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The Use of Mode of Action Information in Risk Assessment: Quantitative Key Events/Dose-Response Framework for Modeling the Dose-Response for Key Events
Citation:
Simon, T., S. Simons Jr., R. Julian Preston, A. Boobis, S. Cohen, N. Doerrer, P. Fenner-Crisp, T. McMullin, C. McQueen, AND J. Rowlands. The Use of Mode of Action Information in Risk Assessment: Quantitative Key Events/Dose-Response Framework for Modeling the Dose-Response for Key Events. CRITICAL REVIEWS IN TOXICOLOGY. CRC Press LLC, Boca Raton, FL, 44(S3):17-43, (2014).
Impact/Purpose:
The present paper describes ways to incorporate information about the timing of occurrence and quantitative dose-response of Key Events (KE) into the KEDRF. This expanded framework is known as the Quantitative Key Events / Dose-Response Framework or Q-KEDRF. In one sense, this is a “how-to” paper which describes methods to incorporate additional information for understanding the particulars of the MOA of a chemical.
Description:
The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Action/Human Relevance Framework and Key Events/Dose Response Framework (KEDRF)to make the best use of quantitative dose-response and timing information for Key Events (KEs). The resulting Quantitative Key Events/Dose-Response Framework (Q-KEDRF) provides a structured quantitative approach for systematic examination of the dose-response and timing of KEs resulting from a dose of a bioactive agent that causes a potential adverse outcome. Two concepts are described as aids to increasing the understanding of mode of action-Associative Events and Modulating Factors. These concepts are illustrated in two case studies; 1) cholinesterase inhibition by the pesticide chlorpyrifos, which illustrates the necessity of considering quantitative dose-response information when assessing the effect of a Modulating Factor, that is, enzyme polymorph isms in humans, and 2) estrogen-induced uterotrophic responses in rodents, which demonstrate how quantitative doseresponse modeling for KE, the understanding of temporal relationships between KEs and a counterfactual examination of hypothesized KEs can determine whether they are Associative Events or true KEs.