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Pharmacokinetic and pharmacodynamic interaction for a binary mixture of chlorpyrifos and diazinon in the rat.

Authors
Timchalk-C; Poet-TS; Hinman-MN; Busby-AL; Kousba-AA
Source
Toxicol Appl Pharmacol 2005 May; 205(1):31-42
NIOSHTIC No.
20029018
Abstract
Chlorpyrifos (CPF) and diazinon (DZN) are two commonly used organophosphorus (OP) insecticides and a potential exists for concurrent exposures. The primary neurotoxic effects from OP pesticide exposures result from the inhibition of acetylcholinesterase (AChE). The pharmacokinetic and pharmacodynamic impact of acute binary exposures of rats to CPF and DZN was evaluated in this study. Rats were orally administered CPF, DZN, or a CPF/DZN mixture (0, 15, 30, or 60 mg/kg) and blood (plasma and RBC), and brain were collected at 0, 3, 6, 12, and 24 h postdosing, urine was also collected at 24 h. Chlorpyrifos, DZN, and their respective metabolites, 3,5,6-trichloro-2-pyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP), were quantified in blood and/or urine and cholinesterase (ChE) inhibition was measured in brain, RBC, and plasma. Coexposure to CPF/DZN at the low dose of 15/15 mg/kg did not alter the pharmacokinetics of CPF, DZN, or their metabolites in blood. A high binary dose of 60/60 mg/kg increased the C(max) and AUC and decreased the clearance for both parent compounds, likely due to competition between CPF and DZN for CYP450 metabolism. At lower doses, most likely to be encountered in occupational or environmental exposures, the pharmacokinetics were linear. A dose-dependent inhibition of ChE was noted in tissues for both the single and coexposures, and the extent of inhibition was plasma > RBC > or = brain. The overall relative potency for ChE inhibition was CPF/DZN > CPF > 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. These experiments represent important data concerning the potential pharmacokinetic and pharmacodynamic interactions for pesticide mixtures and will provide needed insight for assessing the potential cumulative risk associated with occupational or environmental exposures to these insecticides.
Keywords
Pharmacodynamics; Laboratory-animals; Animals; Animal-studies; Organo-phosphorus-pesticides; Exposure-levels; Dosimetry; Blood-samples; Gas-chromatography; Models; Insecticides; Organo-phosphorus-compounds; Neurotoxic-effects; Neurotoxicity; Neurotoxins; Acute-exposure
Contact
Center for Biological Monitoring and Modeling, Battelle, Pacific Northwest Division, PO Box 999, 902 Battelle Boulevard, Richland, WA 99352
CODEN
TXAPA9
CAS No.
2921-88-2; 333-41-5
Publication Date
20050515
Document Type
Journal Article
Email Address
charles.timchalk@pnl.gov
Funding Amount
246279
Funding Type
Grant
Fiscal Year
2005
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-003629
Issue of Publication
1
ISSN
0041-008X
Priority Area
Research Tools and Approaches: Exposure Assessment Methods
Source Name
Toxicology and Applied Pharmacology
State
WA
Performing Organization
Battelle Memorial Institute, Richland, Washington
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