Potential utility of saliva biomonitoring for organophosphate insecticide dosimetry and esterase inhibition.
Kousba A; Poet TS; Timchalk C
Toxicologist 2003 Mar; 72(S-1):305-306
Chlorpyrifos is a phosphothioate, which is a commonly used organophosphate (OP) insecticide. Its active metabolite CPF-oxon is a potential inhibitor of cholinesterase enzymes (ChE) , such as acetylcholinesterase (AChE) and butytylcholinesterase (BuChE). Whereas the inhibition of AChE is associated with neurotoxicity, BuChE inhibition represents a detoxification mechanism and a potential biomarker of exposure/response. In the current study CPF, dissolved in corn oil, was administered orally as a single dose (0, 1, 10, and 50 mg/kg) to male Sprague-Dawley rats followed by saliva and blood collection at 0, 3, 6, and 12 hour post-dosing. CPF and its major metabolite trichloropyridinol (TCP) were quantified in blood and saliva using gas chromatography (GC) and a modified Ellman method was used to monitor the resultant ChE inhibition. A preliminary in vitro study, using both AChE and BuChE specific inhibitors, indicated that the vast majority (>90%) of rat salivary ChE activity was due to BuChE. Utilizing saliva as a source of BuChE, the bimolecular inhibition rate constant (Ki) and the first-order reactivation rate (Kr) were 8000 M-t h-t and 0,08 h-l, respectively. Oral administration produced a dose-dependent Inhibition of ChE in plasma and saliva. At all dose levels the maximum salivary ChE inhibition (3-6 hr post-exposure) was slightly less than that of the plasma, and saliva exhibited a faster ChE recovery. CPF and TCP were quantified in blood, whereas TCP was detected in saliva and onlly at higher doses. Although the saliva TCP concentrations were significantly less than the plasma concentrations, the TCP pharmacokinetics were comparable (i.e. similar half-life). These results suggest that saliva may be a useful biological matrix for monitoring CPF exposure and response either through measuring the metabolite levels or the degree of ChE inhibition. These data will be used for further validation of an already constructed pharmacokinetic/pharmacodynamic model for CPF.
Insecticides; Dosimetry; Phosphates; Neurotoxicity; Detoxification; Laboratory-animals; Animal-studies; Animals; Gas-chromatography; Salivary-glands; In-vitro-study; Pesticides; 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