The aims of the proposed research are a) to improve understanding of absorption of vapors int he respiratory tract and b) to improve extrapolation of toxicological data from animals to prediction of effects in man. Inhalation toxicologists are often presented with conflicting data wherein an inhalant may produce toxic responses affecting different tissues in different animal species. Moreover, toxic responses may be affected in a complicated way be concentration of the toxicant and they may be altered by such modifying influences as co-administration of a second toxicant. Interpretation of the results of inhalation toxicology studies in animals, so that they can be extrapolated with confidence to man, requires knowledge of the many steps that may take place between inhalation of the parent substance and the occurrence of a toxic response. These steps include absorption, distribution and metabolism. The proposed research focuses on the absorptiona and fate of inhaled vapors. To understand how inhaled toxicants exert effects on various tissues in various animal species, it is necessary that we have detailed knowledge about where they are absorbed and where metabolized. The research in this application will determine how concentration and chemical properties of a vapor, presence of more than one vapor, and animal species differences combine to affect site of vapor uptake and appearance of toxic metabolites in the blood. In particular, the following five hypotheses, all of which appear to be tenable based on preliminary results, will be tested. 1. Within classes of compounds, rules based on chemical properties may be formulated to predict vapor uptake (exceptions to these rules may point to important unexpected factors affecting vapor uptake). 2. Nasal uptake of inhaled vapors is substantial and depends, in part, on susceptibility of the vapor to metabolism in the nasal cavity. 3. The appearance of toxic metabolites in the blood during inhalation of a vapor is, to an important extent, a result of respiratory tract metabolism and is influenced by air concentration of the inhaled vapor. 4. Fate of inhaled vapors is affected by the concentration of the inhaled vapor and also by the presence of other vapors. 5. There are major differences in site of uptake (i.e., nose or lungs) and in the fate of inhaled vapors among animal species.
