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4 Contributions of Relevant Health Studies to the Estimation of Reductions in Premature Mortality
Pages 75-127

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From page 75...
... had not included mortality results in it primary estimates of the benefits of reductions in acute exposure to ambient ozone, because of uncertainty about the appropriate interpretation of those results. Previously, EPA had included epidemiologic studies that link ambient ozone concentrations with premature deaths in sensitivity analyses.
From page 76...
... 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.
From page 77...
... With oxygen species and reactive oxygen metabolites generated by exposure, those products of ozone exposure may lead to oxidative stress and the upregulation of transcription factors, such as NF-κB and proinflammatory genes. Correspondingly, antioxidant enzymes (such as glutathione enzymes, superoxide dismutase, and catalase)
From page 78...
... OZONE-MORTALITY STUDIES Given the evidence from toxicologic studies, it is biologically plausible that ozone exposures are also related to death in human populations.
From page 79...
... Those studies examined ozone-mediated mortality while addressing previously unresolved issues related to confounding, exposure variability, and model specifications. Although the studies used different approaches, their major results were similar: each found a statistically significant relationship between ozone exposure and premature mortality that appears robust after controlling for exposure to particulate matter with a diameter of 10 µm or less (PM10)
From page 80...
... Furthermore, the time-series model can include factors that explain differences in effect estimates among the cities, such as re gion, housing characteristics, and measurement method. Meta-analysis is a statistical technique used to aggregate, summa rize, and review previous quantitative research.
From page 81...
... In several locations, ozone was measured only during the peak ozone season, April-October. A two-stage statistical model was used to estimate a national average association between short-term ambient ozone concentrations and mortality risks, accounting for weather, seasonality, long-term trends, and PM10.
From page 82...
... a Range of risk estimates without confidence intervals.
From page 83...
... The mortality effect of a single day of ozone exposure appeared to be distributed over several days. The study further suggested that ozone-mortality effects can be calculated separately from PM-mortality effects because ozone risk estimates were robust to adjustment for PM10.
From page 84...
... Cardiovascular and respiratory mortality Lag time days in days 0, 1, 2, 3, up to a week Adjustment for temperature Yes Yes Adjustment for humidity No No Adjustment for season Yes Yes Consideration of age strata Yes Yes Adjustment for PM10 Yes Yes Adjustment for PM2.5 Yes Yes Adjustment for other No No pollutants RESULTS Non-injury-related 0.39% (95% posterior 1.0% (0 .55-1.40%) with 0-, mortality (per 10-ppb interval, 0.13-0.65%)
From page 85...
... The corresponding figures for 8-h ozone levels were similar. Meta-analyses Three meta-analyses were carried out to obtain a summary or composite estimate of ozone-associated mortality risks while explaining observed heterogeneity in risk estimates.
From page 86...
... 86 TABLE 4-3 Summary of Meta-analyses % Change in Daily Mortality Number of Adjustment per 10 ppb Studies Study Season of Exposure for Other change in ozone Reference (or Cities) Areaa Period Study Metric Lag (d)
From page 87...
... Ito et al. 43 Inter 1990-2003 Year round 24-h average Up to 3 NA All causes, 0.80 2005 non-accidental (0.6-1.0)
From page 88...
... The meta-analysis found a significant overall 0.41% (95% CI, 0.32-0.52%) increase in daily mortality per 10-ppb increase in 1-h maximum ozone concentrations; results in North American and European cities were similar.
From page 89...
... The statistical association was robust to the type of adjustment made for PM, weather, and seasonality. When PM10 or PM2.5 was included in the model, for example, effect estimates for ozone-mediated total mortality were similar, albeit insignificant, at 0.97% (95% PI, 0.03-1.98%)
From page 90...
... Moreover, inasmuch as the meta-analyses are based on individual study results rather than uniform analysis of the "raw" data from each city, it is possible that meta-analyses preferentially included the most significant results (obtained with different ozone exposure matrices and statistical models) , and this, too, would result in higher effect estimates.
From page 91...
... Furthermore, ozone mortality effects were greater after same-day than after previous-day exposures in Levy et al.
From page 92...
... Cohort studies use variation in ambient air-pollution concentrations over space to create contrasts in personal exposure, whereas time-series studies use variation in time. Chronic Ozone Exposure and Life Expectancy Several air-pollution cohort studies have been published in North America and Europe.
From page 93...
... Those few cohort studies have not demonstrated a clear positive association between long-term average ozone concentrations and cardiopulmonary mortality after controlling for PM2.5 A persistent problem in the analyses of long-term associations between ambient ozone and health is the characterization of exposure. Factors such as correlations with copollutants, the far lower concentrations of ozone indoors than outdoors, the relevance of ventilation rates, and the influence of timeactivity patterns -- hamper characterization of the effects of long-term exposure to ozone.
From page 94...
... Interpretation of findings of effects of chronic ozone exposure on mortality is complicated by an unexplained inconsistency reported in the CHS, the largest study, with 8 y of annual followup already published. At the beginning of the cohort study, elementary-school children's lung function correlated with the long-term mean of the 1-h maximum ozone across 12 communities (Peters et al.
From page 95...
... Recent studies had insufficient ranges of ambient ozone concentrations or did not use ambient ozone data at all. In a study conducted more then 20 y ago in the Los Angeles area, both lung function and its decline correlated with oxidant pollutants (Detels et al.
From page 96...
... However, chronic subclinical systemic inflammation due to ozone may well contribute to damages in the lung or the vascular system of the lung, resulting in lower lung function, which is a typical feature of many chronic inflammatory diseases. Thus, the indirect argument for coherence linking chronic effects on lung function with long-term effects on life expectancy has some appeal despite not being stringent proof.
From page 97...
... A normal physiologic aspect of growth and aging is a predictable increase followed by a decline in lung function. In laboratory-based studies designed to evaluate age as an important variable in response to ozone exposure, two investigations (Drechsler-Parks et al.
From page 98...
... to ozone in the elderly but a larger response in female subjects than in males. In both studies, the effective ozone exposure dose (the product of concentration, duration of exposure, and minute ventilation)
From page 99...
... . The preliminary findings of mortality studies are supported by ozone studies that used outcomes other than death, such as those reporting an increase in asthma hospitalizations during days with high ozone concentrations.
From page 100...
... (2003) observed that among GSTM1 null children with high ozone exposure in Mexico City the children who were NQO1ser187ser homozygotes appeared to be protected from the development of asthma compared with NQO1pro187pro homozygotes.
From page 101...
... reported that susceptibility factors had a larger effect in cities with lower ozone concentrations. For instance, the additional increase in ozone-related mortality for the elderly was 1.48% (0.81, 2.15)
From page 102...
... might put a person in the pool of those susceptible to death from ozone exposure, if the person survives and recovers the frailty would be decreased. Although susceptibility factors certainly matter, the distribution of the ozone-mortality effect estimates across the categories of susceptibility is not known; that is, the quantitative details of the heterogeneity of effects are not readily available.
From page 103...
... are attributed primarily to people's spending most of their time indoors, where ozone concentrations tend to be low and uncorrelated with outdoor concentrations. For ozone-mortality studies, which are time-series and case-crossover in design, the use of 24-h ambient concentrations to estimate exposures will result in reduced power to examine associations between ozone exposure and mortality (Carroll et al.
From page 104...
... People are outdoors primarily when maximum 1-h and 8-h ozone concentrations occur in the afternoon, so it is possible that ozone-mortality studies are reflecting maximum ozone exposures averaged over 1 h or 8 h rather than the daily ambient ozone concentration. Given the high correlation between these ambient short-term concentrations and the 24-h mean associations, use of the 24-h concentrations in time-series studies may serve as an equally good proxy for peak exposures.
From page 105...
... Implications of these findings to other ozone mortality studies are not known. At a minimum, the observed large impact of model choices on ozone mortality risk estimates suggests that control for weather is an important source of uncertainty in ozone mortality risk estimates.
From page 106...
... Using this approach, Schwartz showed a significant overall effect of ambient ozone on mortality that was greater in warm as compared to cold seasons, with these effects relatively unchanged when control days were matched on temperature. Similar effects when control days were matched or unmatched on temperature suggest that observed ozone mortality effects are not due to confounding by weather.
From page 107...
... Despite this, 24-h personal ozone exposures have been shown to be poorly correlated with corresponding personal PM2.5 exposures, suggesting that if ozone mortality studies were to include more direct measures of ozone and PM2.5 exposures, issues related to confounding of ozone mortality effects by PM2.5 may be better resolved -- at least for the assessment of daily exposure periods. For shorter exposure averaging periods, confounding of ozone mortality effects by PM2.5 may still be possible, as 1-h personal ozone and PM2.5 exposures were strongly correlated in one study when the technician was outdoors and away from roads (Chang et al.
From page 108...
... . The pulmonary inflammation and increased epithelial permeability that follow ozone exposure may also lead to increased transepithelial transport of deposited particles, which may increase the risk of PM-related systemic effects.
From page 109...
... Three methods were considered to examine the shape of the concentrationresponse function: restricting ozone concentrations below specified values, postulating a threshold function with no risk below the threshold and a linear association above it, and a natural spline formulation of association. A positive association between ambient daily average ozone concentrations and mortality was observed down to 15 ppb for the restriction and spline approaches, and the threshold model could not show any substantial improvement in statistical fit down to concentrations of 5 ppb, the lowest value examined.
From page 110...
... If there is a threshold, it is probably at a concentration below the current ambient air quality standards. Short-Term Mortality Displacement Investigations of acute effects of pollution assess the association between the daily number of events and ambient air quality during the period shortly before death.
From page 111...
... . Questions remain about the methods and assessment of mortality displacement, and the time lost because of acute effects of ambient PM cannot be quantified, but the 3 The term harvesting is sometimes used instead of short-term mortality displacement to refer to the concept that air pollution leads to the death of people who are highly susceptible and near death (and die a few days earlier than they would have without airpollution exposure)
From page 112...
... During an exacerbation of COPD due to, for example, a pneumonia, the patient may be particularly frail during the critical phase of the pneumonia (typically at the end of the first week) and have a transient inability to deal with the additional stress of increased ozone exposure.
From page 113...
... The 20-d distributed-lag effect of ozone on mortality was at most some 60% larger than the immediate lag-0 effect -- a substantially smaller difference than that reported for PM. There is a need for further investigations of short-term mortality displacement and the distribution of lagged subacute effects of ozone, but one can conclude, on the basis of the preliminary analyses and on conceptual grounds, that acute effects of ozone based on the published meta-analytic slopes underestimate to some degree the total acute and subacute effects.
From page 114...
... That "population mean" approach, however, does not reflect the distribution of the amount of time lost because of the deaths that occur as a consequence of increased ozone concentrations or the distribution of pre-existing frailty among those affected. These issues highlight the difficulties in translating the time-series findings into an estimate of life time lost.
From page 115...
... Uncertainty is also associated with ozone concentrations and with the reliability of ambient ozone-monitoring data to indicate ozone exposure. As stated above, the formal approaches to uncertainty analysis in mortality models include Bayesian analysis and Monte Carlo analysis.
From page 116...
... The experts and the rationales and empirical bases of their judgments should be made known. It is important to distinguish between uncertainty due to projecting the future and uncertainty inherent in estimating mortality on the basis of information on the magnitude of ozone exposure, which varies across space and time and among individuals.
From page 117...
... As a result of their own uncertainties, the models will add more uncertainty to the ozone-mortality risk-assessment estimates if they are used to characterize ozone exposures in future studies. Evaluation of these models and their uncertainties can help to quantify and characterize the magnitude of errors in the models.
From page 118...
... . That is, the risk estimates from time-series studies can be used to estimate the life years lost because of acute effects of pollution in the same way that risk estimates from cohort studies are used to derive the time lost because of the chronic, if not total, effects of pollution.
From page 119...
... Risks based on cohort studies are some 10 times larger than those based on acute-effects studies that investigated only the influence of yesterday's concentrations of PM2.5 on today's death rates and some 3-5 times larger than the total acute effects, including death, distributed over several weeks. More recent risk assessments provided separate estimates of acute effects that occur within a few days of exposure and total effects.
From page 120...
... That approach has several limitations that are of concern particularly for chronic effects but conceptually also apply to acute effects, as is the case for the acute effects of ozone on death. Although it is true that pollution increases the mortality risk and thus the number of deaths, one has to emphasize that death is inevitable and that improvement in air quality only postpones death and does not prevent it.
From page 121...
... CONCLUSIONS AND RECOMMENDATIONS Overall Conclusions and Recommendations Human chamber and toxicologic studies have yielded strong evidence indicating that short-term exposure to ozone can exacerbate lung conditions, causing illness and hospitalization, and potentially lead to death. Although it is less abundant, the available evidence on ozone exposure and exacerbation of heart conditions points to another area of concern.
From page 122...
... Emphasis should also be placed on risk estimates obtained from analyzing data on multiple days so as to include delayed acute effects. Such health-benefits estimates should be accompanied by a broad array of analyses of uncertainty, while at the same time understanding that a zero value is highly unlikely.
From page 123...
... Thus, the committee could not conclude at this time that exposure to long term ozone concentrations is related to mortality. Although the associations in the recent time-series studies appear sufficiently robust to provide a basis for estimating benefits, several factors need to be considered in interpretation: • The committee found that short-term ozone exposure is likely to contribute to premature mortality in addition to the risks posed by weather and PM, but studies have not been sufficient to control fully for potential confounding by or interactions with condensed-phase constituents of airborne PM, such as sulfates, acids, carbon, and other elements.
From page 124...
... Conclusion: Although the committee found that short-term ozone exposure is likely to contribute to premature mortality, the optimal way to quantify the effect is unavailable. The method that EPA uses now is appropriate only in very restricted situations that are not likely to be realistic.
From page 125...
... Recommendation: EPA and the scientific community should further explore how individual thresholds may vary and the extent to which thresholds depend on the frailty of the individual at any given moment. The research should involve panel studies of individuals considered to be susceptible to premature death from ozone exposure, such as those with impaired lung function.
From page 126...
... how these seasonal risk differences vary spatially between communities with warmer and cooler winters, and (3) ozone-mortality relationships at lower ozone concentrations.
From page 127...
... However, the uncertainty associated with the models needs to be carefully considered before inferences are drawn from the simulation models for mortality risk assessment.


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