A physiologically based description of the inhalation pharmacokinetics of styrene in rats and humans

A physiologically based pharmacokinetic model which describes the behavior of inhaled styrene in rats accurately predicts the behavior of inhaled styrene in humans. The model consists of a series of mass-balance differential equations which quantify the time course of styrene concentration within four tissue groups representing (1) highly perfused organs, (2) moderately perfused tissues such as muscle, (3) slowly perfused fat tissue, and (4) organs with high capacity to metabolize styrene (principally liver). The pulmonary compartment of the model incorporates uptake of styrene controlled by ventilation and perfusion rates and the blood:air partition coefficient. The metabolizing tissue group incorporates saturable Michaelis-Menten metabolism controlled by the biochemical constants Vmax and Km. With a single set of physiological and biochemical constants, the model adequately simulates styrene concentrations in blood and fat of rats exposed to 80, 200, 600, or 1200 ppm styrene (data from previously published studies). The simulated behavior of styrene is particularly sensitive to changes in the constants describing the fat tissue group, and to the maximum metabolic rate described by Vmax. The constants used to simulate the fate of styrene in rats were scaled up to represent humans. Simulated styrene concentrations in blood and exhaled air of humans are in good agreement with previously published data. Model simulations show that styrene metabolism is saturated at inhaled concentrations above approximately 200 ppm in mice, rats, and humans. At inhaled concentrations below 200 ppm, the ratio of styrene concentration in blood to inhaled air is controlled by perfusion limited metabolism. At inhaled concentrations above 200 ppm, this ratio is controlled by the blood:air partition coefficient and is not linearly related to the ratio attained at lower (nonsaturating) exposure concentrations. These results show that physiologically based pharmacokinetic models provide a rational basis with which (1) to explain the relationship between blood concentration and air concentration of an inhaled chemical, and (2) to extrapolate this relationship from experimental animals to humans.