CFD-PBPK HYBRID MODEL FOR SIMULATING GAS AND VAPOR UPTAKE IN THE RAT NOSE

In laboratory studies of rodents, the inhalation of organic vapors oft en results in preferential damage to olfactory epithelium. Such focal lesion formation may be due either wholly or in part to a correspondin g nonuniformity in the spatial distribution of vapor uptake within the nasal cavities. As a tool for determining this dose distribution, a m athematical model based on a combination of computational fluid dynami cs (CFD) and physiologically based pharmacokinetic (PBPK) modeling was developed for simulating toxicant vapor uptake in the rat nose. The n asal airways were subdivided into four distinct meatuses selected such that each contained a major air flow stream. Each meatus was further divided into four serial regions attached to separate tissue stacks co ntaining mucus, epithelial, and subepithelial compartments. Values for the gas-phase mass transfer coefficients and gas flows in the 16 airw ay regions were determined by a solution of the Navier-Stokes and conv ection-diffusion equations using commercially available CFD software. These values were then input to a PBPK simulation of toxicant transpor t through the 16 tissue stacks. The model was validated by using overa ll uptake data from rodent inhalation studies for three ''unreactive'' vapors that were either completely inert (i.e., acetone), reversibly ionized in aqueous media (i.e., acrylic acid), or prevented from being metabolized by an enzyme inhibitor (i.e., isoamyl alcohol). A sensiti vity analysis revealed that accurate values of the mass transfer coeff icient were not necessary to simulate regional concentrations and upta ke of unreactive vapors in the rat nose, but reliable estimates of dif fusion coefficients in tissue were crucial for accurate simulations. ( C) 1998 Academic Press.