioritization for Computational Toxicology

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

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

  3. Managing Chemical Risks: Faster Science for Better Decisions Too Many Chemicals 9900 Too Little Data (%)

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

  5. ToxCastTM 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 4

  6. Phase I to Phase II and Tox21

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

  8. The Future State: Using Hazard and Exposure Information for Prioritizing Testing and Monitoring H E H E H E H E H E High exposure potential H E Low exposure potential H E H E H E H E ToxCast targets H E H E ToxCast Low Hazard Prediction Low Priority for Bioactivity Profiling H E ToxCast Hazard Prediction H E H E Lower Priority for Testing and Monitoring Intelligent, Targeted Testing Human Biomonitoring 7

  9. Disclaimer Although this work was reviewed by EPA and approved for presentation, it may not necessarily reflect official Agency policy.

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