Development of a physiologically based pharmokinetic and pharmacodynamic (PBPK/PD) model for the organophosphate pesticide, diazinon.
Poet-TS; Kousba-A; Wu-H; Dennison-SL; Timchalk-C
Toxicologist 2003 Mar; 72(S-1):306
Organophosphate (OP) pesticides, like diazinon (DZN), constitute a large class of insecticides that are widely utilized, and the potential exists for significant exposures from multiple routes. The objective was to develop a PBPK/PD model capable of predicting the relationships between exposure, bioactivation, detoxification, and the inhibition of target esterases (EST). In this model, CYP450 metabolism of DZN to the oxon and detoxification to 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP) are both mediated by CYP450s in the liver. Hydrolysis of the oxon via A-EST occurs in the liver and blood and interactions with target B-EST (acetyl, butyryl- and carboxyl-) were modeled as second order processes occurring in the liver, blood, diaphragm and brain. Metabolic rate constants for the CYP450- and A-esterase-mediated metabolism were measured in vitro. B-EST inhibition and regeneration rates have been determined in vitro and model optimization against cholinesterase (ChE) inhibition data. To facilitate model development, single oraldose pharmacokinetic studies were conducted in rats (l - 100 mglkg) and the kinetics of DZN and IMHP as well as the extent of plasma ChE and RBC and brain acetylcholinesterase (AChE) inhibition were determined. In blood, the concentration of IMHP was greater than DZN and the kinetic time-course was linear over the dose-range and reasonably simulated by the model. Peak ChE inhibition occurred at 6 hr post-dosing and the model accurately simulated the dose-dependent inhibition of plasma ChE, RBC AChE and brain AChE. This DZN PBPK/PD model quantitatively estimates target tissue dosimetry and ChE inhibition and will be integral to risk assessments for DZN and OP mixture exposures under a variety of scenarios.
Models; Phosphates; Pesticides; Insecticides; Exposure-levels; Bioactivation; Detoxification; Blood-samples; Liver-cells; Metabolic-rate; In-vitro-studies; Dosimetry; Pesticides-and-agricultural-chemicals
Research Tools and Approaches: Exposure Assessment Methods
The Toxicologist. Society of Toxicology 42nd Annual Meeting and ToxExpo, Cutting-Edge Science, Networking, New Perspectives, March 9-13, 2003, Salt Lake City, Utah
Battelle Memorial Institute, Richland, Washington