Evaluation of a Carbon Tetrachloride Physiologically Based Pharmacokinetic Model Using Real-Time Breath-Analysis Monitoring of the Rat

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Abstract
A methodology has been developed to monitor the exhalation of volatile compounds in rats in a real-time manner. The exhalation data is collected using an innovative breath-analysis system that links the exhaled breath from the rat directly with a mass spectrometer. Because the breath-analysis system generates a new data point approximately every second, this methodology can aid in describing the rapid exponential emptying of the blood compartment that occurs immediately following peak exposure. Furthermore, coupling the real-time collection of biokinetic data with a physiologically descriptive toxico-kinetic model should be useful in elucidating complex in situ chemical-mediated biological reactions, particularly for rapidly occurring processes. The utility of this new methodology is illustrated using carbon tetrachloride (CCl4) as a demonstration compound. An existing physiologically based pharmacokinetic (PBPK) model was taken from the literature and modified to simulate an intravenous route of CCl4 exposure in the male Fischer 344 rat. This PBPK model for the rat accurately described the concentrations of CCl4 in real-time exhaled breath data collected from rats exposed to CCI, via a single intravenous injection.