Morphometric studies in ozone-exposed animals indicate that ozone (O3) toxicity is focal in nature, causing an inflammatory response and epithelial cell injury which are more pronounced in the proximal alveolar region than in other airways. Mathematical stimulations indicate that the same airways are the site of maximum O3 dose to tissue. These findings suggest that the internal distribution of O3 dose is an important determinant in the lung response to O3 exposure. Using a newly-developed bolus-response method, one can noninvasively measure the fraction of inhaled O3 that is absorbed into intact human lungs during a single breath (f). Moreover, f can be determined as a function of longitudinal penetration from the airway opening (Vp). The long range-objectives of this research are: 1) to measure the O3 dose distribution, f(Vp), in different categories of human subjects under a variety of relevant breathing and pollutant exposure conditions; and (2) use these data as a foundation for building a computer model which gives fundamental insights into the diffusion and chemical reaction processes governing the uptake of O3 into lung tissue. During the four years of this research, bolus-response measurements will be performed on a group of healthy men and women in order to achieve the following specific aims: 1. Compare the distribution of O3 dose during nasal breathing and during oral breathing. The hypothesis being tested is that the nose is more effective in protecting the lower airways from O3 than is the mouth. 2. Carry out bolus-response tests at different combinations of inspiratory and expiratory flows. The hypothesis being tested is that the O3 dose distribution is more sensitive to inspiratory than the expiratory flow conditions. 3. Study changes in the O3 dose distribution during exposure to 0.12 ppm O3 or to low concentrations of two copollutants, nitrogen dioxide (NO2) and sulfur dioxide (SO2). The underlying hypotheses are that exposure to O3 and to NO2 cause a distal shift in O3 dose toward the small airways while SO2 exposure causes a proximal shift toward the large airways. 4) Develop a computer simulation of the O3 bolus-response method. Initially, this simulation will be based on a symmetric branching lung geometry with a uniform flow distribution. Modifications to the simulation, such as asymmetric branching, may later become necessary to provide an adequate fit to experimental measurements. 5) Use the simulation to estimate the values of fundamental physico- chemical parameters. Values of the mass transfer and dispersion coefficients in various lung regions will be evaluated as a function of inspiratory and expiratory flow and of pre-exposure conditions by simulating the data collected in aims 1 to 3.
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