Skip directly to search Skip directly to A to Z list Skip directly to page options Skip directly to site content

NIOSHTIC-2 Publications Search

Search Results

Development of a physiologically based pharmacokinetic and pharmacodynamic model to determine dosimetry and cholinesterase inhibition for a binary mixture of chlorpyrifos and diazinon in the rat.

Authors
Timchalk-C; Poet-TS
Source
Neurotoxicology 2008 May; 29(3):428-443
NIOSHTIC No.
20034377
Abstract
Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models have been developed for the organophosphorus (OP) insecticides chlorpyrifos (CPF) and diazinon (DZN). It is anticipated that these OPs could interact at a number of important metabolic steps including: CYP450 mediated activation/detoxification, B-esterases [carboxylesterase (CaE), butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE)] or PON-1 (A-esterase) oxon detoxification. We developed a binary PBPK/PD model for CPF, DZN and their metabolites based on previously published models for the individual insecticides. The metabolic interactions (CYP450) between CPF and DZN were evaluated in vitro and suggests that CPF is more substantially metabolized to its oxon metabolite than DZN, which is consistent with observed in vivo potency (CPF>DZN). Each insecticide inhibited the other's in vitro metabolism in a concentration-dependent manner. The PBPK model code used to describe the metabolism of CPF and DZN was modified to reflect the type of CYP450 inhibition kinetics (i.e. competitive vs. non-competitive), while B-esterase metabolism was described as dose-additive, and no PON-1 interactions were assumed between CPF- and DZN-oxon with the enzyme. The binary model was then evaluated against previously published rodent dosimetry and cholinesterase (ChE) inhibition data for the mixture. The PBPK/PD model simulations of the acute oral exposure to single-mixtures (15 mg/kg) vs. binary-mixtures (15+15 mg/kg) of CFP and DZN resulted in no differences in the predicted pharmacokinetics of either the parent OPs or their respective metabolites, while cholinesterase inhibition was reasonably described using the dose-additive model. A binary oral dose of CPF+DZN (60+60 mg/kg) did result in observable changes in the DZN pharmacokinetics where C(max) was more reasonably fit by modifying the absorption parameters. It is anticipated that at low environmentally relevant binary doses, most likely to be encountered in occupational or environmental related exposures, that the pharmacokinetics are expected to be linear, and ChE inhibition dose-additive.
Keywords
Models; Phosphates; Pesticides; Insecticides; Exposure-levels; Bioactivation; Detoxification; Pesticides-and-agricultural-chemicals; Dosimetry; Laboratory-animals; Laboratory-testing; Pharmacodynamics; Mathematical-models; Risk-analysis; Risk-factors
Contact
C. Timchalk, Center for Biological Monitoring and Modeling, Battelle, Pacific Northwest Division, PO Box 999, Richland, WA 99352
CODEN
NRTXDN
CAS No.
2921-88-2; 333-41-5
Publication Date
20080501
Document Type
Journal Article
Email Address
charles.timchalk@pnl.gov
Funding Amount
246279
Funding Type
Grant
Fiscal Year
2008
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-003629; Grant-Number-R01-OH-008173
Issue of Publication
3
ISSN
0161-813X
Priority Area
Research Tools and Approaches: Exposure Assessment Methods; Agriculture, Forestry and Fishing
Source Name
Neurotoxicology
State
WA
Performing Organization
Battelle Memorial Institute, Richland, Washington
TOP