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

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.