The use of mode of action information in risk assessment: Quantitative key events/dose-response framework for modeling the dose-response for key events

• Published in: Critical reviews in toxicology Vol. 44; no. S3; pp. 17 - 43
• Main Authors: Simon, Ted W., Simons, S. Stoney, Preston, R. Julian, Boobis, Alan R., Cohen, Samuel M., Doerrer, Nancy G., Fenner-Crisp, Penelope A., McMullin, Tami S., McQueen, Charlene A., Rowlands, J. Craig
• Format: Journal Article
• Language: English
• Published: England Informa Healthcare USA, Inc 01-08-2014; Taylor & Francis
• Subjects: Animals; associative event; Carcinogens - chemistry; Carcinogens - metabolism; Carcinogens - toxicity; Dose-Response Relationship, Drug; Humans; key event; mode of action; Models, Theoretical; modulating factor; Q-KEDRF; risk assessment; Risk Assessment - methods; Species Specificity; Toxicology - methods; United States; United States Environmental Protection Agency; United States; modulating factor; risk assessment; associative event; mode of action; key event; Q-KEDRF
• ISSN: 1040-8444; 1547-6898
• DOI: 10.3109/10408444.2014.931925

Abstract
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 polymorphisms in humans, and 2) estrogen-induced uterotrophic responses in rodents, which demonstrate how quantitative dose-response 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.