Developing a Method to Construct Dose-Response Curves for Rats Chronically Exposed to Ozone. J. H. Overton, US Environmental Protection Agency
Whether long-term exposure of humans to ozone can lead to chronic lung disease is unknown. Experimental data from rats chronically exposed to ozone are being used in conjunction with a dosimetry model to develop dose-response curves to estimate chronic effects in humans. This presentation focuses on the rat dose-response development. In each airway of the dosimetry model, ozone transport is approximated by a one-dimensional convection-dispersion equation that accounts for inhalation and exhalation, expansion and contraction, convection, dispersion, molecular diffusion, and absorption at the air-liquid lining surface. The tracheobronchial region of the rat respiratory tract (RT) model is based on cast data and explicitly accounts for the branching nature of this region. Distal to each terminal bronchiole is a single-path representation of an acinus. Experimental data are based on reported studies of the proximal alveolar region of rats exposed to ozone for up to 87 weeks. These studies also reported the approximate RT location of the effects. Given the anatomical model, effects and predicted doses can be linked by their equivalent location, reducing uncertainty in associating specific doses with specific effects. Several issues affect development of the dose-response curve(s). (1) For dose response-curves, the choice of responses will be based on measured morphological variables that are associated with lung diseases. (2) Simulations are not feasible for long experimental exposures times during which ventilation and RT size change. The effect of this on dosimetry will be investigated by simulating changes over shorter times and developing a procedure to extrapolate to longer times. (3) To increase certainty in the values of mass transfer coefficients, the relation between predicted dose, effect(s), location, exposure concentration, and hypothetical dose-response curves will be explored. Once these issues are addressed, rat dose-response curves can be developed. This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.
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