Air Pollution and Lung Function Growth
Is It Ozone?

	ARTICLE

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The effects on lung function of exposure to ambient air pollution have been the focus of a great deal of epidemiologic and experimental research, especially over the last two decades (1). The vast majority of epidemiologic and controlled exposure studies have investigated the effects of acute exposure on short-term responses for a variety of measures of lung function derived from forced expiratory maneuvers. Most of these studies find small effects of daily fluctuations of concentrations of ambient air pollutants on daily changes in lung function (1).

None of the studies of short-term lung function responses to ambient air pollution relate these short-term effects to the longer term consequences for lung function growth and decline. Long-term effects have been evaluated largely by cross-sectional comparisons of subjects who live in environments with varying profiles of ambient air pollution (2). These cross-sectional studies also have observed small effects on measures derived from forced expiratory maneuvers. Reduced levels of forced expiratory volume in 1 s (FEV₁) and forced vital capacity (FVC) in the range of 1.5-3.5% per unit area differences (unit differences vary between studies) have been reported for children (4, 5) and adults (6). Few truly longitudinal studies of the effects of long-term exposure have been undertaken (8, 9), and the data from them are insufficient to estimate what effects can be attributed to any individual component of the complex mixtures of ambient air pollutants. Thus, at present, we have a rather poor understanding of the effects of ambient air pollution exposure on the natural history of lung function growth and decline.

In this context, Frischer and colleagues present an interesting study that concludes that exposure to increasing levels of ambient ozone (O₃) is associated with reduced growth in FVC, FEV₁, and maximum expiratory flow at 50% of vital capacity (MEF₅₀) in children who were observed prospectively from age 8 to 11 yr (approximately) (10). Children from nine areas in Austria that did not contain major industrial sites were studied between January 1994 and December 1996. Maximum expiratory flow-volume (MEFV) curves were obtained between March and May and between September and November of each year (six measurements per child over 3 yr). Exposures to air pollution were derived from ambient monitors at each site and were defined as the average of all 0.5-h means for O₃, nitrogen dioxide (NO₂), and sulfur dioxide (SO₂) and the average of 14-d means for particulate matter ( 10 µm in aerodynamic diameter (PM₁₀, available for only 2¹/₃ yr) in the intervals between the MEFV measurements (summertime, June-September; wintertime, November-February). Standard respiratory history questionnaires were used, and children underwent skin prick testing. The annual average concentrations for NO₂, SO₂, and PM₁₀ were well below the U.S. Environmental Protection Agency (EPA) National Ambient Air Quality Standards (NAAQS). Data for O₃ were provided only as an annual mean, which conforms neither to the old (1 h) nor new (8 h) NAAQS standard. Maximum O₃ concentrations exceeded 60 ppb between 50 and 96 d over the 3 yr of the study (mean summertime peaks, 50 ppb; mean wintertime peaks, 34 ppb). Lung function growth was evaluated as the differences in each of the lung function measures between each two successive surveys.

Among the pollutants studied, mean of the 0.5-h O₃ had the most consistent negative effect on the growth of FVC, FEV₁, and MEF₅₀ after adjustment for sex, atopy, and passive exposure to tobacco smoke in analyses that combined the data across the 3 yr of the study (Table 5). There was little difference in the estimated effects of summertime and wintertime O₃ exposure. These O₃ effects were strengthened when the analyses were restricted to children who reported that they spent the entire summertime in their home area. Previous days' maximum 24-h O₃ concentration had an inconsistent effect on flow and volume measures over the six measurement cycles. There was no evidence of an enhanced negative O₃ effect in children who were defined as atopic (presence of at least one positive skin prick test) or in children who were reported to have been exposed to environmental tobacco smoke. The O₃ effects were not related to the reported asthma, the presence of an acute lower respiratory illness at the time of lung function testing, parental education, or various features of the statistical modeling. Over the 3-yr period, a 10-ppb difference in average O₃ exposure was associated with a predicted decrement of 2% for FVC. The authors do not provide estimated predicted decrements for FEV₁ or MEF₅₀; however, under the assumption of an average FEV₁/FVC ratio of 0.88 and FEF_25-75 between 2.3 and 2.6 L/s in this age range (11), decrements of 3.5 and 7.9-8.9% would be predicted for these measures by the Frischer data.

In contrast to the findings for O₃, the authors report that effects attributable to the other pollutants were less consistent (consistency defined as effects over all measures of function and throughout the year). Closer scrutiny suggests that the "consistency" criterion may have led to an oversimplification of the interpretation. Summertime SO₂, NO₂, and PM₁₀ all were associated with decreased growth of MEF₅₀. The authors note that the correlation data in their Table 3 do not fully reflect the correlations in the data that were used in the multivariable analyses. Moreover, these correlations span data over the entire study for all seasons. In a previous publication (12), the authors provide summertime air pollution data that show moderate positive correlations between O₃, and sulfate (SO₄) and PM₁₀ (no data for NO₂). These data indicate that it is not as easy to isolate the effects of ozone in the summertime as might be supposed by the data in Table 3. Moreover, the site of effect of NO₂ (13), like that of O₃, is the smaller airways (respiratory bronchioles), whose function is more likely to be reflected by changes in midexpiratory flows than by changes in FEV₁ or FVC (14). Environments characterized by elevated O₃ and sulfates also have been associated with decreased levels of MEF₅₀ (4), and PM₁₀ and PM_2.1 have been associated with declines in midexpiratory flows (5). Wintertime NO₂ was associated with decreased growth in all three measures derived from the MEFV curves (Table 5), whereas the results for PM₁₀ did not support the presence of an effect on growth of any of the measures of function. The correlations between PM₁₀ and NO₂ in Table 3 are only modest (0.37), but this can be related to limitations of the data as noted above. Data on seasonal patterns of pollution are not provided, but we can infer that PM₁₀ was increased in wintertime (0.28 correlation with temperature over the entire year). It also is quite likely that PM₁₀ and NO₂ are more highly correlated in the wintertime months than in summertime, because NO₂ concentrations can be expected to be elevated during wintertime as well (Figure 4 [15]). PM₁₀ data were available only on a 14-d basis for 2¹/₃ yr of the study compared with half-hourly data for NO₂ for the full 3 yr of the study. Therefore it is likely that the exposure estimates for PM₁₀ are far less precise (i.e., greater measurement error) than for NO₂. Consequently, it is not unreasonable to consider the associations between wintertime NO₂ and decreased lung function growth as a marker for the effects of wintertime air pollution, which presumably would include a particulate matter component. The wintertime effects on lung growth that are attributed to ozone are more difficult to explain. They also may reflect independent effects of ozone but also could represent a surrogate marker for a wintertime air pollution mixture. Ozone plays a primary role in the conversion of nitric oxide (NO) to NO₂ even during winter months (16). No two-pollutant models were investigated; therefore, any explanation for the association remains conjectural. Certainly, the goal of the Frischer study to identify the contribution of effects of individual air pollutants to health effects that are attributed to longer term exposures to increased levels of air pollutants is important. The feasibility of such an undertaking through epidemiologic studies remains a major research design challenge, given the complex makeup of ambient environments, changes over time in these environments, the difficulty in capturing long-term exposures for individuals, and the high likelihood of overlapping effects of various pollutants (e.g., NO₂, O₃, and transition metals found in PM all exerting oxidant effects, the former two at the same site in the respiratory tract).

There is strong evidence from controlled exposure studies (1, 17, 18) and animal studies (19, 20) to suggest that long-term exposure to ambient O₃ could result in sustained decrements in lung function, particularly measures that are related to small airways (20). Results from a pilot study of college freshman also would suggest that long-term O₃ exposrue has effects that are more consistent and pronounced for measures of small airway function than for FEV₁ or FVC (14). In the latter study, the O₃-associated small airway effects appeared to be independent of long-term exposure to PM₁₀ and NO₂; but these results must be interpreted with caution owing to the small sample in the study. The data from the Frischer study certainly add some additional support for an effect of ozone on measures of small airway function, given that the predicted O₂ effect on MEF₅₀ over 3 yr is nearly two to four times greater than for FEV₁ and FVC, respectively. (Strictly speaking, MEF₅₀ is not purely a measure of small airway function, but is more related to such than is FEV₁.) This result is all the more surprising, because the within-subject variance of midexpiratory flow is more than twice that for FEV₁ or FVC (21).

Perhaps the real importance of the Frischer data relates less to whether the effects that they have observed can be attributed exclusively (I contend that they cannot be so attributed on the basis of the data presented) or even primarily to O₃ exposure, and more to the fact that this study provides prospective evidence of an association between exposure to ambient air pollution and alterations in lung growth in children. Such data, although far from perfect, represent a substantial improvement over data derived from cross-sectional studies. In this context, it is reassuring (from the point of view of epidemiology) that their results are consistent with effect estimates derived from those cross-sectional studies of children for which air pollution-related effects on lung function measures have been observed. Stern and colleagues (4) reported regional differences of 1.7 and 1.3% for FVC and FEV₁ between two areas (one urban, one rural) of Canadia with relatively large differences in annual concentrations of O₃, SO₂, and SO₄ and somewhat smaller differences in PM₁₀. Percentage differences in MEF₅₀ of the magnitude suggested by the Frischer data were observed by Stern and coworkers in children with asthma between the two regions (4). Another cross-sectional study from 24 North American cities (5) estimated 2-3.5% reductions in a variety of measures of flow and volumes per unit changes in various measures of air pollution. The most consistent effect in this study were seen with measures of strongly acidic particles, i.e., SO₄ and PM_2.1. However, in this study volume-corrected measures of FEV₁ and FEF_25-75 were not related to air pollutants, which raises the question that most of the reductions observed in the flow measures were related primarily to volume effects (22).

There is less than universal consistency among cross-sectional epidemiologic studies as to whether long-term exposure to ambient air pollution has long-term effects on lung function in children (3). Cross-sectional studies are fraught with too many methodological problems and, largely, should be abandoned as a design strategy to study the problem addressed in the Frischer study. The approach taken by Frischer and co-workers offers a practical study design that should be emulated. Short-term prospective studies of young children and adolescents will help to develop a more substantive database through which more accurate estimates of effects of ambient air pollution on lung function growth (if, indeed, there are such effects) can be obtained. In light of the substantial body of data on the effects of short-term exposure to air pollutants on measures of lung function and respiratory health and the potential importance of levels and growth of lung function in childhood as a predictor of respiratory morbidity in adult life (23), it behooves us to have more studies of this type.

IRA B. TAGER

Division of Public Health Biology and Epidemiology

School of Public Health

University of California, Berkeley

Berkeley, California

	References

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