Our study is in part consistent with the results of Jerrett and coworkers (13
) that longer-term exposure to ozone is associated with reduced survival. In addition, we have extended that finding in several ways. We find the ozone exposure in the transitional season exerts an independent effect on survival, controlling for summertime ozone. Importantly, we find this association with year-to-year variations in the exposure around its long-term trend within each city, demonstrating that year-to-year fluctuations, and not just very long-term exposures, can influence survival. We also found regional differences that were explained by mean temperature, likely reflecting the use of air conditioning, which reduces exposure.
A key feature of this study is the nature of the exposure contrast. City-specific regressions eliminated potential confounding by factors that vary across city, which is a common concern in most air pollution cohort studies. Rather, we examined whether within-city year-to-year fluctuations in ozone concentrations about their long-term trend were associated with within-city fluctuations of survival rates about their long-term trend. This study design avoids both confounding by cross-sectional factors that vary by city and the short-term factors that confound daily times series, but are not present in annual analyses. It also costs considerable amounts of power, because much of the exposure variation (short-term within city, and long-term across city) is thrown away. However, the large cohorts available using Medicare data allow such an approach. A key advantage is that fluctuations from summer to summer in ozone concentrations around the long-term level and trend in a specific city is unlikely to be correlated with most other predictors of mortality risk, except for temperature, which is controlled in the regression. For example, smoking rates may have fallen differently in different cities, but we cannot see a mechanism that would induce a correlation whereby year-to-year fluctuations around that trend in smoking would be correlated with year-to-year fluctuations in ozone around its trend. Some factors, such as unemployment rates, may fluctuate with emissions of air pollution. However, our cohorts are retired populations unlikely to be effected by unemployment, and ozone is a secondary pollutant whose concentrations vary with emissions in upwind communities, not the local one. However, a key limitation of our study was the inability to control for PM2.5, because it was not available in these cities until 1999. This may have resulted in confounding.
The study also differs from most other air pollution cohort studies in that the entire population over 65 was part of the initial sampling frame, rather than a convenience sample. This avoids selection bias, and confounding by possible selection of more or less healthy samples of the population in towns with more or less air pollution.
The finding of an inverted U-shaped relationship between the ozone effect in a city and its mean temperature, control for which renders regional differences insignificant, suggests that those regional differences are mostly related to temperature. The inverted U shape suggests that temperature is mostly capturing exposure differences. Effects are highest in mild temperatures, when windows are most likely to be open. Other possibilities for regional differences also exist, such as differences in medication, coexposures, and so forth. Future studies should address this issue.
This is the first study of longer-term exposure to ozone that focused on cohorts of susceptible subjects–persons with chronic conditions (specifically COPD, heart failure, diabetes, and MI) and as expected the hazard ratios were higher in these high-risk cohorts than in the American Cancer Society cohort. We should recognize, however, that there are differences between the exposure measures in the different studies. Time-series studies examine the more immediate risk on a high-pollution day. In contrast, long-term studies, such as Jerrett and coworkers (13
), should capture the integrated effects of these acute responses, the effects of semi-chronic effects (response to a high ozone summer), and the additional responses resulting from long-term exposure to ozone over years. Our study focuses on the semi-chronic effect. Hence, comparisons of effect sizes across such studies should recognize that they are examining different things (and in the case of our study, susceptible populations).
In this context, the risks of semi-chronic exposures in this cohort analysis were higher than in studies analyzing the acute effects of ozone on the risk of mortality. For example, in a previous study (11
) we reported a 0.32% increase in total mortality for 10 ppb of 8-hour average ozone, and the meta-analyses of Levy and coworkers (7
) and Ito and coworkers (8
) reported effect size estimates of 0.41% and 0.39% for a 10-ppb increase in maximum hourly ozone. This study report around a 7% (depending on the cohort) increase in mortality per 5 ppb (which is approximately the interquartile range) increase in summer average of 8-hour mean ozone.
Only one cohort study has investigated the effect of warm season average ozone on the risk of death in a large cohort (13
). The authors used data from the American Cancer Society Cancer Prevention Study II cohort and found a 1.1% increase in cardiovascular causes, a 1.5% increase in ischemic heart disease, and a 2.9% increase in respiratory causes, which increase when adjusting for PM2.5
. In that study, the authors investigated a younger population that was more educated and socially advantaged than the general population, which may account for some of the difference in effect size compared with our analysis of older, sicker subjects. They also found the effect primarily in respiratory deaths. Susceptibility alone cannot explain the difference. Given that respiratory deaths are a small fraction of all deaths, our results also suggest an effect of ozone on nonrespiratory deaths.
The biologic mechanism by which ozone can affect mortality is still under examination. A review of toxicologic studies found decreased heart rate, metabolism, blood pressure, and cardiac output when rats are exposed to typical concentrations of ozone (28
A study (22
) found a possible ongoing inflammatory response in the lungs of recreational joggers exposed to ozone and associated copollutants during the summer months. A previous paper (23
) showed that airway inflammation persists after repeated ozone exposure, despite attenuation of some inflammatory markers in bronchoalveolar lavage fluid and adaptation of lung function.
Long-term exposure to ozone was associated with reduced lung function in a study of freshmen at the University of California, Berkeley (24
). The associations were independent of any effects related to PM and NO2
. In the same cohort (26
) the effect of short- and long-term ozone exposures on biomarkers of oxidative stress were examined, and the authors found that estimated 2-week before, 1-month before, and lifetime O3
exposures of young healthy individuals were significantly and independently associated with increased 8-iso-prostaglandin F levels, while controlling for sex and ethnicity.
Another study (25
) examined the association between current respiratory health status and long-term ozone exposure histories in 520 Yale University students. The authors found that lung function was significantly lower in the group with high ozone exposures, and chronic phlegm wheeze and respiratory symptom index were increased in the ozone-exposed group. They conclude that living for 4 or more years in regions of the country with high levels of ozone is associated with diminished lung function and more frequent reports of respiratory symptoms. Ozone exposure has also been associated with reduced heart rate variability (27
Our study presents some major limitations. One is that Medicare does not provide the underlying cause of death. In addition, our definitions of persons with COPD are restrictive. Doubtless there are other persons in the 105 cities, who were covered by Medicare, who had the conditions we were interested in, and who were not included in the cohort either because they were not hospitalized for the condition or because it was misdiagnosed. Although this limits generalizability and moves our focus to a frailer subset of the persons with the conditions, it does not limit internal validity. The main limitation, however, is the absence of information on subject characteristics, such as smoking, body mass index, or medicine use. However, because of our study design, differences in these variables across cities, or long-term trends in smoking within city, cannot confound our estimates. In our model we controlled for all the available personal characteristics, such as age, race, sex, severity of the index admission, and detailed data on previous and secondary diagnosis. Moreover, we conducted a city-specific analysis to remove location-specific differences from the analyses, and removed long-term time trends. Hence, differences across cities in smoking rates cannot confound the association, and neither can long-term time trends in smoking rates within city.
Our findings suggest that long-term exposure to ozone elevates the risk of mortality in different subgroups of susceptible populations.