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.