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Feasibility of Metabolic Parameter Estimation in Pharmacokinetic Models of Carbon Tetrachloride Exposure in Rats
Draper, B., D. Marcin, A. Margolskee, R. Murden, A. Attarian, M. V. EVANS, AND K. YOKLEY. Feasibility of Metabolic Parameter Estimation in Pharmacokinetic Models of Carbon Tetrachloride Exposure in Rats. TOXICOLOGICAL AND ENVIRONMENTAL CHEMISTRY. Taylor & Francis, Inc., Philadelphia, PA, 91(3):521-546, (2009).
Since carbon tetrachloride(CCl4) is highly volatile and lipophilic chemical, it is commonly found in air or water as an environmental contaminant. Exposure can occur by inhalation, ingestion, food, or skin contact. Although CCl4 is slowly metabolized, its highly toxic nature makes identification of its metabolism crucial to quantifying toxicity. Also, because CCl4 is slowly metabolized, metabolic parameters are difficult to estimate. PBPK models have been used to describe distribution of chemicals into the body and to help define internal dose delivered to target tissues. A new technique in sensitivity analysis was used to help increase our confidence in estimated metabolic parameters for this chemical. The existing PBPK scientific literature was researched in order to determine if one PBPK model provided consistent analysis for the existing CCl4 data across several different exposure scenarios. After determining that a route to route model was not readily available, the model results were compared with a group of the available data. Sensitivity analysis was then used to inform future experiments that would increase the potential identifiability of metabolic estimates for this chemical.
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 carbon tetrachloride after exposure, but the pharmacokinetic parameters describing the metabolism of CCl4 are not well characterized. The goal of this research was 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 exposure doses 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 experimentalists that wish to further pursue estimating these metabolic parameters.