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Office of Research and DevelopmentNational Center for Computational Toxicology April 6, 2010
Exposure-Based Chemical Prioritization Workshop: Exploring Opportunities for CollaborationRTP, NCApril 6, 2010
Robert Kavlock, Director
National Center for Computational Toxicology
Exposure Prioritization for Computational Toxicology
Office of Research and DevelopmentNational 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
Office of Research and DevelopmentNational Center for Computational Toxicology 3
Too Many Chemicals
Too Little Data (%)
0
10
20
30
40
50
60
Acute Cancer Gentox
Dev Tox Repro Tox
9900
Managing Chemical Risks: Faster Science for Better Decisions
1
10
100
1000
10000
IRIS TRI Pesticides
Inerts CCL 1 & 2 HPV
MPV
Office of Research and DevelopmentNational Center for Computational Toxicology 4
Human Relevance/ Cost/Complexity
Throughput/ Simplicity
High-Throughput Screening Assays
10s-100s/yr
10s-100s/day
1000s/day
10,000s-100,000s/day
LTS HTSMTS uHTS
batch testing of chemicals for pharmacological/toxicological endpoints using automated liquid handling, detectors, and data
acquisition
Gene-expression
Office of Research and DevelopmentNational Center for Computational Toxicology 55
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
Office of Research and DevelopmentNational Center for Computational Toxicology
Phase I to Phase II and Tox21
Phase I Phase II Tox21
Actives 272 120 700
Inerts 24 100 1000
Antimicrobials 33 100 500
HPV 35 170 1300
MPV 7 60 1500
Green 4 60 500
PCCL 73 150 500
Nano 0 40 0
Pharma 0 150 2500
Consumer/Food additives 0 0 1500
Total 309 700 10000
Office of Research and DevelopmentNational Center for Computational Toxicology
Phase I ToxCast In Vitro Bioactivity
828 of 199,680 Assay-Chemical Pairshad AC50s of less than 1µM
: Assay-Chemical Hit
Assays
ToxC
ast_
320
Ch
emic
als
Cell Free HTSMultiplexed TFHuman BioMapHCSqNPAsCytotox/XMEsImpedanceGenotoxicity
Novascreen(Knudsen et al, submitted)
Attagene(Martin et al, in press)
Bioseek(Houck et al, JBS, 2009)
Cellumen(Houck et al, In prep)
CellzDirect( Rotroff et 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)
Office of Research and DevelopmentNational Center for Computational Toxicology 88
HEHEHE
HEHE
HE
HEHE HE
HEHE HE
Low exposure potentialHigh exposure potential
HEHE
HE
ToxCast Hazard Prediction
Intelligent, Targeted Testing
The Future State: Using Hazard and Exposure Information for Prioritizing
Testing and Monitoring
Human Biomonitoring
ToxCast LowHazard
Prediction Low Priority for Bioactivity Profiling
ToxCast targets
Lower Priority for Testing and Monitoring
Office of Research and DevelopmentNational Center for Computational Toxicology 9
Disclaimer
Although this work was reviewed by EPA and approved for presentation,
it may not necessarily reflect official Agency policy.