Endocrine profiling and prioritization of environmental chemicals using ToxCast data.
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 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.
Reif
David M
DM
National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. reif.david@epa.gov
Martin
Matthew T
MT
Tan
Shirlee W
SW
Houck
Keith A
KA
Judson
Richard S
RS
Richard
Ann M
AM
Knudsen
Thomas B
TB
Dix
David J
DJ
Kavlock
Robert J
RJ
D003661:Decision Support Techniques; D052244:Endocrine Disruptors / Q000145:classification* / Q000633:toxicity; D004703:Endocrine System / Q000187:drug effects; D004785:Environmental Pollutants / Q000145:classification* / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects; D018675:Toxicity Tests / Q000379:methods*
D052244:Endocrine Disruptors; D004785:Environmental Pollutants
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