A hybrid computational fluid dynamics and physiologically based pharmacokinetic model for comparison of predicted tissue concentrations of acrylic acid and other vapors in the rat and human nasal cavities following inhalation exposure

To assist in interspecies dosimetry comparisons for risk assessment of the nasal effects of organic acids, a hybrid computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) dosimetry model was const ructed to estimate the regional tissue dose of inhaled vapors in the rat an d human nasal cavity. Application to a specific vapor would involve the inc orporation of the chemical-specific reactivity, metabolism, partition coeff icients, and diffusivity (in both air and tissue phases) of the vapor. This report describes the structure of the CFD-PBPK model and its application t o a representative acidic vapor, acrylic acid, for interspecies tissue conc entration comparisons to assist in risk assessment. By using the results fr om a series of short-term in vivo studies combined with computer modeling, regional nasal tissue dose estimates were developed and comparisons of tiss ue doses between species were conducted. To make these comparisons, the ass umption was made that the susceptibilities of human and rat olfactory epith elium to the cytotoxic effects of organic acids were similar, based on simi lar histological structure and common mode of action considerations. Inters pecies differences in response were therefore assumed to be driven primaril y by differences in nasal tissue concentrations that result from regional d ifferences in nasal air flow patterns relative to the species-specific dist ribution of olfactory epithelium in the nasal cavity. The results of simula tions with the seven-compartment CFD-PBPK model suggested that the olfactor y epithelium of the human nasal cavity would be exposed to tissue concentra tions of acrylic acid similar to that of the rat nasal cavity when the expo sure conditions are the same. Similar analysis of CFD data and CFD-PBPK mod el simulations with a simpler one-compartment model of the whole nasal cavi ties of rats and humans provides comparable results to averaging over the c ompartments of the seven-compartment model. These results indicate that the general structure of the hybrid CFD-PBPK model applied in this assessment would be useful for target tissue dosimetry and interspecies dose compariso ns for a wide variety of vapors. Because of its flexibility, this CFD-PBPK model is envisioned to be a platform for the construction of case-specific inhalation dosimetry models to simulate in vivo exposures that do not invol ve significant histopathological damage to the nasal cavity.