Feasibility of metabolic parameter estimation in pharmacokinetic models of carbon tetrachloride exposure in rats1

Abstract

Carbon tetrachloride (CCl4) is a toxic chemical that was once used in degreasers and detergents, and some remnants of the chemical may be present in the water supply. Physiologically-based pharmacokinetic (PBPK) modeling can assist in understanding resulting internal doses of CCl4 after exposure, but the pharmacokinetic parameters describing the metabolism of CCl4 are not well characterized. The goal of this study was to provide insights into how to more accurately estimate these values in rats using PBPK modeling and data from previous studies. Three different PBPK models were constructed to describe CCl4 exposure in rats via inhalation, oral ingestion, and venous injection. Each of these models was compared to data, and sensitivity analysis was performed for each model to determine whether the available data could be used to accurately determine the metabolic parameters of interest. These parameter sensitivities were so low that optimization to the available data yielded physiologically unrealistic results. Model sensitivities were analyzed for different doses and routes of exposure in order to find experimental conditions that would allow for greater identifiability of the metabolic parameters. Data were simulated from these models at optimal conditions with varying levels of noise from a normal distribution. Optimizations were then performed to confirm that the original values could be obtained. The experiments developed are left as suggestions for investigators who wish to further pursue estimating these metabolic parameters. 1This problem was investigated by the first five authors under the direction of the last two authors during the NC State Research Experience for Undergraduates in Mathematics: Modeling and Industrial and Applied Mathematics, May 28 August 3, 2007.