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PREDICTIVE PHYSIOLOGICALLY BASED PHARMACOKINETICS MODELING (PBPK) OF PYRETHROID PESTICIDES
Citation:
Godin, S. J., R. TORNERO-VELEZ, E. J. Scollon, M F. Hughes, AND M J. DeVito. PREDICTIVE PHYSIOLOGICALLY BASED PHARMACOKINETICS MODELING (PBPK) OF PYRETHROID PESTICIDES. Presented at Society of Toxicology Annual Meeting, New Orleans, LA, March 06 - 10, 2005.
Description:
Pyrethroids are a class of neurotoxic pesticides that have many different applications in agriculture, horticulture, and homes, and medicinal uses for animals and humans. Differences in the toxicity of pyrethroids are the result of their pharmacokinetic and/or pharmacodynamic properties. Rat LD50 values for three type II pyrethroids, deltamethrin-105mg/kg, esfenvalerate-95mg/kg, and -cyfluthrin-450mg/kg have been reported by their manufacturers. In an effort to develop human exposure-dose-response models for pyrethroid pesticides we have determined in vitro metabolism parameters in rat liver microsomes using a parent depletion approach. We are interested in whether intrinsic hepatic clearance (CLint) is a major determinant of target organ (brain) concentration and therefore a potential determinant of the relative toxicity of these three pyrethroids. We have determined Kmapp, Vmax and, CLint for deltamethrin (Km 3.09?M ? 0.82; Vmax 435.86 pmoles/min/mg MSP ? 27.79; CLint = 8.47E-3 L/hr/mg MSP), esfenvalerate (Km = 7.13?M ? 0.15; Vmax = 353.00 pmoles/min/mg MSP ? 28.15; CLint = 2.97E-3 L/hr/mg MSP), and -cyfluthrin (Km = 16.13?M ? 2.43; Vmax = 810.40 pmoles/min/mg MSP ? 28.15; CLint = 3.02E-3 L/hr/mg microsomal protein). Deltamethrin is cleared nearly 3-fold more rapidly than esfenvalerate or -cyfluthrin. These results do not indicate any correlation between the rate of hepatic clearance and the relative toxicity of these three pyrethroids. From literature derived data and these calculated Clint values; a preliminary PBPK model of exposure to deltamethrin was developed. Based on model predictions it appears that for these three pyrethroids in addition to CLint, critical determinants of pyrethroid target organ concentration include absorption/metabolism in the G.I. tract, and partitioning into and metabolism in the brain. (SJG was funded by NHEERL-DESE, EPA CT826513. This abstract does not represent EPA policy)