Comparison of Four Biologically Based Dosimetry Models for the Deposition of Rapidly Metabolized Vapors in the Rodent Nasal Cavity

Abstract

Various volatile compounds induce toxic effects in the rodent nasal cavity following inhalation exposure. To facilitate interspecies extrapolation for risk assessment, it is necessary to estimate the amount of the compound deposited in the nasal cavity of both the test and target species. Four computer simulation models have been prepared and evaluated for their utility in interspecies extrapolation, description of site-specific toxicity within the nasal cavity, and understanding of systemic toxic effects (or the lack thereof) in rodent bioassays. The simplest model provided an estimate of the fractional penetration of the compound to the lungs and was linked to a one-compartment description of the body. The most complex model used a description of nasal air flow to estimate the amount of compound deposited in various regions of the nasal cavity. This multicompartment nasal cavity was linked to a multicompartment physiologically based pharmacokinetic (PBPK) model describing the systemic tissues. The data for a nasal irritant, ethyl acrylate, were used to evaluate the models. This compound is representative of a variety of organic acids and esters that have induced cytotoxicity in the olfactory epithelium lining the rodent nasal cavity following high-concentration inhalation exposure. No systemic toxicity or carcinogenicity was induced by ethyl acrylate during a chronic inhalation bioassay. The model constructed from a multicompartment nasal cavity linked to a PBPK description of the body was found to have the most utility for adequately describing regional toxicity in the nasal cavity, for evaluating the delivered dose and potential for toxicity at systemic organs, and for interspecies extrapolation.