Endocrine Profiling and Prioritization of Environmental Chemicals Using ToxCast Data

作者：David M. Reif, Matthew T. Martin, Shirlee Tan, Keith A. Houck, Richard Judson, Ann M. Richard, Thomas B. Knudsen, David J. Dix, Robert J. Kavlock · 发表于：Environmental Health Perspectives · 年份：2010 · DOI：10.1289/ehp.1002180 · 被引用次数：403 · 研究领域：Effects and risks of endocrine disrupting chemicals、Environmental Toxicology and Ecotoxicology、Toxic Organic Pollutants Impact

BACKGROUND: The prioritization of chemicals for toxicity testing is a primary goal of the U.S. Environmental Protection Agency (EPA) ToxCast™ program. Phase I of ToxCast used a battery of 467 in vitro, high-throughput screening assays to assess 309 environmental chemicals. One important mode of action leading to toxicity is endocrine disruption, and the U.S. EPA's Endocrine Disruptor Screening Program (EDSP) has been charged with screening pesticide chemicals and environmental contaminants for their potential to affect the endocrine systems of humans and wildlife. OBJECTIVE: The goal of this study was to develop a flexible method to facilitate the rational prioritization of chemicals for further evaluation and demonstrate its application as a candidate decision-support tool for EDSP. METHODS: Focusing on estrogen, androgen, and thyroid pathways, we defined putative endocrine profiles and derived a relative rank or score for the entire ToxCast library of 309 unique chemicals. Effects on other nuclear receptors and xenobiotic metabolizing enzymes were also considered, as were pertinent chemical descriptors and pathways relevant to endocrine-mediated signaling. RESULTS: Combining multiple data sources into an overall, weight-of-evidence Toxicological Priority Index (ToxPi) score for prioritizing further chemical testing resulted in more robust conclusions than any single data source taken alone. CONCLUSIONS: Incorporating data from in vitro assays, chemical descriptors, and biol...