TOXICOLOGY OF NASAL GAS DEPOSITION IN FIVE SPECIES

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Regional deposition patterns determine the dose delivered to respiratory tract target cells during inhalation exposure and, therefore, are critical in determining the ultimate toxic response. The proposed research focusses on upper respiratory tract (URT) deposition of reactive gases. Specifically, the research is aimed at providing detailed information on species differences in URT deposition of acetaldehyde, acrolein and nitrogen dioxide (NO2); at providing quantitative data on deposition of these gases at both high inspired concentrations, such as those used in inhalation toxicity testing, and also lower, more environmentally relevant concentrations; and at examining deposition in animals exposed to mixtures of these gases to determine if simultaneous exposure conditions such as those occurring in the environment, alter deposition patterns of these three reactive gases. In addition, these experiments will examine deposition under both unidirectional and cyclic flow conditions to determine if data obtained by commonly used unidirectional flow methodologies are reasonably predictive of events occurring under more physiologic, cyclic flow conditions. To meet these aims, deposition of acetaldehyde, acrolein and/or NO2 will be measured under constant velocity unidirectional and cyclic flow conditions in the surgically isolated URT of the anesthetized Sprague-Dawley rat, B6C3F1 mouse, Syrian hamster and Hartley guinea pig, four species commonly employed in inhalation toxicity testing. Measurements will be made in animals exposed to each gas individually and also in animals exposed to combinations of these gases. Inhalation dosimetric relationships are necessary for accurate hazard assessment, particularly for comparison of toxicity data among animal species, extrapolation of high dose (concentration) studies to low dose scenarios, and use of toxicity data derived from exposures to individual agents to predict toxicity in more complicated multi-toxicant exposure settings. By providing detailed dosimetric information on each of these areas of hazard assessment, the proposed research will, in the long-term, dramatically enhance our ability to understand and extrapolate toxicity data for reactive gases such as those used in this research. In addition, the proposed research is aimed at examination of a widely used but unvalidated mathematic mass-transfer model for URT reactive gas deposition. These modeling efforts will not only provide insights into critical factors controlling deposition mechanisms, but also may lead to the development of predictive models of URT deposition. Thus, the proposed research, by enhancing our ability to understand, extrapolate and predict URT dosimetric relationships for reactive gases, will significantly advance our knowledge in this important area of inhalation toxicology.