Development of physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD models to determine dosimetry and cholinesterase inhibition following exposure to binary mixtures of organophosphorus insecticides.
Timchalk C; Kousba A; Busby AL; Poet TS
Toxicologist 2007 Mar; 96(1):274
PBPK/PD models have been developed for the organophosphorus (OP) insecticides chlorpyrifos (CPF) and diazinon (DZN). These insecticides share common metabolic activation/detoxification pathways and a common mechanism of neurotoxicity associated with excessive cholinergic stimulation. To develop a binary OP PBPK/PD model, rats were orally administered CPF, DZN or a CPF/DZN mixture (0, 15, 30 or 60 mg/kg) and blood (plasma and RBC), brain and urine were collected for analysis. Chlorpyrifos, DZN and their respective metabolites, trichloropyridinol and isopropy-methyl-hydroxypyrimidine were quantified in blood and/or urine and cholinesterase (ChE) inhibition was measured in brain, RBC, and plasma. Co-exposure to CPF/DZN at the low dose (15/15 mg/kg) did not alter the pharmacokinetics of CPF, DZN or their metabolites in blood. Whereas, a high binary dose (60/60 mg/kg) increased the Cmax and AUC and decreased the clearance for both parent compounds, likely due to competition between CPF and DZN for CYP450 metabolism. At lower doses the pharmacokinetics appeared linear. A dose-dependent inhibition of ChE was noted in tissues for both the single and co-exposures, and the extent of inhibition was plasma > RBC > or equal to brain. The overall relative potency for ChE inhibition was CPF > CPF/DZN > DZN. A comparison of the ChE response at the low binary dose (15/15 mg/kg), where there were no apparent pharmacokinetic interactions, suggested that the overall ChE response was additive. Based on these pharmacokinetic results a binary OP PBPK/PD model has been developed. This model facilitates understanding the mixture interactions and the potential for additivity, synergism or antagonism from multi-OP exposures. It is envisioned that this binary model will be useful for accessing exposure and health risk to a wide range of exposed individuals.
Animal-studies; Physical-reactions; Models; Bioactivation; Mathematical-models; Statistical-analysis; Pharmacodynamics; Physical-reactions; Drug-receptor; Drug-interaction; Risk-analysis; Risk-factors; Dose-response; Organo-phosphorus-pesticides; Organo-phosphorus-compounds; Pesticides-and-agricultural-chemicals; Neurotoxicology; Neurotoxins; Neurotoxic-effects
Research Tools and Approaches: Exposure Assessment Methods; Agriculture, Forestry and Fishing
The Toxicologist. Society of Toxicology 46th Annual Meeting and ToxExpo, March 25-29, 2007, Charlotte, North Carolina
Battelle Memorial Institute, Richland, Washington