Long-Term Exposure to Ozone and Small Airways: A Large Impact?

Ozone is perhaps the best studied air pollutant in terms of acute respiratory effects, and review of recent evidence confirms that shortterm exposure is associated with acute decrements in lung function (1). In fact, the National Ambient Air Quality Standard for ozone promulgated by the U.S. Environmental Protection Agency is based primarily on evidence frommultiple controlled human-exposure studies conducted over the past several decades showing acute decrements in lung function (2). Multihour ozone concentrations of 80 ppb or higher consistently produce significant decreases in FEV1 and FVC in healthy adults that typically resolve within 24 hours (1, 2). Multiple epidemiological studies have also demonstrated acute decrements in spirometric lung function with real-world exposures during exercise (1–4). Despite the robust human experimental and epidemiological evidence of the acute effects of short-term ozone exposure on lung function, the evidence for chronic effects of longterm exposure to higher concentrations of ozone is relatively sparse and less clear. Such evidence by necessity must come from epidemiological studies. Perhaps the best study of chronic exposure to air pollution on growth of lung function, the Children’s Health Study conducted in southern California, revealed detrimental effects of annual average exposure to fine particulate matter (particulate matter <2.5 μm in aerodynamic diameter) and nitrogen dioxide but surprisingly not to ozone (5). In contrast, a similar longitudinal study of children in Mexico City did demonstrate a significant detrimental effect of chronic exposure to ozone on growth of lung function (6). Other more recent studies have shown adverse effects of long-term exposure to ozone on lung function in children (7, 8). Several studies in young adults have shown associations between lifetime cumulative exposure to ozone and decreased lung function parameters consistent with small airway obstruction. Two such studies involved college students in the United States, one involving Yale freshmen and 10-year average summer-season daily 1-hour maximum ozone concentrations in the region of their home residence (9) and the other involving University of California, Berkeley, freshmen from southern California (high ozone) and northern California (low ozone) (10). Both of these studies revealed an association with living in higher ozone regions before enrollment at students’ respective schools and reduced lung function, including forced expiratory flow at 25–75% of FVC (FEF25–75) and FEF at 75% of FVC (FEF75). Until recently, very few data were available on the potential effects of long-term ozone exposure on lung function in older adults. In this issue of the Journal, Niu and colleagues (pp. 450–458) report the results of one of the first studies to specifically address this data gap (11). This study from China has several strengths, including a sample size of more than 50,000 adults older than 20 years, reasonable ozone exposure assessment at the residential level, adjustment for coexposure to particulate matter <2.5 μm in aerodynamic diameter (PM2.5) and other covariates, good-quality spirometry enabling assessment of parameters associated with small airway obstruction, and appropriate sensitivity analyses, including adjustment for short-term exposure to ozone. The primary finding of interest is the association of the seasonal average residential ozone concentration of the previous warm season (May to October) and “small airway dysfunction,” defined as decreased values of two of the three parameters FEF50, FEF75, and FEF25–75. This finding is consistent with the results of the two U.S. college freshmen studies described above. Niu and colleagues’ study is not without limitations. First and foremost, like the U.S. college freshmen studies, it used a crosssectional design that limits causal inference. The authors of the present study indicate that they will be following the study cohort in the future, and the results of a longitudinal analysis of ozone exposure on change in lung function will be of considerable interest. In addition, like most studies of air pollution health effects that rely on outdoor air concentrations, either measured or modeled, there is likely exposure misclassification given variable time study participants spend outdoors. That said, the exposure measurement error in Niu and colleagues’ study is likely nondifferential and thus may bias the results toward the null. An interesting secondary finding of Niu and colleagues’ study is an enhanced effect of long-term ozone exposure on small airway obstruction among participants with chronic obstructive pulmonary disease. This finding is somewhat consistent with the results of a reasonably large cohort study conducted between 2000 and 2018 in six U.S. metropolitan regions showing that long-term exposure to ambient ozone was significantly associated with both increasing emphysema assessed quantitatively using computed tomography imaging and decreased FEV1 (12). In terms of biological plausibility, long-term exposure of infant rhesus monkeys to ozone has been shown to cause structural changes in small airway and lung development (13). Compared with control infants, ozone-exposed animals had fewer nonalveolarized airway generations, hyperplastic bronchiolar epithelium, and altered smooth muscle bundle orientation in terminal and respiratory bronchioles. The results of this rhesus monkey study support the findings of the U.S. college freshmen studies showing an association between long-term ozone exposure and spirometric parameters consistent with small airway obstruction in young adults. The results of Niu and colleagues’ study suggest that these small airway effects persist later in adulthood. The clinical impact of these effects is not entirely clear, but the effect modification observed in individuals with chronic obstructive pulmonary disease may be an indicator of greater risk among those with preexisting respiratory conditions, consistent with recent evidence that small airway obstruction is a predictor of accelerated decline in FEV1 (14). This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please contact Diane Gern (dgern@thoracic.org).