Pharmacokinetic and pharmacodynamic interactions of a binary mixture of chlorpyrifos and diazinon in the rat.
Timchalk-C; Poet-TS; Hinman-MN; Busby-AL; Kousba-A
Toxicologist 2004 Mar; 78(S-1):425
Chlorpyrifos (CPF) and diazinon (DZN) are organophosphosphorus (OP) insecticides, with the potential for concurrent exposures. Their oxon metabolites are potent inhibitors of cholinesterases (ChE). This study evaluated the impact of an acute binary OP exposure on dosimetry and ChE inhibition in rats. Groups (3-4/time point) of male S-D rats were orally administered CPF, DZN or a CPF/DZN mixture (0, 15, or 60 mg/kg) and blood and brain were collected at 0, 3, 6, 12 and 24 hr post-dosing. CPF, DZN and their respective metabolites trichloropyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP) were quantified in blood and/or urine using gas chromatography. A modified Ellman method was used to measure ChE inhibition in blood and brain. Co-exposure at 15 mg/kg, did not appreciably alter the pharmacokinetics of CPF, DZN or TCP. The total amount of urinary TCP was decreased approximately 50% for the co-exposed group, but the amount of urinary IMHP was not altered. Co-exposure to 60 mg/kg delayed and increased the Cmax for both CPF (1.6x) and DZN (7.2x), and resulted in the respective blood AUCs increasing 145 and 422%. The AUC for TCP decreased to 82%, but was slightly increased (107%) for IMHP. For the co-exposed group the total amount of urinary TCP was decreased approximately 60%, but did not appreciably alter the amount of IMHP excreted relative to the single exposure. These results suggest that both CPF and DZN are capable of inhibiting each other's metabolism, but the effect is observed at higher doses (>15 mg/kg). A dose-dependent inhibition of ChE activity was also noted in plasma, RBC and brain homogenates for both the single and co-exposures to CPF and DZN. In all tissues, CPF exposure resulted in greater ChE inhibition than DZN, however the overall ChE response appeared to be additive for the co-exposures. These results characterize both the pharmacokinetic and pharmacodynamic interactions of CPF and DZN in the rat and will be used to further develop a binary kinetic/dynamic model for OPs.
Pharmacodynamics; Laboratory-animals; Animals; Animal-studies; Organo-phosphorus-pesticides; Exposure-levels; Dosimetry; Blood-samples; Gas-chromatography; Models; Insecticides; Organo-phosphorus-compounds; Neurotoxic-effects; Neurotoxicity; Neurotoxins; Acute-exposure
Research Tools and Approaches: Exposure Assessment Methods
The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland
Battelle Memorial Institute, Richland, Washington