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The U.S. Tox21 program has screened a library of approximately 10,000 (10K) environmental chemicals and drugs in three independent runs for estrogen receptor alpha (ER alpha) agonist and antagonist activity using two types of ER reporter gene cell lines, one with an endogenous full length ER alpha (ER-luc; BG1 cell line) and the other with a transfected partial receptor consisting of the ligand binding domain (ER-bla; ER alpha beta-lactamase cell line), in a quantitative high-throughput screening (qHTS) format. The ability of the two assays to correctly identify ER alpha agonists and antagonists was evaluated using a set of 39 reference compounds with known ERa activity. Although both assays demonstrated adequate (i.e. 80%) predictivity, the ER-luc assay was more sensitive and the ER-bla assay more specific. The qHTS assay results were compared with results from previously published ER alpha binding assay data and showed >80% consistency. Actives identified from both the ER-bla and ER-luc assays were analyzed for structure-activity relationships (SARs) revealing known and potentially novel ERa active structure classes. The results demonstrate the feasibility of qHTS to identify environmental chemicals with the potential to interact with the ERa signaling pathway and the two different assay formats improve the confidence in correctly identifying these chemicals.