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Age-dependent pharmacokinetic and pharmacodynamic response in preweanling rats following oral exposure to the organophosphorus insecticide chlorpyrifos.

Authors
Timchalk-C; Poet-TS; Kousba-AA
Source
Toxicology 2006 Mar; 220(1):13-25
NIOSHTIC No.
20029770
Abstract
Previous studies have indicated that juvenile rats are more susceptible than adults to the acute toxicity from exposure to the organophosphorus insecticide chlorpyrifos (CPF) and age-dependent differences in metabolism and sensitivity to cholinesterase (ChE) inhibition may be responsible. Metabolism involves CYP450 activation and detoxification of CPF to CPF-oxon and 3,5,6-trichloro-2-pyridinol (TCP), as well as cholinesterase (acetyl- and butyrylcholinesterase), carboxylesterase (CaE), and A-esterase (PON-1) detoxification of CPF-oxon to TCP. The pharmacokinetics of CPF, TCP, and the extent of blood (plasma/RBC), and brain ChE inhibition in rats were determined on postnatal days (PND)-5, -12, and -17 following oral gavage administration of 1 and 10mg CPF/kg of body weight. As has been seen in adult animals, for all preweanling ages the blood TCP exceeded the CPF concentration, and within each age group there was no evidence of non-linear kinetics over the dose range evaluated. Consistent with previous results, younger animals demonstrated a greater sensitivity to ChE inhibition as evident by the age-dependent inhibition of plasma, RBC, and brain ChE. The brain may be particularly sensitive in younger animals (i.e. PND-5) due to substantially lower levels of ChE activity relative to later preweanling stages and adults. Of particular importance was the observation that even in rats as young as PND-5, the CYP450 metabolic capacity was adequate to metabolize CPF to both TCP and CPF-oxon based on the detection of TCP in blood and extensive ChE inhibition (biomarker of CPF-oxon) at all ages. In addition, the increase in the blood TCP concentration ( approximately 3-fold) in PND-17 rats relative to the response in the younger rats, are consistent with an increase in CYP450 metabolic capacity with age. This is the first reported study that evaluated both the pharmacokinetics of the parent pesticide, the major metabolite, and the extent of ChE inhibition as a function of preweanling age. The results suggest that in the preweanling rat, CPF was rapidly absorbed and metabolized, and the extent of metabolism and ChE inhibition was age-dependent.
Keywords
Pharmacodynamics; Laboratory-animals; Animals; Animal-studies; Organo-phosphorus-pesticides; Insecticides; Toxic-effects; Exposure-levels; Exposure-assessment
Contact
Battelle Pacific Northwest Division, Center for Biological Monitoring and Modeling, 902 Battelle Boulevard, Richland, WA 99352, USA
CODEN
TXCYAC
CAS No.
2921-88-2
Publication Date
20060301
Document Type
Journal Article
Email Address
charles.timchalk@pnl.gov
Funding Amount
246279
Funding Type
Grant
Fiscal Year
2006
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-003629
Issue of Publication
1
ISSN
0300-483X
Priority Area
Research Tools and Approaches: Exposure Assessment Methods
Source Name
Toxicology
State
WA
Performing Organization
Battelle Memorial Institute, Richland, Washington
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