Advances in biologically based models for respiratory tract uptake of inhaled volatiles

Physiologically based pharmacokinetic models for volatile organic chemicals typically describe the respiratory tract as a single compartment in which chemicals in the alveolar air space and the arterial blood are in instantaneous equilibrium. These models also assume that the distribution of chemical in the air-stream is uniform throughout the respiratory tract and that uptake is significant only in the alveolar region. A functional role for the upper respiratory tract in the uptake of volatile chemicals has been largely ignored. While these models have worked well for chemicals with low aqueous solubility in biological fluids, systemic uptake of highly soluble volatiles is overestimated. Thus, there is a significant effort to describe the critical determinants for uptake of soluble chemicals and to formulate models with more biologically relevant descriptions of respiratory tract structure and function. Investigators have addressed this problem from several viewpoints. Airflow patterns in the respiratory tract, regional metabolism, diffusion-dependent uptake, and the cyclic nature of respiration are now being incorporated into current models. Use of dosimetric models that incorporate relevant biology for inhaled chemicals will ultimately result in more meaningful human risk assessments.