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INTEGRATED IN VITRO TESTING AND QSAR MODEL DEVELOPMENT TO RANK AND PRIORITIZE CHEMICALS FOR TIERED ENDOCRINE DISRUPTING CHEMICAL (EDC) TESTING
Impact/Purpose:
A challenge facing EPA in developing a screening and testing program to identify endocrine disrupting chemicals (EDCs) is determining how to prioritize chemicals for further testing. Initially, chemical ranking and prioritization schemes for EDC potential relied exclusively on existing chemical-specific human health and wildife exposure and effects data, resulting in a tendency to focus on those compounds for which data exist. The use of 3-D structure-activity relationships (SAR) is an approach to eliminate this bias and expand the knowledge base for prioritization. SAR approaches to enhance prioritization efforts have been accepted internationally.
Description:
The primary objective of this research is to develop and validate an integrate suite of in vitro bioassays that may serve as the basis for models to rank and prioritize large inventories of chemicals for EDC activity. The assays will be developed using an aquatic species and focus on estrogen-receptor mediated responses. The assays employ measurement endpoints that are mechanistically credible indicators of ER-mediated activity and are amenable for use in QSAR development. The data generated from these bioassays can be used directly in a weight-of-evidence approach to evaluate small numbers of chemicals and indirectly as the basis for developing predictive SAR models for ranking and prioritizing large numbers of chemicals This research aims to develop and evaluate in vitro protocols for evaluating chemicals that interact with the ER, develop and evaluate in vitro protocol for distinguishing estrogenic from anti-estrogenic activity, develop and evaluate in vitro protocol for measure chemical-induced alterations in ER activity, assess interspecies extrapolation and assess ways to include metabolic activation in the predictive model.