PNNL

Abstract

Chlorpyrifos (CPF) is a commonly used organophosphorus pesticide. Several pharmacokinetic and pharmacodynamic studies have been conducted in rats in which CPF was administered as a single bolus dose. However, there is limited data regarding the pharmacokinetics and pharmacodynamics following daily exposure. Since occupational exposures often consist of repeated, daily exposures, there is a need to evaluate the pharmacokinetics and pharmacodynamics of CPF under exposure conditions which more accurately reflect real world human exposures. In this study, the pharmacokinetics and pharmacodynamics of CPF were assessed in male Long Evans rats exposed daily to CPF (0, 3 or 10mg/kg/day, s.c. in peanut oil) over a ten day study period. Throughout the study, multiple pharmacokinetic (urinary TCPy levels and tissue CPF and metabolite levels) and pharmacodynamic (blood and brain AChE activity) determinants were measured. Average blood AChE activity on day ten was 54 and 33 percent of baseline among animals in the 3 and 10mg/kg/day CPF treatment groups, respectively, while average brain AChE activity was 67 and 28 percent of baseline. Comparable dose-response relationships between brain AChE inhibition and blood AChE inhibition, suggests that blood AChE activity is a valid biomarker of brain AChE activity. The pharmacokinetic and pharmacodynamic measures collected in this study were also used to optimize a rat physiologically based pharmacokinetic/ pharmacodynamic (PBPK/PD) model for multiple s.c. exposures to CPF based on a previously published rat PBPK/PD model for CPF following a single bolus injection. This optimized model will be useful for determining pharmacokinetic and pharmacodynamic responses over a wide range of doses and durations of exposure, which will improve extrapolation of results between rats and humans.