Endocrine Profiling and Prioritization of Environmental Chemicals Using ToxCast Data
Reif, David M., Martin, Matthew T., Tan, Shirlee W., Houck, Keith A., Judson, Richard S., Richard, Ann M., Knudsen, Thomas B., Dix, David J., Kavlock, Robert J., Environmental Health Perspectives
BACKGROUND: The prioritization of chemicals for toxicity testing is a primary goal of the U.S. Environmental Protection Agency (EPA) ToxCast[TM] program. Phase I of ToxCast used a battery of 467 in vitro, high-through put 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.
KEY WORDS: androgen, chemical prioritization, data integration, endocrine disruption, estrogen, screening, ToxCast, toxicity profile, ToxPi. Environ Health Perspect 118:1714-1720 (2010). doi:10.1289/ehp.1002180 [Online 8 September 2010]
In 1996, the U.S. Congress passed two laws affecting the regulation of pesticides and other chemicals. Both of these laws, the Food Quality Protection Act of 1996 (FQPA 1996) and the Safe Drinking Water Act Amendments of 1996 (SDWA Amendments 1996), contained provisions for assessing the potential for chemicals to interact with the endocrine system. The FQPA (1996) required the U.S. Environmental Protection Agency (EPA) to
develop a Screening program, using appropriate validated rest 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 such other endocrine effect as the Administrator may designate.
Chemicals identified for testing under the two statutes include all pesticide chemicals (both active and inert ingredients in pesticide formulations), as well as any other substances that may have an effect that is cumulative with effects of a pesticide if the administrator determines that a substantial population is exposed co such a substance. Furthermore, the SDWA Amendments (1996) state that
In addition to the substances referred to in ... the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 346a(p)(3)(B)) ... the Administrator may provide for testing under the screening program authorized by [the FFDCA] ... of any other substance that may be found in sources of drinking water if the Administrator determines that a substantial population may be exposed to such substance.
Based largely on recommendations from the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), a U.S. EPA advisory committee convened to recommend approaches to addressing the requirements of the FQPA (Gray 1998), the U. …