ToxSci Advance Access originally published online on September 5, 2007
Toxicological Sciences 2007 100(2):345-359; doi:10.1093/toxsci/kfm232
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Published by Oxford University Press 2007.
A Physiologically Based Pharmacokinetic/Pharmacodynamic Model for Carbofuran in Sprague-Dawley Rats Using the Exposure-Related Dose Estimating Model
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* General Dynamics Information Technology, Henderson, Nevada 89074
National Exposure Research Laboratory, U.S. Environmental Protection Agency (EPA), Las Vegas, Nevada 89193
Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York 14214
1 To whom correspondence should be addressed at U.S. EPA, Human Exposure and Atmospheric Sciences Division, 944 East Harmon, Las Vegas, Nevada 89193-3478. Fax: (702) 798-2261. E-mail: okino.miles{at}epamail.epa.gov.
Received April 3, 2007; accepted August 25, 2007
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Abstract |
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Carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl-N-methylcarbamate), a broad spectrum N-methyl carbamate insecticide, and its metabolite, 3-hydroxycarbofuran, exert their toxicity by reversibly inhibiting acetylcholinesterase (AChE). To characterize AChE inhibition from carbofuran exposure, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was developed in the Exposure-Related Dose Estimating Model (ERDEM) platform for the Sprague-Dawley (SD) rat. Experimental estimates of physiological, biochemical, and physicochemical model parameters were obtained or based on data from the open literature. The PBPK/PD model structure included carbofuran metabolism in the liver to 16 known metabolites, enterohepatic circulation of glucuronic acid conjugates, and excretion in urine and feces. Bolus doses by ingestion of 50 µg/kg and 0.5 mg/kg carbofuran were simulated for the blood and brain AChE activity. The carbofuran ERDEM simulated a half-life of 5.2 h for urinary clearance, and the experimental AChE activity data were reproduced for the blood and brain. Thirty model parameters were found influential to the model outputs and were chosen for perturbation in Monte Carlo simulations to evaluate the impact of their variability on the model predictions. Results of the simulation runs indicated that the minimum AChE activity in the blood ranged from 29.3 to 79.0% (as 5th and 95th percentiles) of the control level with a mean of 55.9% (standard deviation = 15.1%) compared to an experimental value of 63%. The constructed PBPK/PD model for carbofuran in the SD rat provides a foundation for extrapolating to a human model that can be used for future risk assessment.
Key Words: carbofuran; PBPK/PD model; Exposure-Related Dose Estimating Model (ERDEM); Monte Carlo simulation; risk assessment.
Disclaimer: The U.S. Environmental Protection Agency through its Office of Research and Development funded and managed the research described here under contract GS-35F-4357D to General Dynamics Information Technology. It has been subjected to Agency review and approved for publication.