Development of a Generic Physiologically Based Kinetic Model for the Prediction of Internal Exposure to Organophosphate Pesticides

Since their introduction into agriculture, the toxicity of organophosphate (OP) pesticides has been widely studied in animal models. However, next generation risk assessment (NGRA) intends to maximize the use of novel approach methodologies based on in vitro and in silico methods. Therefore, this study describes the development and evaluation of a generic physiologically based kinetic (PBK) model for acute exposure to OP pesticides in rats and humans using quantitative structure property relationships and data from published <i>in vitro</i> studies. The models were evaluated using in vivo studies from the literature for chlorpyrifos, diazinon, fenitrothion, methyl-parathion, ethyl-parathion, dimethoate, chlorfenvinphos, and profenofos. Evaluation was performed by comparing simulated and in vivo observed time profiles for blood, plasma, or urinary concentrations and other toxicokinetic parameters. Of simulated concentration-time profiles, 87 and 91% were within a 5-fold difference from observed toxicokinetic data from rat and human studies, respectively. Only for dimethyl-organophosphates further refinement of the model is required. It is concluded that the developed generic PBK model provides a new tool to assess species differences in rat and human kinetics of OP pesticides. This approach provides a means to perform NGRA for these compounds and could also be adopted for other classes of compounds.