QSARs for Endocrine Disruption Priority Setting Database 2: The Integrated 4-Phase Model John D. Walker a *, Hong Fang b , Roger Perkins b and Weida Tong c a TSCAInteragencyTestingCommittee(ITC),U.S.EnvironmentalProtectionAgency(M7401),Washington,DC20460 b NorthropGrummanInformationTechnology,Jefferson,Arkansas72079 c NationalCenterforToxicologicalResearch(NCTR),Jefferson,Arkansas72079 Abstract Version 2 of the Endocrine Disruption Priority Setting Database(EDPSD2)isadecisionsupporttooldeveloped bytheU.S.EnvironmentalProtectionAgency.EDPSD2is organized into 4 categories (exposure-related, effects- related, combined exposure-and effects-related and spe- cially-targeted priorities) that are supported by several compartments and information sources. The effects-relat- ed category includes a Quantitative Structure Activity Relationship compartment that is supported by two models for predicting estrogen receptor binding affinities of chemicals in EDPSD2. This paper describes the categoriesandcompartmentsofEDPSD2andtheuseof the Integrated 4-Phase model to predict the estrogen receptorbindingaffinitiesofchemicalsinEDPSD2. 1 Introduction The1996FoodQualityProtectionAct(FQPA,21U.S.C. ßß201±415) requires the U.S. Environmental Protection Agency(U.S.EPA)toimplementprogramsforscreening and testing of pesticide chemical active ingredients and ™inert∫formulationingredientsfortheirabilitytodisrupt estrogenfunctions.Inresponse,theU.S.EPAestablished theEndocrineDisruptorsScreeningandTestingAdvisory Committee(EDSTAC).TheEDSTACrecommendedthat the U.S. EPA create an Endocrine Disruption Priority SettingDatabase(EDPSD)asatoolthatcouldbeusedto assist rapid sorting and priority setting of chemicals for endocrinedisruptionscreeningandtesting. EDPSD 1 was developed for and demonstrated to EDSTACataDecember1997publicmeeting[1].Quanti- tativeStructureActivityRelationships(QSARs)werenot usedforEDPSD1[2]. FollowingthedevelopmentofEDPSD1,theU.S.EPA developedEDPSD2(http:/www.epa.gov/scipoly/oscpendo/ index.htm).EDPSD2isamulti-userclient/serverapplica- tiondevelopedusingVisualBasic6.0forthe™frontend∫ screensanduserinterface,MicrosoftAccess97forthe™back end∫database,andSeagateCrystalReports7forthereports (http:/www.erg.com/endocrine). The EDPSD2 QSAR compartment includes two inde- pendently-developed QSAR-based models for predicting Quant.Struct.-Act.Relat., 22 (2003) ¹2003WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim0931-8771/03/010&-0001$17.50+.50/0 1 * To receive all correspondence: Phone: (202) 564-7526, Fax: (202)564-7528,E-mail:walker.johnd@epa.gov Key words: QSARs, receptor binding, estrogen, EDPSD, Inte- grated4-Phase Abbreviations: EDPSD ±EndocrineDisruptionPrioritySettingDatabase QSARs ± Quantitative Structure Activity Relationships RBAs ± receptor binding affinities FQPA ± Food Quality Protection Act FIFRA ± Federal Insecticide, Fungicide, and Rodenticide Act U.S. EPA ± U.S. Environmental Protection Agency EDSTAC ± Endocrine Disruptors Screening and Testing Advisory Committee MDL ± Molecular Design Limited ISIS ± Information Systems\9 Integrated Scientific In- formation System SMILES ± Simplified Molecular Input Line Entry System HQSAR ± Hologram QSAR ER ± estrogen receptor 2D ± 2 dimensional 3D ± 3 dimensional CAS ± Chemical Abstract Service CoMFA ± Comparative Molecular Field Analysis HSDB ± Hazardous Substances Data Bank RTECS \R ± Registry of Toxic Effects of Chemical Substances ATSDR ± Agency for Toxic Substances Disease Registry EAFUS ± Everything Added to Food in the United States AQUIRE ± AQUatic toxicity Information REtrieval (AQUIRE) database TERRETOX ± Terrestrial Toxicity database OECD ± Organization for Economic Cooperation and Development SIDS ± Screening Information Data Set ICCA ± International Council of Chemical Associations PLS ± partial least squares QSARsforEndocrineDisruptionPrioritySettingDatabase2:TheIntegrated4-PhaseModel