APPLICATION OF A HYBRID COMPUTATIONAL FLUID-DYNAMICS AND PHYSIOLOGICALLY-BASED INHALATION MODEL FOR INTERSPECIES DOSIMETRY EXTRAPOLATION OFACIDIC VAPORS IN THE UPPER AIRWAYS

This study provides a scientific basis for interspecies extrapolation of nasal olfactory irritants from rodents to humans. By using a series of short-term in vivo studies, in vitro studies with nasal explants, and computer modeling, regional nasal tissue dose estimates were made and comparisons of tissue doses between species were conducted. To mak e these comparisons, this study assumes that human and rodent olfactor y epithelium have similar susceptibility to the cytotoxic effects of o rganic acids based on similar histological structure and common mode o f action considerations. Interspecies differences in susceptibility to the toxic effects of acidic vapors are therefore assumed to be driven primarily by differences in nasal tissue concentrations that result f rom regional differences in nasal air flow patterns relative to the sp ecies-specific distribution of olfactory epithelium in the nasal cavit y. The acute, subchronic, and in vitro studies have demonstrated that the nasal olfactory epithelium is the most sensitive tissue to the eff ects of inhalation exposure to organic acids and that the sustentacula r cells are the most sensitive cell type of this epithelium. A hybrid computational fluid dynamics (CFD) and physiologically based pharmacok inetic (PBPK) dosimetry model was constructed to estimate the regional tissue dose of organic acids in the rodent and human nasal cavity. Th e CFD-PBPK model simulations indicate that the olfactory epithelium of the human nasal cavity is exposed to two- to threefold lower tissue c oncentrations of a representative inhaled organic acid vapor, acrylic acid, than the olfactory epithelium of the rodent nasal cavity when th e exposure conditions are the same. The magnitude of this difference v aries somewhat with the specific exposure scenario that is simulated. The increased olfactory tissue dose in rats relative to humans may be attributed to the large rodent olfactory surface area (greater than 50 % of the nasal cavity) and its highly susceptible location (particular ly, a projection of olfactory epithelium extending anteriorly in the d orsal meatus region). In contrast, human olfactory epithelium occupies a much smaller surface area (less than 5% of the nasal cavity), and i t is in a much less accessible dorsal posterior location. in addition, CFD simulations indicate that human olfactory epithelium is poorly ve ntilated relative to rodent olfactory epithelium. These studies sugges t that the human olfactory epithelium is protected from irritating aci dic vapors significantly better than rat olfactory epithelium due to s ubstantive differences in nasal anatomy and nasal air flow. Furthermor e, the general structure of the hybrid CFD-PBPK model used for this st udy appears to be useful for target tissue dosimetry and interspecies dose comparisons for a wide range of inhaled vapors, (C) 1998 Academic Press.