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EDKB: Endocrine Disruptors Knowledge Base at the FDA

Huixiao Hong, Ph.D.

Center for BioinformaticsDivision of Systems Biology

National Center for Toxicological ResearchUS 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

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Outline

1. Endocrine disruptors issues.

2. EDKB overview.

3. Ongoing research.

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Endocrine Disruptors (History)

1996

Food Quality Protection Act

Safe Drinking Water Act

US Congress

Our Stolen Future Theo Colborn

Dianne DumanoskiJohn Peterson Myers

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Importance to FDA

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Molecular Mechanisms

Stefan O Mueller, Anal Bioanal Chem (2004) 378: 582-587

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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

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EDKB Overview: Data

Assay type # of

recordsStandard chemical

to be compared

Endpoint Log (Activity) Range

ER Binding 616 Estradiol (2.0) RBA 2.94 ~ -4.5

AR Binding 230 R1881 (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

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EDKB Overview: Data Flowchart

Structuresearch

Graphicalview

Summarytable

User Interface

ED data from NCTRED data from accumulated literature

Query Results

Oracle database

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EDKB Overview: Data Model

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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.

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EDKB Overview: Users

Number of times EDKB database was accessed ('05-'09)

0

100

200

300

400

500

600

1st half '05 2nd half '05 1st half '06 2nd half '06 1st half '07 2nd half '07 1st half '08 2nd half '08 1st half '09 2nd half '09

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Active/Inactive Assignment

Pre-Filters

Quantitative Predictions

Priority Setting

Phase I

Phase II

Phase III

Phase IV

Database

Hits

EDKB Overview: Priority setting

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Nishihara: J Health Sci 46:282-298 (2000)

EDKB Overview: Filters

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Decision tree model

Molecular descriptors

EDKB Overview: Classification

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EDKB Overview: Quantitative model

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Ongoing Research: Data collection

Enhanced EDKB

Existing EDKB

Literature

ToxCast Tox21

NCTR NTP

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Ongoing Research: Data collection

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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

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Ongoing Research: Future applications

EPA~86,000

FDA(SRS)~23,000

-- -

+++

PredictiveModels

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