The ToxCast Chemical Universe and ACToR (Aggregated Computational Toxicology Resource)

1. 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.

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

3. 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

4. Phased Development of ToxCast

5. 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

6. 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”

7. Types of Data Available • Identity • Names, synonyms • CAS registry numbers • Chemical structure • Biochemical assays • In Vivo Toxicology • Production volume • Regulations • Exposure

8. 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 Data Classes and Phenotypes

9. Examples of Data Sources

10. 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

11. 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%

12. 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

13. Overlap Matrix by Candidate Chemical Source

14. Bisphenol A 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 >200 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)

15. 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

16. ACToR Web Browser ACToR API Targeted Testing Chemical Chemical ID, Structure … Assay DevToxDB Genomics BioRefDB ToxMiner ToxRefDB Tabular Data, Links to Web Resources MicroArray Data Biological Reference Data Data Mining Specialized Toxicology Databases Internet Searches http://actor.epa.gov/actor ACToRAggregated Computational Toxicology Resource

17. ACToR Statistics

18. Screen Shots

22. 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

23. Phase I (With Tox Data) Other with Tox Data Other – no Tox Data 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?

24. 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