title: The use of mode of action information in risk assessment: quantitative key events/dose-response framework for modeling the dose-response for key events.
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.
authors: Ted Simon LLC , Winston, GA , USA.
authors: Ted W
authors: TW
authors: Simon
authors: S Stoney
authors: SS
authors: Simons
authors: R Julian
authors: RJ
authors: Preston
authors: Alan R
authors: AR
authors: Boobis
authors: Samuel M
authors: SM
authors: Cohen
authors: Nancy G
authors: NG
authors: Doerrer
authors: Penelope A
authors: PA
authors: Fenner-Crisp
authors: Tami S
authors: TS
authors: McMullin
authors: Charlene A
authors: CA
authors: McQueen
authors: J Craig
authors: JC
authors: Rowlands
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008962:Models, Theoretical; D018570:Risk Assessment / Q000379:methods*; D013045:Species Specificity; D014116:Toxicology / Q000379:methods*; D014481:United States; D014484:United States Environmental Protection Agency
chemical_list: D002273:Carcinogens
keywords: Q-KEDRF; associative event; key event; mode of action; modulating factor; risk assessment