exposure error, epidemiologic designs and methods of analysis, measures of the effects of ozone exposure on death, and uncertainty contribute to our ability to estimate ozone-related mortality risk and to apply the estimates to risk and benefits analysis.

BIOLOGIC PLAUSIBILITY

The mechanisms by which ozone can damage health and possibly lead to mortality remain a subject of considerable clinical interest. Toxicologic studies have attempted to identify the mechanisms by using a variety of techniques, from ultrastructural, biochemical, and cytologic analyses to in vivo measurement of airflow mechanics. The techniques generally examine the effects of controlled ozone exposures of less than 8 h and, to a smaller extent, exposures of several days to increased ambient concentrations.

The findings of a number of toxicologic studies provide insights to suggest the potential for a number of events by which ozone exposure could lead to increased mortality, including lung inflammation leading to local pulmonary compromise (Devlin et al. 1991; Holz et al. 1999; Koren et al. 1991; Ratto et al. 2006; Bosson et al. 2007), worsening of pre-existing cardiopulmonary disease, systemic release of mediators that affect adverse cardiovascular events (Hollingsworth et al. 2007), effects on the autonomic nervous system that could contribute to increased airway responsiveness (Chen et al. 2003) or reduced heart rate variability, and an increase in factors that lead to vascular changes (Chuang et al. 2007). Definitive proof of such occurrences leading to mortality are not found in the current scientific literature, however, there is ample evidence ozone can induce mechanisms through a sequence of events to trigger oxidative stress or inflammation pathways, which can contribute to release of pulmonary or systemic mediators. The events may further result in the exacerbation of a pre-existing respiratory or cardiovascular condition. Chen et al. (2004) found increased sensitivity to aeroallergens in a subgroup of asthmatics following exposure to 200 ppb ozone. There exists the biological plausibility that for a few individuals with pre-existing cardiopulmonary or chronic respiratory disease, such oxidative or inflammatory events could also cause death, via the onset of an asthmatic attack (Selgrade et al. 2008), myocardial infarction, or vascular event. Inflammatory events have been shown to occur for 20-30 h after inhalation of ozone even at ambient concentrations in the range of 0.08-0.10 ppm (Ratto et al. 2006; Chuang et al. 2007). There is less information on the airway inflammatory response to ozone at low concentrations, such as at or below 0.08 ppm.

The oxidative stress and inflammation cascade is initiated by an ozone-mediated airway and lung tissue response (Chuang et al. 2007). Ozone can initiate the cascade immediately after inhalation when it comes in contact with epithelial lining fluids and cellular membranes, most often at nasal epithelial surfaces and at the junction of the bronchioles and the alveolar region (centriaci-



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