May 14, 2008 Office of Research and Development National Center for Computational Toxicology EPA’s ToxCast Program for Predicting Toxicity and Prioritizing Chemical Testing http://www.epa.gov/ncct/toxcast IJC SAB presentation This work was reviewed by EPA and approved for presentation but does not necessarily reflect official Agency policy. Mention of trade names or commercial products does not constitute endorsement or recommendation by EPA for use.
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May 14, 2008Office of Research and DevelopmentNational Center for Computational Toxicology
EPA’s ToxCast Program for Predicting Toxicity and Prioritizing Chemical Testing
http://www.epa.gov/ncct/toxcast
IJC SAB presentation
This work was reviewed by EPA and approved for presentation but does not necessarily reflect official Agency policy. Mention of trade names or commercial products does not constitute endorsement or recommendation by EPA for use.
1Office 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
2Office of Research and DevelopmentNational Center for Computational Toxicology
FY09$15-20k>400ExtrapolationKnown Human Toxicants>100IIb
???
>400
>400
Number of Assays
Data poor
Expanded Structure and Use
Diversity
Data Rich(pesticides)
Chemical Criteria
FY11-12
FY10
FY07-08
TargetDate
$10-15k
$15-20k
$20k
Cost per Chemical
Prediction and Prioritization
Extension
Signature Development
PurposeNumber of Chemicals
Phase
ThousandsIII
>300IIc
320I
Affordable science-based system for categorizing chemicalsIncreasing confidence as database grows Identifies potential mechanisms of actionRefines and reduces animal use for hazard ID and risk assessment
8Office of Research and DevelopmentNational Center for Computational Toxicology
Target Chemicals ~10,000
Chemicals with Toxicity Data(Training)
HTSCharacterization
Discover & Validate“Hazard Model”
ToxCast Phase I & II
Chemicals wo/Phenotype Data(Test)
Metabolite Prediction
HTSCharacterization
Apply“Hazard Model”
Mechanism-basedHazard Prediction
Prioritized Chemicals
ToxCast Phase II & III
ToxCast Screening and Prioritization
9Office of Research and DevelopmentNational Center for Computational Toxicology
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
10Office of Research and DevelopmentNational Center for Computational Toxicology
Biological Organization of ToxCast
Receptors& Enzymes
Biological Pathways
Cellular Processes
Tissue / Organ Endpoints
Chemicals
Direct Molecular Interactions
11Office of Research and DevelopmentNational Center for Computational Toxicology
ToxCast Data Matrix:Predicting In Vivo from In Vitro
T1
Toxicity Endpoints
… TN
CN
…
C3
C2
C1
SN…S1CN…C1AN…A1PN…P1
Gene Expression Signatures
CellularAssays
In-vitro / Biochemical Assays
Physico-Chemical Properties
ToxCast320Chemicals
Chemical HTS HCS Genomics In Vivo
[320 chemicals] x [265 assays] x [multiple endpoints] x [multiple concentrations] = millions of datapoints
Che
mic
als
Assays
12Office of Research and DevelopmentNational Center for Computational Toxicology
Key Components of ToxCastProof of Concept
• Chemicals
• Traditional Toxicity Phenotypes
• HTS Assays covering Toxicity Pathways
• Data Analysis and Interpretation
13Office of Research and DevelopmentNational Center for Computational Toxicology
14Office of Research and DevelopmentNational Center for Computational Toxicology
Toxicology Reference Database: ToxRefDB
• ToxRefDB is being developed as part of EPA’s ToxCast research program (www.epa.gov/ncct/toxcast).
• ToxRefDB captures existing information from Office of Pesticide Program (OPP) Data Evaluation Records (DER) into an electronic database that supports ToxCast and other analyses.
• DER are OPP's treatment-related effects summaries, based on the toxicology studies submitted by pesticide registrants.
15Office of Research and DevelopmentNational Center for Computational Toxicology
In Vivo Chronic/Cancer Bioassay Effects and Endpoints in ToxRefDB
Effects & EndpointsTo
xCas
t Pha
se I
Che
mic
als
16Office of Research and DevelopmentNational Center for Computational Toxicology
Common Phenotypes in Chronic Rodent Studies
17Office of Research and DevelopmentNational Center for Computational Toxicology
The Home of TFomics TM
attageneattageneattageneattagene
Nine contracts provide chemical procurement; hundreds of biochemical, cellular, tissue and genomic assays; model
organisms; and the capacity to screen up to 10,000 chemicals
ToxCast Contracts for Generating HTS and Genomics Data
Compound Focus, Inc.a subsidiary of
18Office of Research and DevelopmentNational Center for Computational Toxicology