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MODELING THE TOXICOKINETICS OF INHALED TOLUENE IN RATS: THE IMPACT OF CONDITIONING AND PHYSICAL ACTIVITY
Citation:
KENYON, E. M., V. A. BENIGNUS, C. R. EKLUND, J. W. HIGHFILL, W. M. OSHIRO, T. E. SAMSAM, AND P. J. BUSHNELL. MODELING THE TOXICOKINETICS OF INHALED TOLUENE IN RATS: THE IMPACT OF CONDITIONING AND PHYSICAL ACTIVITY. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH - PART A: CURRENT ISSUES. Taylor & Francis, Inc., Philadelphia, PA, 71(4):249-65, (2008).
Impact/Purpose:
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 utilizing our own data from toluene-exposed Long Evans rats, and (2) to evaluate the ability of model to simulate data from the published literature and explain differing toluene kinetics.
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 utilizing our own data from toluene-exposed Long Evans rats, and (2) to evaluate the ability of model to simulate data from the published literature and explain differing toluene kinetics. Compartments in the model are lung, slowly and rapidly perfused tissue groups, fat, liver, gut 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 single most influential parameter for our experimental conditions was alveolar ventilation; other moderately influential parameters (depending upon concentration) included cardiac output, rate of metabolism, and blood flow to fat. Based on both literature review and sensitivity analysis, 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). Rats that were weight-maintained compared to free-fed rats in our studies could be modeled with a single set of parameters. Heart rate (HR) measurements in rats performing a lever pressing task compared to sedentary rats indicated that the HR increased in proportion to task intensity. For rats acclimated to eat in the laboratory during the day, both sedentary rats and rats performing a lever pressing task required different alveolar ventilation rates to successfully predict the data. Model evaluation using data from diverse sources together with statistical evaluation of the resulting fits revealed that the model appropriately predicted blood and brain toluene concentrations with some minor, but clear, exceptions. These results (1) emphasize the importance of experimental conditions and physiological status in explaining differing kinetic data, and (2) point to the need to consider simulation conditions when estimating internal dose metrics for effects studies in which kinetic data were not collected.
