Pharmacokinetics and pharmacodynamics of chlorpyrifos in adult male Long-Evans rats following repeated subcutaneous exposure to chlorpyrifos

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.

Repeated exposure to neurotoxic levels of chlorpyrifos alters hippocampal expression of neurotrophins and neuropeptides

“…The dose levels, route of administration and duration of exposure for this study were based on published exposure studies of human agricultural workers exposed to CPF for 15–30 days during the cotton growing season in Egypt (Farahat et al, 2010, 2011; Fenske et al, 2012). Using both a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model and experimental data, Ellison et al (2011) reported that this dosing paradigm inhibits blood ChE activity in rats to an extent comparable to that reported in the Egyptian agricultural workers (Ellison et al, 2011). …”

Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

“…The rate of dermal penetration and absorption varies greatly between OP agents, and the toxicokinetics of OPs absorbed through the skin can be different from those that occur by other routes of exposure. Intraperitoneal (IP) injection and oral administration, for example, achieve higher systemic dosing than dermal exposure (Ellison et al, 2011). Although inhalation is also a significant route of occupational exposure, especially when considering aircraft crew and maintenance workers exposed to T O CP (de Ree et al, 2014; Hardos et al, 2016), we found a limited number of published OP inhalation animal studies.…”

Experimental strategy for translational studies of organophosphorus pesticide neurotoxicity based on real-world occupational exposures to chlorpyrifos

“…TCPy was quantified in urine samples collected from rats daily, and cholinesterase activity was measured in blood samples collected every 2 to 3 days. These data have been used to optimize a PBPK/PD model for CPF in rats that is relevant to occupational exposures in humans (Ellison et al, 2011). Our data indicate that exposure of adult male Long Evans rats to CPF at 3 and 10 mg/kg/d s.c., simulate human CPF exposure patterns as confirmed by urinary TCPy levels and blood ChE depression comparable to that observed in the Egyptian pesticide application workers (see arrow between top two rectangles in Figure 1).…”

“…Our data indicate that exposure of adult male Long Evans rats to CPF at 3 and 10 mg/kg/d s.c., simulate human CPF exposure patterns as confirmed by urinary TCPy levels and blood ChE depression comparable to that observed in the Egyptian pesticide application workers (see arrow between top two rectangles in Figure 1). For example, blood AChE was inhibited 69 ± 15 and 38 ± 11 percent (mean ± SD) in rats following daily sc exposure to CPF at 3 and 10 mg/kg/d x 7 days (Ellison et al, 2011). Similar inhibition of blood AChE was observed in the more heavily exposed CPF applicators in the Egyptian cohort (Farahat et al, 2011).…”