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 Innovative Science To Improve Public Health
Outline 1. Endocrine disruptors issues. 2. EDKB overview. 3. Ongoing research. Innovative Science To Improve Public Health 2
Endocrine Disruptors (History) 1996 Our Stolen Future Theo Colborn Dianne Dumanoski John Peterson Myers Food Quality Protection Act Safe Drinking Water Act US Congress Innovative Science To Improve Public Health 3
Importance to FDA Innovative Science To Improve Public Health 4
Molecular Mechanisms Stefan O Mueller, Anal Bioanal Chem (2004) 378: 582 -587 Innovative Science To Improve Public Health 5
EDKB Overview • Started the project in 1996 • Multidisciplinary team: v biologists/toxicologists, bio/cheminformaticians, computational chemists, software engineers, statisticians, regulatory agents • Collaborated with ACC and EPA v 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 v v v 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 Innovative Science To Improve Public Health 6
EDKB Overview: Data Standard chemical to be compared Endpoint Assay type # of records Log (Activity) Range ER Binding 616 Estradiol (2. 0) RBA 2. 94 ~ -4. 5 AR Binding 230 R 1881 (2. 0) RBA 3. 18 ~ -3. 56 Uterotropic 1707 Estradiol (2. 0) RP 3. 93 ~ -3. 44 Cell proliferation 160 Estradiol (2. 0) RPP 3. 0 ~ -4. 22 Reporter gene 544 Estradiol (2. 0) RP 2. 18 ~ -5. 38 Innovative Science To Improve Public Health 7
EDKB Overview: Data Flowchart ED data from accumulated literature ED data from NCTR Oracle database Results Query User Interface Structure search Graphical view Summary table Innovative Science To Improve Public Health 8
EDKB Overview: Data Model Innovative Science To Improve Public Health 9
Individual chemical info and ref. EDKB Overview: Interface Link to external resources, e. g. , Pub. Chem, Tox. Net, etc. Chemical structure & similarity search Graphic Activity Profiles Query interface Innovative Science To Improve Public Health Excel-like spreadsheet for view and export 10
EDKB Overview: Users Innovative Science To Improve Public Health 11
EDKB Overview: Priority setting Database Phase III Phase IV Pre-Filters Active/Inactive Assignment Quantitative Predictions Priority Setting Innovative Science To Improve Public Health Hits 12
EDKB Overview: Filters Innovative Science To Improve Public Health Nishihara: J Health Sci 46: 282 -298 (2000) 13
EDKB Overview: Classification Decision tree model Molecular descriptors Innovative Science To Improve Public Health 14
EDKB Overview: Quantitative model Innovative Science To Improve Public Health 15
Ongoing Research: Data collection Literature Existing EDKB Enhanced EDKB NCTR NTP Tox. Cast Tox 21 Innovative Science To Improve Public Health 16
Ongoing Research: Data collection Innovative Science To Improve Public Health 17
Ongoing Research: Data collection Assay type # of Chem. In Symyx # of Chem. In EDKB ER Binding 3731 368 AR Binding 556 210 Uterotropic 1223 1119 Cell proliferation 141 137 Reporter gene 1517 493 Innovative Science To Improve Public Health 18
Ongoing Research: Future applications EPA ~86, 000 Predictive Models ++ + FDA(SRS) ~23, 000 Innovative Science To Improve Public Health -- 19
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