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

Ted W. Simon, S. Stoney Simons, R. Julian Preston, Alan R. Boobis, Samuel Monroe Cohen, Nancy G. Doerrer, Penelope A. Fenner-Crisp, Tami S. Mcmullin, Charlene A. Mcqueen, Craig J. Rowlands

Research output: Contribution to journalReview article

41 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)17-43
Number of pages27
JournalCritical reviews in toxicology
Issue numberSUPPL.3
Publication statusPublished - Aug 2014



  • Associative event
  • Key event
  • Mode of action
  • Modulating factor
  • Risk assessment

ASJC Scopus subject areas

  • Toxicology

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