Ozone (O3) is an outdoor air pollutant that causes site-specific damage and remodeling of tissue along the? epithelial surface of the lungs. This project is based on the following interrelated hypotheses: the focal? nature of O3-induced tissue responses is directly related to the spatial distribution of O3and its reaction? products; and the distribution of O3 and its reaction products can be predicted from mathematical transport? models that incorporate information about airway anatomy and O3-substrate reactions in the epithelial lining? Fluid (ELF). The overarching objective of this work is to develop exposure-dose-response relationships in? the respiratory system of 1 month to 12 month old male rhesus monkeys and 1 week to adult Sprague-? Dawley rats. In terms of human development, a 6 month old rhesus monkey corresponds to a 1 or 2 year? old child. Therefore, the results of this study will lead to a better understanding of the effect that O3 has on? human children, and will improve our ability to extrapolate data from developing animal lungs to human? ungs. A second objective of this research is to compare the dose-response processes in the nasal cavities? to those occurring in the tracheo-bronchial tree. This will allow us to judge whether or not the nose can be? used as a sentinel of health effects in the lower respiratory tract.? The following specific aims are associated with this project:? 1) Develop computer reconstructions of the geometries along axial airway paths in monkey and rat lungs.? 2) Formulate models of O3 transport in ELF that incorporate O3 diffusion, substrate efflux and the production? of toxic substances by reactions between O3 and substrates.? 3) Continue development of axisymmetric single-path models that predict longitudinal dose distributions of? O3 and toxic products along axial airway paths in the developing rat and primate lungs.? 4) Continue the development of computational fluid dynamics models for simulating the threedimensional? dose distributions at selected sites such as the nasal cavities and airway bifurcations.? 5) Establish dose-response relationships for rats and for monkeys by correlating the predicted dose? distributions with the spatial occurrence of histochemical endpoints.? 6) Evaluate the utility of the exposure-dose-response paradigm in extrapolating O3 susceptibility across? species, airway sites and exposure patterns in animals at various stages of post-natal development.? The simulations of O3 distribution carried out in this project are central to the overall Program Objective to? understand the age, site, cell, and post-natal susceptibilities to O3 exposure pattern. This project will have? strong interactions with the other components of this Program-Project. Histochemical O3 and biochemical? data generated in Projects 1-3 will be crucial for estimating input parameters to the model simulations, for? validating models, and for developing dose-response relationships. The Biostatistics and Respiratory? Structure Core will provide geometric airway .reconstructions that are essential to the dosimetry simulations.? Core C will also assist in the statistical analyses of dose-response relationships and in the evaluation of? model precision.?
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