Toxicological Sciences 66, 34-53 (2002)
Copyright © 2002 by the Society of Toxicology
BIOTRANSFORMATION AND TOXICOKINETICS |
A Physiologically Based Pharmacokinetic and Pharmacodynamic (PBPK/PD) Model for the Organophosphate Insecticide Chlorpyrifos in Rats and Humans
* Battelle Pacific Northwest Division, Chemical Dosimetry, PO Box 999, Richland, Washington 99352;
Dow AgroSciences, 9330 Zionsville, Indianapolis, Indiana 46268; and
The Dow Chemical Co., Midland, Michigan 48674
A PBPK/PD model was developed for the organophosphate insecticide chlorpyrifos (CPF) (O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl]-phosphorothioate), and the major metabolites CPF-oxon and 3,5,6-trichloro-2-pyridinol (TCP) in rats and humans. This model integrates target tissue dosimetry and dynamic response (i.e., esterase inhibition) describing uptake, metabolism, and disposition of CPF, CPF-oxon, and TCP and the associated cholinesterase (ChE) inhibition kinetics in blood and tissues following acute and chronic oral and dermal exposure. To facilitate model development, single oral-dose pharmacokinetic studies were conducted in rats (0.5–100 mg/kg) and humans (0.5–2 mg/kg), and the kinetics of CPF, CPF-oxon, and TCP were determined, as well as the extent of blood (plasma/RBC) and brain (rats only) ChE inhibition. In blood, the concentration of analytes followed the order TCP >> CPF >> CPF-oxon; in humans CPF-oxon was not quantifiable. Simulations were compared against experimental data and previously published studies in rats and humans. The model was utilized to quantitatively compare dosimetry and dynamic response between rats and humans over a range of CPF doses. The time course of CPF and TCP in both species was linear over the dose range evaluated, and the model reasonably simulated the dose-dependent inhibition of plasma ChE, RBC acetylcholinesterase (AChE), and brain (rat only) AChE. Model simulations suggest that rats exhibit greater metabolism of CPF to CPF-oxon than humans do, and that the depletion of nontarget B-esterase is associated with a nonlinear, dose-dependent increase in CPF-oxon blood and brain concentration. This CPF PBPK/PD model quantitatively estimates target tissue dosimetry and AChE inhibition and is a strong framework for further organophosphate (OP) model development and for refining a biologically based risk assessment for exposure to CPF under a variety of scenarios.
Key Words: physiologically based pharmacokinetics; organophosphate insecticide; chlorpyrifos; esterase inhibition.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E. R. Lowe, T. S. Poet, D. L. Rick, M. S. Marty, J. L. Mattsson, C. Timchalk, and M. J. Bartels The Effect of Plasma Lipids on the Pharmacokinetics of Chlorpyrifos and the Impact on Interpretation of Blood Biomonitoring Data Toxicol. Sci., April 1, 2009; 108(2): 258 - 272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Marty, J. Y. Domoradzki, S. C. Hansen, C. Timchalk, M. J. Bartels, and J. L. Mattsson The Effect of Route, Vehicle, and Divided Doses on the Pharmacokinetics of Chlorpyrifos and Its Metabolite Trichloropyridinol in Neonatal Sprague-Dawley Rats Toxicol. Sci., December 1, 2007; 100(2): 360 - 373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Timchalk, A. A. Kousba, and T. S. Poet An Age-Dependent Physiologically Based Pharmacokinetic/Pharmacodynamic Model for the Organophosphorus Insecticide Chlorpyrifos in the Preweanling Rat Toxicol. Sci., August 1, 2007; 98(2): 348 - 365. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Foxenberg, B. P. McGarrigle, J. B. Knaak, P. J. Kostyniak, and J. R. Olson Human Hepatic Cytochrome P450-Specific Metabolism of Parathion and Chlorpyrifos Drug Metab. Dispos., February 1, 2007; 35(2): 189 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Kousba, T. S. Poet, and C. Timchalk Age-Related Brain Cholinesterase Inhibition Kinetics following In Vitro Incubation with Chlorpyrifos-Oxon and Diazinon-Oxon Toxicol. Sci., January 1, 2007; 95(1): 147 - 155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. C. Moser, M. Casey, A. Hamm, W. H. Carter Jr., J. E. Simmons, and C. Gennings Neurotoxicological and Statistical Analyses of a Mixture of Five Organophosphorus Pesticides Using a Ray Design Toxicol. Sci., July 1, 2005; 86(1): 101 - 115. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. G. M. Smulders, T. J. H. Bueters, S. Vailati, R. G. D. M. van Kleef, and H. P. M. Vijverberg Block of Neuronal Nicotinic Acetylcholine Receptors by Organophosphate Insecticides Toxicol. Sci., December 1, 2004; 82(2): 545 - 554. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Kousba, L. G. Sultatos, T. S. Poet, and C. Timchalk Comparison of Chlorpyrifos-Oxon and Paraoxon Acetylcholinesterase Inhibition Dynamics: Potential Role of a Peripheral Binding Site Toxicol. Sci., August 1, 2004; 80(2): 239 - 248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ashani and S. Pistinner Estimation of the Upper Limit of Human Butyrylcholinesterase Dose Required for Protection against Organophosphates Toxicity: a Mathematically Based Toxicokinetic Model Toxicol. Sci., February 1, 2004; 77(2): 358 - 367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Chambers and S. F. Oppenheimer Organophosphates, Serine Esterase Inhibition, and Modeling of Organophosphate Toxicity Toxicol. Sci., February 1, 2004; 77(2): 185 - 187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. S. Poet, H. Wu, A. A. Kousba, and C. Timchalk In Vitro Rat Hepatic and Intestinal Metabolism of the Organophosphate Pesticides Chlorpyrifos and Diazinon Toxicol. Sci., April 1, 2003; 72(2): 193 - 200. [Abstract] [Full Text] [PDF]
|
|