title: Evaluation of the scientific underpinnings for identifying estrogenic chemicals in nonmammalian taxa using mammalian test systems.
abstract: The US Environmental Protection Agency has responsibility for assessing endocrine activity of more than 10 000 chemicals, a task that cannot reasonably be achieved solely through use of available mammalian and nonmammalian in vivo screening assays. Hence, it has been proposed that chemicals be prioritized for in vivo testing using data from in vitro high-throughput assays for specific endocrine system targets. Recent efforts focused on potential estrogenic chemicals-specifically those that activate estrogen receptor-alpha (ERα)-have broadly demonstrated feasibility of the approach. However, a major uncertainty is whether prioritization based on mammalian (primarily human) high-throughput assays accurately reflects potential chemical-ERα interactions in nonmammalian species. The authors conducted a comprehensive analysis of cross-species comparability of chemical-ERα interactions based on information concerning structural attributes of estrogen receptors, in vitro binding and transactivation data for ERα, and the effects of a range of chemicals on estrogen-signaling pathways in vivo. Overall, this integrated analysis suggests that chemicals with moderate to high estrogenic potency in mammalian systems also should be priority chemicals in nonmammalian vertebrates. However, the degree to which the prioritization approach might be applicable to invertebrates is uncertain because of a lack of knowledge of the biological role(s) of possible ERα orthologs found in phyla such as annelids. Further, comparative analysis of in vitro data for fish and reptiles suggests that mammalian-based assays may not effectively capture ERα interactions for low-affinity chemicals in all vertebrate classes. Environ Toxicol Chem 2016;35:2806-2816. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US Government work and, as such, is in the public domain in the United States of America.
authors.affiliation: Mid-Continent Ecology Division, US Environmental Protection Agency, Duluth, Minnesota. ankley.gerald@epa.gov.
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Ankley
authors.affiliation: Mid-Continent Ecology Division, US Environmental Protection Agency, Duluth, Minnesota.
authors.forename: Carlie A
authors.initials: CA
authors.lastname: LaLone
authors.affiliation: Toxicity Assessment Division, US Environmental Protection Agency, Research Triangle Park, North Carolina.
authors.forename: L Earl
authors.initials: LE
authors.lastname: Gray
authors.affiliation: Mid-Continent Ecology Division, US Environmental Protection Agency, Duluth, Minnesota.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Villeneuve
authors.affiliation: Mid-Continent Ecology Division, US Environmental Protection Agency, Duluth, Minnesota.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Hornung
mesh_terms: D000663:Amphibians / Q000378:metabolism; D000818:Animals; D001717:Birds / Q000378:metabolism; D052244:Endocrine Disruptors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004703:Endocrine System / Q000187:drug effects* / Q000378:metabolism; D004784:Environmental Monitoring / Q000379:methods*; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism*; D005399:Fishes / Q000378:metabolism; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D011485:Protein Binding; D012098:Reproduction / Q000187:drug effects; D015398:Signal Transduction; D013045:Species Specificity; D014481:United States; D014484:United States Environmental Protection Agency
chemical_list: C506487:ESR1 protein, human; D052244:Endocrine Disruptors; D047628:Estrogen Receptor alpha
keywords: Estrogen; Hazard assessment; Prioritization; Species extrapolation