You are here:
MODELING THE TOXICOKINETICS OF INHALED TOLUENE IN RATS: THE IMPACT OF FEEDING STATUS, PHYSICAL ACTIVITY AND STRAIN
Citation:
KENYON, E. M., V. A. BENIGNUS, C. R. EKLUND, AND P. J. BUSHNELL. MODELING THE TOXICOKINETICS OF INHALED TOLUENE IN RATS: THE IMPACT OF FEEDING STATUS, PHYSICAL ACTIVITY AND STRAIN. Presented at Society of Toxicology Annual Meeting, Charlotte, NC, March 25 - 29, 2007.
Description:
Toluene is found in petroleum-based fuels and used as a solvent in consumer products and industrial applications. The critical effects following inhalation exposure involve the brain and nervous system in both humans and experimental animals whether exposure duration is acute or chronic. The goals of this modeling effort were two-fold: (1) evaluate and explain the influence of feeding status and activity level on toluene pharmacokinetics, and (2) apply this model to the analysis of data in the published literature to explain differing toluene kinetics. Compartments in the model are lung, slowly and rapidly perfused tissue groups, fat, liver, GI tract and brain; tissue transport is blood-flow limited and metabolism occurs in the liver. Chemical-specific parameters and initial organ volumes and blood flow rates were obtained from the literature. Sensitivity analysis revealed that the most influential parameters for our experimental conditions were cardiac output, alveolar ventilation and fat volume; other parameters (e.g., partitions and metabolic rate parameters) were either well defined (multiple consistent experimental results with low variability) or relatively non-influential (e.g. organ volumes other than fat). Model-based analysis of our data and that of other investigators suggests that there is a toluene-specific effect on ventilation parameters that differs between active and sedentary rats and is dose-dependent as well. However, rats that were weight-maintained compared to free-fed rats in our studies and those of other investigators could be modeled with a single set of parameters provided that experimental data were obtained from rats exposed to toluene in whole body inhalation chambers. These results point to (1) the importance of experimental conditions and physiological status in explaining apparently conflicting kinetic data and (2) the need to match simulation conditions to experimental conditions when estimating internal doses for effects in studies that lack kinetic data. (This abstract does not necessarily reflect EPA policy.)