1. 1 Innovative Science To Improve Public Health EDKB: Endocrine Disruptors Knowledge Base at the FDA Huixiao Hong, Ph.D. Center for Bioinformatics Division of Systems Biology National Center for Toxicological Research US Food and Drug Administration 3900 NCTR Rd., Jefferson, AR 72079 The views in the presentation are my personal opinions and do not necessary reflect those of the US FDA

2. 2 Innovative Science To Improve Public Health Outline 1.Endocrine disruptors issues. 2.EDKB overview. 3.Ongoing research.

3. 3 Innovative Science To Improve Public Health Endocrine Disruptors (History) 1996 Food Quality Protection Act Safe Drinking Water Act US Congress Our Stolen Future Theo Colborn Dianne Dumanoski John Peterson Myers

4. 4 Innovative Science To Improve Public Health Importance to FDA

5. 5 Innovative Science To Improve Public Health Molecular Mechanisms Stefan O Mueller, Anal Bioanal Chem (2004) 378: 582-587

6. 6 Innovative Science To Improve Public Health EDKB Overview Started the project in 1996 Multidisciplinary team:  biologists/toxicologists, bio/cheminformaticians, computational chemists, software engineers, statisticians, regulatory agents Collaborated with ACC and EPA  Worked with EPA over 3 years ( 2001-2004) on the ER predictive model and the AR assay validation for potential use in regulation Three main accomplishments  Assayed over >200 chemicals for ER and AR binding, respectively  Developed a knowledge base that contains various in vitro and in vivo assay data (in house and literature), available from our website (http://edkb.fda.gov)  Developed predictive models for both ER and AR binding

7. 7 Innovative Science To Improve Public Health EDKB Overview: Data Assay type # of records Standard chemical to be compared EndpointLog (Activity) Range ER Binding616Estradiol (2.0)RBA2.94 ~ -4.5 AR Binding230R1881 (2.0)RBA3.18 ~ -3.56 Uterotropic1707Estradiol (2.0)RP3.93 ~ -3.44 Cell proliferation 160Estradiol (2.0)RPP3.0 ~ -4.22 Reporter gene544Estradiol (2.0)RP2.18 ~ -5.38

8. 8 Innovative Science To Improve Public Health EDKB Overview: Data Flowchart Structure search Graphical view Summary table User Interface ED data from NCTR ED data from accumulated literature Query Results Oracle database

9. 9 Innovative Science To Improve Public Health EDKB Overview: Data Model

10. 10 Innovative Science To Improve Public Health EDKB Overview: Interface Link to external resources, e.g., PubChem, ToxNet, etc. Excel-like spreadsheet for view and export Graphic Activity Profiles Query interface Chemical structure & similarity search Individual chemical info and ref.

11. 11 Innovative Science To Improve Public Health EDKB Overview: Users

12. 12 Innovative Science To Improve Public Health Active/Inactive Assignment Pre-Filters Quantitative Predictions Priority Setting Phase I Phase II Phase III Phase IV Database Hits EDKB Overview: Priority setting

13. 13 Innovative Science To Improve Public Health Nishihara: J Health Sci 46:282-298 (2000) EDKB Overview: Filters

14. 14 Innovative Science To Improve Public Health Decision tree model Molecular descriptors EDKB Overview: Classification

15. 15 Innovative Science To Improve Public Health EDKB Overview: Quantitative model

16. 16 Innovative Science To Improve Public Health Ongoing Research: Data collection Enhanced EDKB Existing EDKB Literature ToxCast Tox21 NCTR NTP

17. 17 Innovative Science To Improve Public Health Ongoing Research: Data collection

18. 18 Innovative Science To Improve Public Health Ongoing Research: Data collection Assay type # of Chem. In Symyx # of Chem. In EDKB ER Binding3731368 AR Binding556210 Uterotropic12231119 Cell proliferation141137 Reporter gene1517493

19. 19 Innovative Science To Improve Public Health Ongoing Research: Future applications EPA ~86,000 FDA(SRS) ~23,000 -- - ++ + Predictive Models

20. 20 Innovative Science To Improve Public Health

21. 21 Innovative Science To Improve Public Health