TOXICOLOGY OF NASAL GAS DEPOSITION IN FIVE SPECIES

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It has recently been discovered that the nasal mucosa is rich in xenobiotic metabolizing enzymes, however, their quantitative importance in the in vivo setting is not known. The primary aim of the proposed research is to provide quantitative information on the extent to which inhaled vapors are metabolized in nasal tissues in vivo. Towards this end the deposition of nine vapors will be measured in the surgically isolated upper respiratory tract of anesthetized Fischer 344 rats and golden Syrian hamsters. The selected vapors are substrates for either alcohol dehydrogenase, carboxylesterase or mixed function oxidases, enzymes known to be present in the nasal mucosa in high levels. The extent of metabolism will be estimated by mathematic modeling of the deposition data and by measurement of deposition in naive and metabolic inhibitor-pretreated animals. Metabolism in the nasal mucosa has the potential to be of critical and fundamental importance in the respiratory and systemic toxicity of inhaled vapors. Metabolism at the site of entry results in high local concentrations of metabolite(s) and limits the amount of parent compound available for absorption into the general circulation. Nasal metabolism also enhances deposition of inhaled vapors in the site and, thus, spares the lungs from their toxic effects. The limited information currently available on the disposition of deposited vapors suggests 50% or more of the deposited burden may be metabolized in situ in nasal tissues. Because it may exert a profound effect on overall toxicity, quantitative knowledge on the extent of metabolism at the site of entry is essential for a complete understanding of the toxicity of any substance. By quantitating and providing insights into the important factors involved in this processs, the proposed research will significantly advance our knowledge of fundamentally important principles of inhalation toxicology and in the long-term will enhance our ability to predict and interpret the regional respiratory and systemic toxicity of inhaled vapors.