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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004422-02
Application #
3252572
Study Section
Toxicology Study Section (TOX)
Project Start
1987-08-01
Project End
1992-07-31
Budget Start
1988-08-01
Budget End
1989-07-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Lovelace Respiratory Research Institute
Department
Type
DUNS #
City
Albuquerque
State
NM
Country
United States
Zip Code
87108
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Dahl, A R; Gerde, P (1994) Uptake and metabolism of toxicants in the respiratory tract. Environ Health Perspect 102 Suppl 11:67-70
Dahl, A R; Lewis, J L (1993) Respiratory tract uptake of inhalants and metabolism of xenobiotics. Annu Rev Pharmacol Toxicol 33:383-407
Snipes, M B; Spoo, J W; Brookins, L K et al. (1991) A method for measuring nasal and lung uptake of inhaled vapor. Fundam Appl Toxicol 16:81-91
Maples, K R; Dahl, A R (1991) Blood levels of propylene oxide during propylene inhalation and effect on hepatic and nasal cytochrome P-450 concentrations. Drug Metab Dispos 19:835-7
Gerde, P; Dahl, A R (1991) A model for the uptake of inhaled vapors in the nose of the dog during cyclic breathing. Toxicol Appl Pharmacol 109:276-88
Dahl, A R; Snipes, M B; Gerde, P (1991) Sites for uptake of inhaled vapors in beagle dogs. Toxicol Appl Pharmacol 109:263-75
Dahl, A R (1990) Dose concepts for inhaled vapors and gases. Toxicol Appl Pharmacol 103:185-97