The impact of repeated nicotine and alcohol co-exposure on the in vivo chlorpyrifos pharmacokinetics and pharmacodynamics.
Lee-S; Poet-TS; Smith-JN; Busby-Hjerpe-AL; Timchalk-C
Toxicologist 2010 Mar; 114(1):340
Chlorpyrifos (CPF) is an organophosphorus insecticide widely used in agriculture. The neurotoxicity of CPF results from inhibition of cholinesterase (ChE) by its metabolite, chlorpyrifos-oxon (CPF-oxon), which subsequently leads to cholinergic hyperstimulation. The objective of this study was to evaluate the influence of repeated nicotine and ethanol co-exposure on in vivo CPF pharmacokinetics and pharmacodynamics. The routine consumption of tobacco products and alcoholic beverages may modify key metabolic and physiological processes. Blood and urine profiles of the non-toxic metabolite, 3,5,6-trichloro-2-pyridinol (TCPy) along with changes in plasma and brain ChE activities were measured in male S-D rats (approximately 300 g). Animals were co-exposed to CPF (1 or 5 mg/kg/day, po), ethanol (1 g/kg/day, po) and nicotine (1 mg/kg/day, sc), for 7 days. Rats were sacrificed at times from 1 to 24 hr post-last dosing of CPF. There were apparent differences in blood TCPy pharmacokinetics following nicotine and ethanol pretreatment in both CPF dosegroups, which showed higher TCPy peak concentrations and increased blood TCPy AUC (approximately 2-fold) in ethanol/nicotine pretreated groups over saline pretreatment groups. Brain acetylcholinesterase (AChE) activities from ethanol and nicotinetreated groups showed substantially less inhibition following repeated 5 mg CPF/kg dosing compared to CPF-only controls (96 +/- 13 and 66 +/- 7% of na´ve at 4 hr postlast dosing, respectively). Inhibition of brain AChE activities was minimal in both 1 mg CPF/kg dosing groups, but a similar trend indicating less inhibition following ethanol/nicotine pretreatment was apparent. No alcohol/nicotine treatment effects were observed in plasma ChE activities. This study shows that repeated exposure to alcohol and nicotine (i.e., from smoking) could alter the pharmacokinetics and pharmacodynamics of CPF.
Airborne-particles; Biochemistry; Biological-effects; Chemical-hypersensitivity; Chemical-reactions; Exposure-assessment; Exposure-levels; Exposure-methods; Inhalation-studies; Laboratory-animals; Laboratory-testing; Microbiology; Microchemistry; Microscopic-analysis; Particulate-dust; Particulates; Pesticides-and-agricultural-chemicals; Pharmacodynamics; Statistical-analysis; Toxic-effects; Toxins
Research Tools and Approaches: Exposure Assessment Methods
The Toxicologist. Society of Toxicology 49th Annual Meeting and ToxExpo, March 7-11, 2010, Salt Lake City, Utah
Battelle Memorial Institute, Richland, Washington