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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003676-08
Application #
2153386
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1985-03-01
Project End
1997-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
8
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
06269
Morris, J B (1999) A method for measuring upper respiratory tract vapor uptake and its applicability to quantitative inhalation risk assessment. Inhal Toxicol 11:943-65
Stanek, J J; Morris, J B (1999) The effect of inhibition of aldehyde dehydrogenase on nasal uptake of inspired acetaldehyde. Toxicol Sci 49:225-31
Morris, J B; Stanek, J; Gianutsos, G (1999) Sensory nerve-mediated immediate nasal responses to inspired acrolein. J Appl Physiol 87:1877-86
Morris, J B (1997) Uptake of acetaldehyde vapor and aldehyde dehydrogenase levels in the upper respiratory tracts of the mouse, rat, hamster, and guinea pig. Fundam Appl Toxicol 35:91-100
Morris, J B (1997) Dosimetry, toxicity and carcinogenicity of inspired acetaldehyde in the rat. Mutat Res 380:113-24
Morris, J B; Blanchard, K T (1992) Upper respiratory tract deposition of inspired acetaldehyde. Toxicol Appl Pharmacol 114:140-6
Morris, J B (1991) Deposition of acetone vapor in the upper respiratory tract of the B6C3F1 mouse. Toxicol Lett 56:187-96
Morris, J B; Clay, R J; Trela, B A et al. (1991) Deposition of dibasic esters in the upper respiratory tract of the male and female Sprague-Dawley rat. Toxicol Appl Pharmacol 108:538-46
Morris, J B (1990) First-pass metabolism of inspired ethyl acetate in the upper respiratory tracts of the F344 rat and Syrian hamster. Toxicol Appl Pharmacol 102:331-45
Cavanagh, D G; Morris, J B (1987) Mucus protection and airway peroxidation following nitrogen dioxide exposure in the rat. J Toxicol Environ Health 22:313-28

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