Presentation to EPA Chemical Prioritization Community of Practice

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The ToxCast Chemical Universeand ACToR
(Aggregated Computational Toxicology Resource)

• Presentation to EPA Chemical Prioritization
  Community of Practice
• October 23, 2008

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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Outline

• Defining the chemicals of interest for ToxCast
• The Chemical Landscape Project
• ACToR
• A resource for aggregating data on these
  chemicals
• Next Steps

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ToxCast Screening and Prioritization
Target Chemicals 10,000
Chemicals wo/Phenotype Data (Test)
Chemicals with Toxicity Data (Training)
Metabolite Prediction
HTS Characterization
HTS Characterization
ToxCast Phase I II
ToxCast Phase II III
Apply Hazard Model
Discover Validate Hazard Model
Mechanism-based Hazard Prediction
Prioritized Chemicals
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Phased Development of ToxCast
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The Chemical Landscape Project

• What is the unique set of chemicals EPA is most
  concerned with?
• Targets for the overall ToxCast Program
• How much is know about these chemicals?
• Where are the data gaps?
• Collaboration across EPA
• ORD, OPP, OPPT, OW, GLNPO, EDSP

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Define Lists of Chemicals of Interest

• HPV, MPV
• IUR 2002
• Pesticide and antimicrobial active and inert
  ingredients
• OPPIN
• Toxic Release Inventory
• Drinking water contaminants
• OW CCL 1-3, PCCL, DWSHA
• Hazardous Air Pollutants
• Endocrine disruptor Screening Program chemicals
• Potential persistent and bioaccumulative
  compounds from GLNPO
• IRIS, ToxCast, ToxRefDB

Environmental Chemicals
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Types of Data Available

• Identity
• Names, synonyms
• CAS registry numbers
• Chemical structure
• Biochemical assays
• In Vivo Toxicology
• Production volume
• Regulations
• Exposure

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Data Classes and Phenotypes

• Type Classes
• Tabular
• Summary calls
• Descriptive
• Links to web sites

• Phenotypes
• General Hazard
• Subchronic Toxicity
• Chronic Toxicity
• Carcinogenicity
• Genotoxicity
• Developmental Toxicity
• Reproductive Toxicity
• Dermal Toxicity
• Neurotoxicity
• Food Safety

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Examples of Data Sources
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Summary of Chemical Landscape Analysis

• Total Count 9,912
• Fraction of chemicals evaluated for specific
  classes of toxicity
• General Hazard (usually acute data) 59
• Carcinogenicity 26
• Genotoxicity 28
• Developmental Toxicity 29
• Reproductive Toxicity 11
• Manuscript submitted to EHP sept2008

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Subject of High Quality Study

• Potential sources of data from ToxCast
  validation
• ToxRefDB 4
• IRIS 5
• NTP 12
• OECD SIDS 3
• HPVIS 10
• ATSDR 2
• IARC 5
• One or more high quality sources 28

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Other Summary Statistics

• Fraction of chemicals evaluated for specific data
  types
• Production volume listed 60
• Subject to EPA Regulations 47
• Chemical Structure available 72
• Physico-chemical properties calculated 59
• Appropriate Physchem for HTS 31
• Good Physchem high quality Tox 1,046 chemicals
• Candidates for validation step of ToxCast Phase II

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Overlap Matrix by Candidate Chemical Source
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ACToRAggregated Computational Toxicology Resource

• One-stop shop for information on environmental
  chemicals
• 500,000 unique chemicals
• Multiple Domains
• Physchem, biological, use levels, regulations
• Brings together data from gt200 sources
• EPA, FDA, NTP, other governmental, academic,
  industry
• Supports the EPA ToxCast screening and
  prioritization program
• What are the target chemicals for ToxCast?
• How much do we know about those chemicals?
• Modeled on NCBI databases http//www.ncbi.nlm.nih
  .gov/
• http//epa.gov/actor (November 2008)

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Main Concepts

• Data Collection
• Chemical
• Substance
• Compound
• Generic Chemical ( CAS Registry Number)
• All data on all substances with same CASRN is
  aggregated together
• Assay
• Assay Component
• Assay Result

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ACToRAggregated Computational Toxicology Resource
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ACToR Statistics
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Screen Shots
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Landscape Next Steps

• Goal is prioritization of Phase II, III ToxCast
  chemicals
• List has expanded to include other Tox21
  nominations
• Characterize chemicals along several axes
• Single chemical vs. mixture
• Amenable to HTS (DMSO solubility, volatility are
  issues)
• Toxicity already characterized or not
• Known safe or known toxic
• Is exposure potential known or calculable?
• Cluster chemicals
• Structural classes
• Physico-chemical properties

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Working with Chemical Structure Based Clusters
and ToxCast Predictive Signatures in Phase II
III
Attempt to validate on red Pass validation and
extension to second chemical class,
and Extrapolate on black Fail need to re-train
Train on green Validate on red Extrapolate on
black
Extrapolate on black?
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Summary

• The universe of chemicals to be examined by
  ToxCast has been defined
• 10K 12K
• About 25 have characterized toxicity
• Chemical structure, toxicology and other
  information is being used to prioritize chemicals
  for Phase II
• ACToR is a new resource for finding information
  on environmental chemicals
• Publicly available soon
• Pulling in data or links to all publicly
  available data sources on these chemicals