A model for absorption of low-volatile toxicants by the airway mucosa

Inhaled chemical toxicants can damage the lungs during two phases: (1) the first-pass phase, in which toxicants are initially absorbed through the air/blood barrier, or (2) the circulation-transport phase, in which toxicants are transported back through the lungs with the circulating blood. While respiratory-tract dosimetry for inhaled toxicants is relatively easy to evaluate for the circulation-transport phase, it is more problematic for the first-pass phase and can involve higher local concentrations of toxicants. This article describes a respiratory-tract dosimetry model that simulates both the rate of absorption and the local concentration of low-volatile organic toxicants in the airway mucosa. The model simulates the non-steady-state diffusion of organic solutes from the air interface through the epithelium and into the capillary bed below. Cellular tissues are described as a heterogeneous, two-phase medium, with a minor lipid phase dispersed in a major aqueous phase. Results show that the lipid-phase/aqueous-phase partition coefficient, PC(L/A), is a critical factor in determining the rate of absorption of solutes in the airway mucosa. For a PC(L/A) in the range 1 to 100, absorption is limited by blood flow and occurs with typical half-times from about 1 to 10 min. As PC(L/A) increases above 100, absorption is gradually limited by the rate of diffusion through the air/blood barrier, and absorption half-times increase to hours. Over the same range, the concentration gradient in the mucosa changes from almost uniform to more nonuniform, and the site-of-entry epithelium becomes more selectively exposed. As a result, with increasing PC(L/A), protoxicants of lower reactivities can still be activated in significant quantities in the airway epithelium and thus act as site-of-entry toxicants. The presented results are important for understanding exposure/target-dose relationships of chemical carcinogens and for conducting reliable risk assessments.