PBPK modeling of the major chlorpyrifos metabolite trichloropyridinol: a potential biomonitoring strategy.
Timchalk-C; Busby-AL; Poet-TS
Toxicologist 2008 Mar; 102(1):281
Chlorpyfios (CPF) is a commonly utilized organophosphorous insecticide and the major urinary metabolite, trichloropyridinol (TCPy), is used to biomonitor for exposure. Saliva has been proposed as a potential non-invasive biomonitoring matrix, but the utility of saliva TCPy to biomonitor for CPF exposures requires a methodology to correlate saliva TCPy with total CPF dose. In this regard, a TCPy PBPK model was developed to link with a validated CPF model to determine the relationship between blood and salivary TCPy in both rats and humans. The TCPy model includes fat, rapidly perfused, and slowly perfused compartments and compartments from which metabolism of CPF or CPF-oxon leads to TCPy production (brain, diaphragm, liver, and blood). Urinary clearance of TCPy was modeled as first-order elimination from the blood compartment and clearance into the saliva was perfusion-based. The pharmacokinetics of TCP in blood and urine were previously determined in rats following CPF oral doses of 1, 10 and 50 mg/kg, and the results used to calibrate the TCPy model. Based on maximum log likelihood function (MLLF) analysis, the model reasonable fit the TCPy blood and saliva concentrations (82 & 87% variation explained) at all doses with the TCPy concentration in blood exceeded saliva (~2-fold), although the kinetics were comparable. The model also reasonably predicted blood concentrations and urinary elimination of TCPy in humans exposed orally to 0.5 mg/kg CPF dose (MLLF >89% variation explained). These findings suggest that the TCPy PBPK model simulates blood and urinary TCPy concentrations following oral exposure to known doses of CPF in both rats and humans. Secondly based on the rat, the TCPy model simulates the kinetics of TCPy clearance from saliva; suggesting that the model can back estimate CPF dosimetry using saliva TCPy. PBPK modeling of TCPy in saliva may represent a viable quantitative biomonitoring approach with broad application for evaluating both occupational and environmental exposures to CPF.
Urinalysis; Urine-chemistry; Pesticides-and-agricultural-chemicals; Pesticide-residues; Occupational-exposure; Work-environment; Blood-analysis; Laboratory-animals; Insecticides
Agriculture, Forestry and Fishing
The Toxicologist. Society of Toxicology 47th Annual Meeting and ToxExpo, March 16-20, 2008, Seattle, Washington
Battelle Pacific Northwest Laboratories