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Impact of repeated nicotine and alcohol coexposure on in vitro and in vivo chlorpyrifos dosimetry and cholinesterase inhibition.

Authors
Lee-S; Poet-TS; Smith-JN; Hjerpe-AL; Gunawan-R; Timchalk-C
Source
J Toxicol Environ Health, A 2011 Oct; 74(20):1334-1350
NIOSHTIC No.
20039860
Abstract
Chlorpyrifos (CPF) is an organophosphorus insecticide, and neurotoxicity results from inhibition of acetylcholinesterase (AChE) by its metabolite, chlorpyrifos-oxon. Routine consumption of alcohol and tobacco modifies metabolic and physiological processes impacting the metabolism and pharmacokinetics of other xenobiotics, including pesticides. This study evaluated the influence of repeated ethanol and nicotine coexposure on in vivo CPF dosimetry and cholinesterase (ChE) response (ChE- includes AChE and/or butyrylcholinesterase (BuChE)). Hepatic microsomes were prepared from groups of naive, ethanol-only (1 g/kg/d, 7 d, po), and ethanol + nicotine (1 mg/kg/d 7 d, sc)-treated rats, and the in vitro metabolism of CPF was evaluated. For in vivo studies, rats were treated with saline or ethanol (1 g/kg/d, po) + nicotine (1 mg/kg/d, sc) in addition to CPF (1 or 5 mg/kg/d, po) for 7 d. The major CPF metabolite, 3,5,6-trichloro-2-pyridinol (TCPy), in blood and urine and the plasma ChE and brain acetylcholinesterase (AChE) activities were measured in rats. There were differences in pharmacokinetics, with higher TCPy peak concentrations and increased blood TCPy AUC in ethanol + nicotine groups compared to CPF only (approximately 1.8- and 3.8-fold at 1 and 5 mg CPF doses, respectively). Brain AChE activities after ethanol + nicotine treatments showed significantly less inhibition following repeated 5 mg CPF/kg dosing compared to CPF only (96 +/- 13 and 66 +/- 7% of naive at 4 h post last CPF dosing, respectively). Although brain AChE activity was minimal inhibited for the 1-mg CPF/kg/d groups, the ethanol + nicotine pretreatment resulted in a similar trend (i.e., slightly less inhibition). No marked differences were observed in plasma ChE activities due to the alcohol + nicotine treatments. In vitro, CPF metabolism was not markedly affected by repeated ethanol or both ethanol + nicotine exposures. Compared with a previous study of nicotine and CPF exposure, there were no apparent additional exacerbating effects due to ethanol coexposure.
Keywords
Insecticides; Cholinesterase-inhibitors; Organo-phosphorus-compounds; Brain-function; Organo-phosphorus-pesticides; Acetylcholinesterase; Neurotoxic-effects; Neurotoxins; Metabolites; Ethanols; Laboratory-animals; Laboratory-testing; Dose-response; Exposure-assessment; Animal-studies; Pharmacodynamics; In-vitro-studies; In-vivo-studies
Contact
C. Timchalk, Biological Monitoring and Modeling, Pacific Northwest National Laboratory, 902 Battelle Blvd, PO Box 999, MSIN: P7-59, Richland, WA 99352, USA
CODEN
JTEHD6
CAS No.
2921-88-2; 5598-15-2; 64-17-5; 54-11-5; 6515-38-4
Publication Date
20111015
Document Type
Journal Article
Email Address
Charles.timchalk@pnl.gov
Funding Type
Grant
Fiscal Year
2012
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-003629; B11122011
Issue of Publication
20
ISSN
1528-7394
Source Name
Journal of Toxicology and Environmental Health, Part A: Current Issues
State
GA; WA
Performing Organization
Battelle Memorial Institute, Richland, Washington
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