Computational ToxicologyDavid J. Dix, Ph.D.National Center for Computational Toxicology Office of Research & DevelopmentU.S. Environmental Protection AgencyResearch Triangle Park, NC 27711Email: [email protected]://www.epa.gov/ncct/Biochemical and Molecular ToxicologyUNC ENVR/TOXC 44201dec20092“…to integrate modern computing and information technology with molecular biology to improve Agency prioritization of data requirements and risk assessment of chemicals”3ToxicityCellChangesMolecularTargetsTissuesCellularNetworksCellular SystemsTissueDoseMolecularPathwaysThe Grand Challenge of Computational Toxicology: Predicting Human ToxicityBiochemical HTSCell-Based HTSComplex Cellular and HCS HTSModel Organism MTSToxRefDBVirtual TissuesExposure4Science, February 2008Future of Toxicity Testing and Environmental Risk Assessments NAS report, July 2007EPA strategy, March 2009CTRP 2ndgen plan, Sept 2009Science, August 21, 20095NAS, June 2007. Toxicity Testing in the Twenty-first Century: A Vision and a Strategy6EPA Strategic Plan (2009)Strategic Goals•Toxicity Pathway ID and Screening•Pathway Based Risk Assessment•Institutional Transitionhttp://www.epa.gov/spc/toxicitytesting/index.htm72ndGeneration CompToxImplementation Plan (FY09-12)http://www.epa.gov/ncct/bosc_review/2009/files/CompTox_BOSC_09.pdfhttp://www.epa.gov/ncct/bosc_review/2009/agenda.htmlExpand beyond hazard prioritization Increase emphasis on Exposure Prioritization Systems approaches to modeling toxicity Input into NexGen risk assessmentsSupport EPA’s Strategic Plan for Evaluating the Toxicity of Chemicals Provide online databases, knowledgebases and analysis tools Expand Tox21 and other communities Collaborate and communicate with EPA Programs and Regions8Enabling the Transformation in ToxicologyInformation Technology and ManagementHigh Throughput ScreeningMolecular, Cellular and Systems Biology Pathway BasedTesting9ACToRACToRChemical StructureChemical IdentityAssay DefinitionsAssay DataChemical PropertiesGenesPathwaysDiseasesStatistical WorkflowChemical WorkflowAssay WorkflowToxRefDBVT-KBDSSToxCompTox Databases: A Foundation for Predictive/Systems ToxicologyExposureDB10CTRP Databases and Analysis Tools- Online or Coming Soonhttp://epa.gov/ncct/dsstox/http://actor.epa.gov/actor/faces/ACToRHome.jspToxMiner- ToxCast/ExpoCast data- Chemical descriptors- Statistical workflow- Pathway mapping- Prioritization workflow11Tox21 and Other Communities200420062005 2007200820092010FDAATSDREU JRC10K2.8K1.4KTox21 Chemical Library12Incorporating Metabolism and Dosimetry into HTS and Predictive ModelingSG2G1MG0Cell CycleNRSignalingXenobioticMetabolismLipidMetabolismMAPKSignalingOxidativeStressDNA DamageMitochondrialFunctionDNA DamageSensingRepairApoptosisProliferationNecrosisPathway Effects Key Events Adverse OutcomesSG2G1MG0Cell CycleNRSignalingXenobioticMetabolismLipidMetabolismMAPKSignalingOxidativeStressDNA DamageMitochondrialFunctionDNA DamageSensingRepairApoptosisProliferationNecrosisSG2G1MG0Cell CycleNRSignalingXenobioticMetabolismLipidMetabolismMAPKSignalingOxidativeStressDNA DamageMitochondrialFunctionDNA DamageSensingRepairApoptosisProliferationNecrosisPathway Effects Key Events Adverse OutcomesV-Liver Modeling of Metabolism, Dosimetry and Toxicity13Systems Models: Virtual Tissueschemicalspathways networks cell statestissue functionQuantitative Dose-Response Models Quantitative Dose-Response Models Next GenerationRisk assessmentsNext GenerationRisk assessmentsMoving beyond empirical models, to multi-scale models of complex biological systems.Identify Key Targets and Pathways For PrioritizationIdentify Key Targets and Pathways For Prioritization14ExpoCast-NERLExposureBackground ExposureHumanEnvironmentBiomonitoringPopulationUptakeNNNNH NHClExposure MediaContactProductsSourcesChemicalsHostSusceptibilityBiotransformationExposomeInformatics ApproachesNetwork ModelsKnowledge SystemsMechanistic ModelsExposureDatabaseDistribution/FateExpanding Exposure Science for Prioritization and Toxicity TestingNCCTExpoCast15Future Chemical PrioritizationsToxRefDBToxCastExposureSource/StressorFormationTransport/FateEnvironmentalConcentrationProduction/ Import Vol umesChemicals in Consumer ProductsEnvironment alReleasesProduct Usa ge Informatio nIndoor Air Monitoring Dat aHuma n Exposure MonitoringProduct ion/ Process Infor mationEnvironmental TransformationOutdoor Air Monitoring DataExposure LimitsAct ivity Patt er ns InformationHum an Biological Monitoring DataEPA HPVISEPA I UREU ESI SEPA TRIDOE GHGHousehold Products DBCosmetic Voluntary Reg. DBEPA Pesticide Usag e DataUK Pharma-ceu tical Usag e EPA HPVISATSDR ToxProfilesDEA NFLISEnvironmental Fate SimulatorECOTOX DBCESARDOE IndoorAirNHEXASCTEP P EPA NATAEPA AIRS/AFSUN IPCC GHGNHEXASEUROPA Pest-DietEPA NHAP SEPA CHADCDC NHANE SNHEXASCTEPPNIOSH NOESAIHA WEELOSHA PELExposureSource/StressorFormationTransport/FateEnvironmentalConcentrationProduction/ Import Vol umesChemicals in Consumer ProductsEnvironment alReleasesProduct Usa ge Informatio nIndoor Air Monitoring Dat aHuma n Exposure MonitoringProduct ion/ Process Infor mationEnvironmental TransformationOutdoor Air Monitoring DataExposure LimitsAct ivity Patt er ns InformationHum an Biological Monitoring DataEPA HPVISEPA I UREU ESI SEPA TRIDOE GHGHousehold Products DBCosmetic Voluntary Reg. DBEPA Pesticide Usag e DataUK Pharma-ceu tical Usag e EPA HPVISATSDR ToxProfilesDEA NFLISEnvironmental Fate SimulatorECOTOX DBCESARDOE IndoorAirNHEXASCTEP P EPA NATAEPA AIRS/AFSUN IPCC GHGNHEXASEUROPA Pest-DietEPA NHAP SEPA CHADCDC NHANE SNHEXASCTEPPNIOSH NOESAIHA WEELOSHA PELExpoCastToxMinerSG2G1MG0Cell CycleNRSignalingXenobioticMetabolismLipidMetabolismMAPKSignalingOxidativeStressDNA DamageMitochondrialFunctionDNA DamageSensingRepairApoptosisProliferationNecrosisSG2G1MG0Cell CycleNRSignalingXenobioticMetabolismLipidMetabolismMAPKSignalingOxidativeStressDNA DamageMitochondrialFunctionDNA DamageSensingRepairApoptosisProliferationNecrosisVirtual TissuesChemical StructuresChemical StructuresNNNHOONHOCH3CH3ONOSClClClClClOOOHPNHOSOOCH3CH3CH3NNNHOONHOCH3CH3ONOSClClClClClOOOHPNHOSOOCH3CH3CH3Priority = f(Chemical Descriptors + ToxCast + V-Tissues + Exposure)ReproductiveDevelopmentalCancer16No alertNo additional assessmentTier 3 Assessments• Few (dozens) chemicals –high hazard and exposure• Based on all policy relevant data and emerging science• Best
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