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Enhancing high throughput toxicology - development of putative adverse outcome pathways linking US EPA ToxCast screening targets to relevant apical hazards.
Fay, K., Dan Villeneuve, D. Martinovic-Weigelt, G. Ankley, AND S. Edwards. Enhancing high throughput toxicology - development of putative adverse outcome pathways linking US EPA ToxCast screening targets to relevant apical hazards. SETAC, North America, Salt Lake City, UT, November 01 - 05, 2015.
High throughput toxicology programs, such as ToxCast and Tox21, have provided biological effects data for thousands of chemicals at multiple concentrations. Compared to traditional, whole-organism approaches, high throughput assays are rapid and cost-effective, yet they generally do not directly measure endpoints of regulatory utility (e.g., survival, growth, reproduction, disease). In an effort to leverage these data for risk assessment and regulatory decision-making, a project is underway to develop putative adverse outcome pathways (pAOPs) which will link US EPA ToxCast assay endpoints to potential hazards of regulatory concern (Office of Economic Cooperation and Development [OECD] AOP Development Programme, Project 1.27). Putative AOPs are being deposited in the internationally harmonized AOP knowledgebase (AOPkb.org). Approximately 760 Toxcast assays were mapped to 300 unique biological targets (e.g., proteins, genes, transcription factors). Putative AOPs were developed by considering the role of these targets in normal biology and hypothesizing the potential consequences of chemical-induced perturbations. As of May 2015, over 50 putative AOPs covering roughly 10% of the toxicological space considered in Toxcast had been developed. The goals of the on-going effort are to (1) enhance interpretation and use of available ToxCast screening data for hazard identification and prioritization, (2) identify important gaps in the ToxCast suite of assays, and (3) aid prioritization of toxicologically-relevant pathways for development into more formal AOPs descriptions including weight of evidence assembly and evaluation. Cataloging of these pAOPs in the AOP knowledge-base will also allow for the broader scientific community to engage in the further vetting and development of these AOPs.