title: Screening Chemicals for Estrogen Receptor Bioactivity Using a Computational Model.
abstract: The U.S. Environmental Protection Agency (EPA) is considering high-throughput and computational methods to evaluate the endocrine bioactivity of environmental chemicals. Here we describe a multistep, performance-based validation of new methods and demonstrate that these new tools are sufficiently robust to be used in the Endocrine Disruptor Screening Program (EDSP). Results from 18 estrogen receptor (ER) ToxCast high-throughput screening assays were integrated into a computational model that can discriminate bioactivity from assay-specific interference and cytotoxicity. Model scores range from 0 (no activity) to 1 (bioactivity of 17β-estradiol). ToxCast ER model performance was evaluated for reference chemicals, as well as results of EDSP Tier 1 screening assays in current practice. The ToxCast ER model accuracy was 86% to 93% when compared to reference chemicals and predicted results of EDSP Tier 1 guideline and other uterotrophic studies with 84% to 100% accuracy. The performance of high-throughput assays and ToxCast ER model predictions demonstrates that these methods correctly identify active and inactive reference chemicals, provide a measure of relative ER bioactivity, and rapidly identify chemicals with potential endocrine bioactivities for additional screening and testing. EPA is accepting ToxCast ER model data for 1812 chemicals as alternatives for EDSP Tier 1 ER binding, ER transactivation, and uterotrophic assays.
authors.affiliation: †U.S. EPA, Office of Chemical Safety and Pollution Prevention, Washington, D.C. 20004, United States.
authors.forename: Patience
authors.initials: P
authors.lastname: Browne
authors.affiliation: ‡U.S. EPA, Office of Research and Development, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Judson
authors.affiliation: §National Toxicology Program, Interagency Center for the Evaluation of Alternative Toxicological Methods, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Warren M
authors.initials: WM
authors.lastname: Casey
authors.affiliation: ∥Integrated Laboratory Systems, Inc., National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Kleinstreuer
authors.affiliation: ‡U.S. EPA, Office of Research and Development, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Thomas
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000032:analysis; D003198:Computer Simulation; D052244:Endocrine Disruptors / Q000032:analysis* / Q000633:toxicity; D057166:High-Throughput Screening Assays / Q000379:methods*; D010636:Phenols / Q000032:analysis; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D015203:Reproducibility of Results; D018675:Toxicity Tests; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D010636:Phenols; D011960:Receptors, Estrogen; C006780:bisphenol A; D000098826:Bisphenol A Compounds