Use of a Physiologically Based Pharmacokinetic Model and Computer Simulation for Retrospective Assessment of Exposure to Volatile Toxicants

Abstract

Personal protective equipment often is used to prevent exposure to volatile toxicants. The effectiveness of such equipment can be evaluated by (1) measuring the postexpo-sure concentration of toxicant in expired breath and (2) using a physiologically based pharmacokinetic (PB-PK) model to estimate retrospectively the actual exposure concentration (i.e., the concentration leaking through the protective equipment). A study was conducted to validate this paradigm. Male Fischer 344 rats were exposed by inhalation (7 h) to 300, 600, and 1200 ppm chloropentafluorobenzene (CPFB), and expired CPFB was measured for 1 h postexposure. Animals were held in a restrainer plethys-mograph and their ventilation was measured during the entire experiment. Confinement in this apparatus affected ventilation. It showed minute-to-minute variability, and alveolar ventilation averaged about 42 l/kg.h, which is several times the rate for unrestrained, resting rats. A PB-PK model for CPFB therefore was configured to utilize actual ventilation rate data, In additional, optimization indicated that the cardiac outputhentilation rate ratio in the restrained rats was about 0.6. A value of 1.0 is commonly used for unrestrained rats at rest. Accurate simulations of expired CPFB concentrations were then obtained. Finally, the PB-PK model was exercised to depict estimation of exposure concentration when exposure duration, ventilation rate, and postexposure expired breath concentration were known.