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Evaluation of Androgen Assay Results Using a Curated Hershberger Database
Kleinstreuer, N., P. Browne, X. Chang, R. Judson, W. Casey, P. Ceger, C. Deisenroth, N. Baker, K. Markey, AND R. Thomas. Evaluation of Androgen Assay Results Using a Curated Hershberger Database. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, 81:272-280, (2018). https://doi.org/10.1016/j.reprotox.2018.08.017
Screening environmental chemicals for endocrine disrupting effects is of high importance to ensure protection of human health and ecological systems. Several global initiatives aim to implement rapid, cost-effective approaches to detect potential chemical interactions with key steroid hormone pathways, i.e. estrogen, androgen, and thyroid. One such example is the US Environmental Protection Agency’s (EPA) Endocrine Disruptor Screening Program (EDSP), which was established in 1998 and in 2015 began accepting data generated from high throughput screening (HTS) assays and computational tools in lieu of guideline methods (US EPA 2015b). Following the publication of the National Academies of Sciences report, Toxicity Testing in the 21st Century (NRC 2007) and the establishment of the federal Tox21/ToxCast research programs, significant technological and computational advancements have resulted in effective tools for screening and prioritization of chemicals, some of which are acceptable replacements for animal-based test methods.
• We used 39 reference chemicals with reproducible AR pathway effects in rodents to evaluate the ToxCast/Tox 21 AR model based on 11 in vitro assays. • Agreement was 66% (19/29), with ten inconclusive in vitro model chemicals; most discrepancies were explained by in vitro to in vivo extrapolation. • In vitro false negatives were low potency chemicals in vivo; lowest effect levels were above doses estimated from top in vitro tested concentration. • The AR model had 100% positive predictive value, i.e. no false positives and chemicals with conclusive results were consistently positive in vivo. • The AR model is a critical tool for rapidly screening chemicals and anchoring adverse effects in intact animals to an endocrine mode of action.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL CENTER FOR COMPUTATIONAL TOXICOLOGY