Academic journal article Environmental Health Perspectives

Application of Adverse Outcome Pathways to U.S. EPA's Endocrine Disruptor Screening Program

Academic journal article Environmental Health Perspectives

Application of Adverse Outcome Pathways to U.S. EPA's Endocrine Disruptor Screening Program

Article excerpt


Many chemicals have the potential to interfere with normal endocrine functioning, which may lead to a variety of adverse outcomes including developmental deformities, impaired reproduction, and decreased survival. Potential adverse outcomes following exposure to endocrine-active substances have been the subject of intensive study and have been described in numerous research papers and reviews (e.g., Colborn and Clement 1992; Kavlock et al. 1996; WHO 2002; WHO/UNEP 2012; Hotchkiss et al. 2008; Soto and Sonnenschein 2010; Nohynek et al. 2013; Gore et al. 2015a). Although most research studies focus on one endocrine pathway or on one part of one endocrine pathway, the endocrine system is inherently integrative and adaptive. Endocrine effects can vary enormously by the organ and time point examined, even within the same individual. Conclusions from various researchers or reviewers on endocrine disruption have sometimes been divergent or even contradictory, suggesting that our scientific understanding of the etiology of adverse outcomes in humans and wildlife through endocrine mechanisms is far from complete. Many organizations including the U.S. EPA, the National Institutes of Health (NIH), the Organisation for Economic Cooperation and Development (OECD), the World Health Organization (WHO), and the United Nations Environmental Programme (UNEP) have supported research, developed guidance, and published standardized test guidelines to evaluate endocrine disruption in humans and wildlife.

U.S. EPA's Endocrine Disruptor Screening Program

The U.S. EPA's Endocrine Disruptor Screening Program (EDSP) screens and tests chemicals to determine potential endocrine effects in humans and wildlife. The EDSP was established in 1998 following amendments to the Federal Food, Drug, and Cosmetic Act (FFDCA) and the Safe Drinking Water Act (SDWA), mandating the U.S. EPA to screen chemicals for potential estrogenic effects in humans and providing authority to include other endocrine effects (U.S. Congress 1996a, 1996b). In response, the U.S. EPA convened the Endocrine Disruption Screening and Testing Advisory Committee (EDSTAC), consisting of regulatory, industry, and academic experts, to advise the agency on development and implementation of an endocrine disruptor screening program. The committee recommended expanding the scope of the EDSP to evaluate chemical effects on the androgen and thyroid pathways in wildlife and humans and to do so employing a two-tiered screening and testing strategy (EDSTAC 1998).

The first tier of assays screens chemicals for potential activity in estrogen, androgen, and thyroid pathways in both sexes of several vertebrate taxa. The battery of 11 complementary assays includes five in vitro assays that provide mechanistic data and six short-term, in vivo assays including bioassays measuring changes in organ weights and assays conducted in organisms with functional neuroendocrine axes (Figure 1). Tier 1 assays were designed to maximize sensitivity; however, considering collective results from multiple complementary assays relevant to each endocrine pathway was intended to reduce the limitations of each individual assay and to provide confidence in the hypothesized mode of action (U.S. EPA 2011).

Results of the Tier 1 screening battery were considered with other scientifically relevant information (OSRI; e.g., guideline studies submitted to the U.S. EPA in the pesticide registration process, research published in peer-reviewed literature; https://www.epa. gov/endocrine-disruption/status-endocrine-disruptor-screeningprogram-other- scientifically-relevant) to determine the weight of evidence (WoE) supporting a chemical's potential endocrine activity. Criteria considered in WoE evaluations were described in a guidance document (U.S. EPA 2011) and included consideration of the nature of effects within and across studies and their biological plausibility, consistency of biological effects observed within and among species/sexes both within Tier 1 assays and OSRI, and if effects occurred in the absence of systemic toxicity. …

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