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Endocrine Profiling and Prioritization of Environmental Chemicals Using ToxCast Data
Citation:
REIF, D., M. T. MARTIN, S. TAN, K. A. HOUCK, R. JUDSON, A. M. RICHARD, T. B. KNUDSEN, D. J. DIX, AND R. J. KAVLOCK. Endocrine Profiling and Prioritization of Environmental Chemicals Using ToxCast Data. ENVIRONMENTAL HEALTH PERSPECTIVES. National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, 118(12):2-8, (2010).
Impact/Purpose:
In 1996, Congress passed two laws affecting the regulation of pesticides and other chemicals. Both of these laws, the Food Quality Protection Act (FQPA) (FQPA 1996) and the Safe Drinking Water Act (SDWA) Amendments (SDWA, Amendments 1996), contained provisions for assessing the potential for chemicals to interact with the endocrine system. The FQPA required EPA to “develop a screening program, using validated test systems and other scientifically relevant information, to determine whether certain substances may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.
Description:
The prioritization of chemicals for toxicity testing is a primary goal of the U.S. EPA’s ToxCast™ program. Phase I of ToxCast utilized 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. Objectives: 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 define putative endocrine profiles and derive 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 ‘ToxPi’ (Toxicological Priority Index) 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 biological pathways in this prioritization schema provided a flexible, comprehensive visualization and ranking of each chemical’s potential endocrine activity. Importantly, ToxPi profiles provide a transparent visualization of the relative contribution of all information sources to an overall priority ranking. The method developed here is readily adaptable to diverse chemical prioritization tasks.
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Endocrine Profiling and Prioritization of Environmental Chemicals Using ToxCast Data