Development of a Physiologically-Based Pharmacokinetic (PB-PK) Model and Human Health Risk Assessment for Coumarin. H. Clewell and R. Gentry, The K.S. Crump Group, Inc., ICF Kaiser, Ruston, LA; and J. Gearhart, S. Born, and L. Lehman-McKeeman, The Procter and Gamble Co., Cincinnati, OH
Coumarin, a fragrance ingredient, is a mouse lung and rat liver toxicant. Administration of coumarin has been associated with an increased incidence of lung tumors in B6C3F1 mice in oral gavage studies, and liver tumors were observed in male Sprague-Dawley rats chronically fed coumarin in the diet (Carlton et al., Fund. Appl. Toxicol.30,145-151,1996). Species differences in the cytochrome P450-mediated metabolism of coumarin are integrally linked to the toxicity of this chemical. In humans, coumarin is metabolized primarily to the nontoxic 7-hydroxycoumarin metabolite. In contrast, coumarin 3,4-epoxidation predominates in rodents. To understand the relationship between coumarin bioactivation, toxicity, and carcinogenicity, a PB-PK model for coumarin was developed. Simulation of coumarin pharmacokinetics associated with administered doses from the animal toxicity and carcinogenicity data was conducted to derive dose metrics to identify the most likely metabolite associated with toxicity. The model was then extended to simulate dose metrics in the human following likely exposure situations. Mode of action for coumarin carcinogenicity was also determined, based on integration of the available qualitative and quantitative kinetic and toxicity information. The dose metrics were then used, in conjunction with the most appropriate dose-response model based on the proposed mode of action for coumarin, to conduct a human health risk assessment for coumarin.
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