title: Pharmacokinetic and pharmacodynamic interaction for a binary mixture of chlorpyrifos and diazinon in the rat.
abstract: Chlorpyrifos (CPF) and diazinon (DZN) are two commonly used organophosphorus (OP) insecticides and a potential exists for concurrent exposures. The primary neurotoxic effects from OP pesticide exposures result from the inhibition of acetylcholinesterase (AChE). The pharmacokinetic and pharmacodynamic impact of acute binary exposures of rats to CPF and DZN was evaluated in this study. Rats were orally administered CPF, DZN, or a CPF/DZN mixture (0, 15, 30, or 60 mg/kg) and blood (plasma and RBC), and brain were collected at 0, 3, 6, 12, and 24 h postdosing, urine was also collected at 24 h. Chlorpyrifos, DZN, and their respective metabolites, 3,5,6-trichloro-2-pyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP), were quantified in blood and/or urine and cholinesterase (ChE) inhibition was measured in brain, RBC, and plasma. Coexposure to CPF/DZN at the low dose of 15/15 mg/kg did not alter the pharmacokinetics of CPF, DZN, or their metabolites in blood. A high binary dose of 60/60 mg/kg increased the C(max) and AUC and decreased the clearance for both parent compounds, likely due to competition between CPF and DZN for CYP450 metabolism. At lower doses, most likely to be encountered in occupational or environmental exposures, the pharmacokinetics were linear. A dose-dependent inhibition of ChE was noted in tissues for both the single and coexposures, and the extent of inhibition was plasma > RBC > or = brain. The overall relative potency for ChE inhibition was CPF/DZN > CPF > DZN. A comparison of the ChE response at the low binary dose (15/15 mg/kg), where there were no apparent pharmacokinetic interactions, suggested that the overall ChE response was additive. These experiments represent important data concerning the potential pharmacokinetic and pharmacodynamic interactions for pesticide mixtures and will provide needed insight for assessing the potential cumulative risk associated with occupational or environmental exposures to these insecticides.
authors.affiliation: Center for Biological Monitoring and Modeling, Battelle, Pacific Northwest Division, Richland, WA 99352, USA. charles.timchalk@pnl.gov
authors.forename: C
authors.initials: C
authors.lastname: Timchalk
authors.forename: T S
authors.initials: TS
authors.lastname: Poet
authors.forename: M N
authors.initials: MN
authors.lastname: Hinman
authors.forename: A L
authors.initials: AL
authors.lastname: Busby
authors.forename: A A
authors.initials: AA
authors.lastname: Kousba
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004390:Chlorpyrifos / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D002802:Cholinesterases / Q000187:drug effects / Q000378:metabolism; D003976:Diazinon / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004357:Drug Synergism; D004912:Erythrocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D007441:Intubation, Gastrointestinal; D008297:Male; D008657:Metabolic Clearance Rate; D011728:Pyridones / Q000097:blood / Q000652:urine; D011743:Pyrimidines / Q000097:blood / Q000652:urine*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002800:Cholinesterase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; C012587:3,5,6-trichloro-2-pyridinol; D002802:Cholinesterases; D004390:Chlorpyrifos; D003976:Diazinon