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PBPK MODELING OF DELTAMETHRIN IN RATS
GODIN, S., R. TORNERO-VELEZ, E. SCOLLON, D. G. ROSS, M. F. HUGHES, R. CONOLLY, AND M. J. DEVITO. PBPK MODELING OF DELTAMETHRIN IN RATS. Presented at Society of Toxicology Annual Meeting, Seattle, WA, March 16 - 20, 2008.
The pyrethroid pesticide deltamethrin is cleared nearly twice as rapidly in human liver microsomes compared to rat liver microsomes. A species difference such as this could influence the toxic potency of deltamethrin between rats and humans. PBPK modeling is a tool that can be utilized to examine the impact that such a species difference may have on exposure-dose relationships. A previous PBPK model for deltamethrin in the rat by Mirfazaelian et al. (Toxicol Sci. 2006 Oct;93(2):432-42) suggests that absorption is dose dependent with little absorption of environmentally relevant exposures. In addition, the model employs both flow and diffusion-limited compartments and splits the blood compartment into plasma and red blood cells. Oral bioavailability studies were designed to examine the dose dependency in absorption. The results of theses studies indicate there was no significant difference in the fraction absorbed of oral doses of 0.3 and 3.0 mg deltamethrin/Kg. In contrast to the previous model which utilized both flow- and diffusion-limited tissue compartments the current model described all tissue compartments with diffusion-limited kinetics. The present model also describes the blood as a single compartment. These changes resulted in an improved ability of the deltamethrin PBPK model to describe the shape of the tissue concentration-time curves for both literature data and data from the present oral bioavailability studies. The description of the liver by diffusion- limited kinetics has the effect of reducing the impact of the species difference in metabolism since diffusion is the rate limiting step in the metabolic elimination of deltamethrin.
PBPK modeling is used to examine the impact that species differences may have on exposure-dose relationships of deltamethrin.
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
EXPERIMENTAL TOXICOLOGY DIVISION