Extrapolating Dose in Vitro to Dose in Vivo of a Neurotoxic Pyrethroid Pesticide Using Empirical Approaches and a PBPK Model

摘要

Pyrethroids are a class of neurotoxic synthetic insecticides. Exposure to pyrethroids can be widespread because of their use in agriculture, medicine, and in residential homes and schools. Our studies are focused on generating in vitro and in vivo data for the development of physiologically-based pharmacokinetic models (PBPK) for pyrethroids. Using deltamethrin as a model compound, in vitro metabolic and in vivo tissue time-course data in the rat were determined and used in development of a PBPK model. This model adequately simulated the in vivo blood time course data after intravenous and oral administration of deltamethrin. The model was then used to predict the in vivo administered dose of deltamethrin that would result in blood concentrations equal to in vitro media concentrations of deltamethrin that reduce hippocampal cell firing. The in vitro media concentrations that resulted in a 10 and 50% decrease in cell firing were 10 times lower than the predicted in vivo concentrations. This suggests that the in vitro system may not account for the kinetic or dynamic differences between the two systems or that neuronal cells are more responsive to deltamethrin in vitro than in vivo.