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

Crit Rev Toxicol. 2014 Aug;44 Suppl 3:17-43. 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.

Keywords: Q-KEDRF; associative event; key event; mode of action; modulating factor; risk assessment.

Publication types

  • Review

MeSH terms

  • Animals
  • Carcinogens / chemistry
  • Carcinogens / metabolism
  • Carcinogens / toxicity*
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Theoretical*
  • Risk Assessment / methods*
  • Species Specificity
  • Toxicology / methods*
  • United States
  • United States Environmental Protection Agency

Substances

  • Carcinogens