(See Neas et al., p. 629; Lee and Schwartz, p. 633; and Fairley, p. 637)
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In this issue of Environmental Health Perspectives there are papers by Fairley, Neas et al., and Lee and Schwartz. Although these papers present different approaches, they provide a reasonable representation of state-of-the-art epidemiologic research that evaluates daily changes in mortality and air pollution. The authors of these papers include investigators who have been primary contributors to the development of this research.
The earliest and most methodologically simple studies that evaluated day-to-day changes in mortality associated with air pollution were studies that focused on severe air pollution episodes. These studies simply compared death counts for several days or weeks before, during, and after pollution episodes. Substantially elevated cardiopulmonary mortality associated with severe air pollution episodes in Meuse Valley, Belgium, in 1930 (1); Donora, Pennsylvania, in 1948 (2); and London, England, in 1952 (3) clearly demonstrated a link between mortality and extremely elevated concentrations of particulate and/or sulfur oxide air pollution.
In the 1970s and 1980s, a few studies were reported that involved collecting daily mortality and pollution data from a single city or community for several years and analyzing correlations in the data (4). Such an approach did not require extreme pollution episodes and did allow for evaluation of potential mortality effects of relatively low, more common levels of pollution. Correlations between daily mortality and air pollution were observed, but these studies suffered from very limited pollution data and somewhat inadequate statistical methods. In the early 1990s, Fairley (5), Schwartz and Dockery (6-8), and a few other researchers (9,10) reported the results of several daily time-series mortality studies using more advanced, uniform, and rigorous statistical modeling techniques. The primary statistical approach was formal time-series modeling of count data using Poisson regression. These studies indicated a link between daily mortality counts and particulate air pollution, even at pollution levels well below prevailing ambient air quality standards.
There were several questions and concerns that reflected legitimate skepticism about the inherent limitations of these studies: a) Could the results be replicated? b) Were the observed air pollution/mortality associations due to biased analytic approaches or statistical modeling techniques? c) Were these associations due to confounding because of inadequate control of long-term time trends, seasonality, weather, or some other pollutant? d) Were these associations biologically significant or plausible? e) Could nonspurious air pollution-mortality associations really be observed at pollution levels well below U.S. ambient air quality standards? f ) Is there a threshold level of air pollution below which there are no health effects?
Subsequent research efforts, including the three mortality and air pollution papers in this issue, have at least partially addressed some of the above questions and concerns. The results have been largely replicated by other researchers (11), and more importantly, similar associations have been observed in many other cities with very different climates, weather conditions, and pollution mixes, as discussed in numerous recent reviews (4,12-17). Furthermore, increasingly rigorous and sophisticated statistical time-series modeling techniques have also been used to try to better control for potential confounders. For example, generalized additive models (GAM) that use nonparametric smoothing have allowed for highly flexible fitting of seasonality and long-term time trends as well as nonlinear associations with weather variables such as temperature and humidity (18-20). These nonparametric smoothing approaches have allowed for modeling flexible nonlinear exposure-response relationships with air pollution to explore for a no-effects threshold. A well-defined threshold has not been consistently observed. The exposure-response relationship between particulate air pollution and mortality has generally been near linear. Synoptic weather modeling has also been used in some of the studies (20,21). The air pollution effects generally persisted after controlling for weather by either nonparametric smooths of temperature and humidity or controlling for synoptic weather patterns.
Fairley's original analysis (5) of the Santa Clara, California, data reported in 1990 was one of the early works using daily time-series Poisson regression to analyze daily mortality counts and air pollution. His analysis of more recent data from the same metropolitan area, reported in this issue, takes advantage of many of the more recent advances in time-series modeling techniques. The results are similar to his original findings.
The two case-crossover studies by Neas et al. and Lee and Schwartz, reported in this issue, provide an interesting alternative approach to analyzing mortality effects of short-term exposure to air pollution. Rather than using time-series analysis to evaluate associations between daily death counts and air pollution, these two studies use a clever adaptation of the common case-control design. Both papers describe this approach in some detail. Basically, this approach matches exposures at the period of time of death (case period) with one or more periods when the death did not occur (control periods) and evaluates potential excess risk using conditional logistic regression. Deceased individuals essentially serve as their own controls. By choosing control periods on the same day of the week and within 1-3 weeks of death, this approach restructures the analysis such that day of week, seasonality, long-term time trends, and changes in population size and composition are dealt with by design rather than by statistical modeling. Because this approach focuses on individual deaths rather than death counts, there are more opportunities to evaluate factors that may modify or influence the mortality effects of air pollution.
The case-crossover approach has some drawbacks. The results can be sensitive to the selection of control periods, especially when clear time trends exist. Neas et al. and Lee and Schwartz suggest choosing symmetric control periods both before and after the date of death. Using a control period following the time of death, however, is somewhat conceptually unappealing. Also, the case-crossover approach has lower statistical power due largely to the loss of information from control periods that cannot be included in the analysis.
Although the three mortality and air pollution studies in this issue of EHP contribute to the many previous studies that have evaluated day-to-day changes in mortality associated with air pollution, they do not provide substantial information on the specific pollutant or mix of pollutants responsible for the observed mortality effects or biological plausibility. For example, in the Santa Clara analysis, Fairley evaluated a wide range of air pollutants and found the strongest mortality associations with particles, especially fine particles (
2.5 µm in aerodynamic diameter; PM2.5) including ammonium nitrate particles. In Philadelphia, Pennsylvania, only total suspended particulates (TSP) were analyzed by Neas et al. Lee and Schwartz analyzed TSP, SO2, and O3 in Seoul, Korea, and mortality was most consistently associated with SO2. The authors suggested that SO2 may be acting as the better indicator of fine particles in Seoul. Recent reviews (4,12-17) of the overall epidemiologic evidence support a probable link between fine combustion-related particulate air pollution and cardiopulmonary disease and mortality. Also, several recent studies have reported that chronic long-term exposure to inhalable or fine particulate pollution is associated with an elevated risk of mortality (22-25). Nevertheless, there is remaining uncertainty about the role of chemistry versus size of the particles and the role of co-pollutants including O3, CO, SO2, NO2, and others.
There is also substantial uncertainty with regard to the biologic plausibility of these associations. Biologic plausibility is enhanced by the observation of a coherent cascade of cardiopulmonary health effects and by the fact that noncardiopulmonary health end points are not typically associated with the air pollution. An overall review of the literature (4,12-17) reveals that a remarkable cascade of cardiopulmonary health end points has been observed to be associated with day-to-day changes in particulate air pollution. In addition to cardiopulmonary mortality, particulate air pollution has been associated with emergency room and physician's office visits for asthma and other respiratory disorders, hospital admissions for cardiopulmonary disease, increased reported respiratory symptoms, and decreased lung function. Recently, there have been studies that have attempted to look at specific physiologic end points, in addition to lung function, such as plasma viscosity (26), hypoxemia and heart rate (27), heart rate variability (28,29), and acute inflammatory responses (30-31). However, more research on the pathophysiologic pathway linking cardiopulmonary mortality and particulate air pollution clearly should be conducted.
It is not clear that the case-crossover design is necessarily superior or inferior to the various advanced time-series approaches, but it is an interesting and clever alternative approach. What does appear clear is that the various reasonable approaches and methods provide similar results, contributing further evidence that the associations between daily mortality and ambient air pollution are relatively robust and are probably not due to methodologic bias or confounding by day of week, seasonality, long-term time trends, or weather variables. A better understanding of the specific pollutants or mix of pollutants responsible for the adverse health effects and a better understanding of the biological mechanisms involved are needed.
C. Arden Pope III
Brigham Young University
Provo, Utah
cap3@email.byu.edu
References and Notes
1. Firket J. The cause of the symptoms found in the Meuse Valley during the fog of December, 1930. Bull Acad R Med Belg 11:683-741 (1931).
2. Ciocco A, Thompson DJ. A follow-up of Donora ten years after: methodology and findings. Am J Public Health 51:155-164 (1961).
3. Logan WPD, Glasg MD. Mortality in London fog incident, 1952. Lancet 1:336-338 (1953).
4. Pope CA III, Dockery DW. Epidemiology of particle effects. In: Air Pollution and Health. (Holgate ST, Samet JM, Koren JH, Maynard RL, eds). New York:Academic Press, 1999.
5. Fairley D. The relationship of daily mortality to suspended particulates in Santa Clara County, 1980-1986. Environ Health Perspect 89:159-168 (1990).
6. Dockery DW, Schwartz J, Spengler JD. Air pollution and daily mortality: associations with particulates and acid aerosols. Environ Res 59:362-373 (1992).
7. Schwartz J, Dockery DW. Particulate air pollution and daily mortality in Steubenville, Ohio. Am J Epidemiol 135:12-19 (1992).
8. Schwartz J, Dockery DW. Increased mortality in Philadelphia associated with daily air pollution concentrations. Am Rev Respir Dis 145:600-604 (1992).
9. Kinney PL, Ozkaynak H. Association of daily mortality and air pollution in Los Angeles County. Environ Res 54:99-120 (1991).
10. Pope CA III, Schwartz J, Ransom MR. Daily mortality and PM10 pollution in Utah Valley. Arch Environ Health 47:211-217 (1992).
11. Samet JM, Zeger SL, Berhane K. The association of mortality and particulate air pollution. In: Particulate Air Pollution and Daily Mortality: Replication and Validation of Selected Studies. The Phase I Report of the Particle Epidemiology Evaluation Project. Cambridge, MA:Health Effects Institute, 1995.
12. U.S.EPA. Air Quality Criteria for Particulate Matter. EPA/600/P-95/001cf. Washington, DC:U.S.Environmental Protection Agency, 1996.
13. Vedal S. Ambient particles and health: lines that divide. J Air Waste Manag Assoc 47:551-581 (1997).
14. Committee of the Environmental and Occupational Health Assembly of the American Thoracic Society (CEOHA-ATS). Health effects of outdoor air pollution. Am J Respir Crit Care Med 153:3-50 (1996).
15. Brunekreef B, Dockery DW, Krzyzanowski M. Epidemiologic studies on short-term effects of low levels of major ambient air pollution components. Environ Health Perspect 103(suppl 2):3-13 (1995).
16. CEPA/FPAC Working Group on Air Quality Objectives and Guidelines. National Ambient Air Quality Objectives for Particulate Matter. Cat. No. H46-2/98-220. Ottawa, Ontario, Canada:Minister, Public Works and Government Services, 1998.
17. WHO-EURO. Update and Revision of the Air Quality Guidelines for Europe. EUR/ICP/EHAZ 94 05/PB01. Copenhagen:World Health Organization-European Region, 1995.
18. Schwartz J. Air pollution and daily mortality in Birmingham, Alabama. Am J Epidemiol 137:1136-1147 (1993).
19. Pope CA III, Schwartz J. Time series for the analysis of pulmonary health data. Am J Respir Crit Care Med 154:S229-S233 (1996).
20. Pope CA III, Kalkstein LS. Synoptic weather modeling and estimates of the exposure-response relationship between daily mortality and particulate air pollution. Environ Health Perspect 104:414-420 (1996).
21. Samet JM, Zeger SL, Kelsall JE, Xu J, Kalkstein LS. Does weather confound or modify the association of particulate air pollution with mortality? An analysis of the Philadelphia data 1973-1980. Environ Res 77:9-19 (1998).
22. Abbey DE, Nishino N, McDonnell WF, Burchette RJ, Knutsen SF, Beeson WL, Yang JX. Long-term inhalable particles and other air pollutants related to mortality in nonsmokers. Am J Respir Crit Care Med 159:373-382 (1999).
23. Dockery DW, Pope CA III, Xu X, Spengler JD, Ware JH, Fay ME, Ferris BG, Speizer FA. An association between air pollution and mortality in six U.S. cities. N Engl J Med 329:1753-1759 (1993).
24. Pope CA III, Thun MJ, Namboodiri MM, Dockery DW, Evans JS, Speizer FE, Heath CW Jr. Particulate air pollution as a predictor of mortality in a prospective study of U.S. adults. Am J Respir Crit Care Med 151:669-674 (1995).
25. Woodruff TJ, Grillo J, Schoendorf KC. The relationship between selected causes of postneonatal infant mortality and particulate air pollution in the United States. Environ Health Perspect 105:608-612 (1997).
26. Peters A, Doring A, Wichmann HE, Koenig W. Increased plasma viscosity during the 1985 air pollution episode: a link to mortality? Lancet 349:1582-1587 (1997).
27. Pope CA III, Dockery DW, Kanner RE, Villegas GM, Schwartz J. Oxygen saturation, pulse rate, and particulate air pollution: a daily time-series panel study. Am J Respir Crit Care Med 159:365-372 (1999).
28. Liao D, Creason J, Shy C, Williams R, Watts R, Zweidinger R. Daily variation of particulate air pollution and poor cardiac autonomic control in the elderly. Environ Health Perspect 107:521-525 (1999).
29. Pope CA III, Verrier RL, Lovett EG, Larson AC, Raizenne ME, Kanner RE, Schwartz J, Villegas GM, Gold DR, Dockery DW. Heart rate variability associated with particulate air pollution. Am Heart J (in press).
30. Tan WC, van Eeden S, Qiu DW, Liam BL, Dyachokova Y, Hogg JL. Particulate air pollution, bone marrow stimulation and the pathogenesis of excess cardiovascular and pulmonary deaths. Am J Respir Crit Care Med 155:1441-1447 (1997).
31. Salvi S, Blomberg A, Rudell B, Kelly F, Sandstrom T, Holgate ST, Frew A. Acute inflammatory responses in the airways and peripheral blood after short-term exposure to diesel exhaust in healthy human volunteers. Am J Respir Crit Care Med 159:702-709 (1999).
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(See Galizia and Kinney, p. 675)
Ozone is the most persistent, intractable air pollutant in urban air. In 1995, over 70 million people in the United States lived in areas not meeting the 1-hr U.S. Environmental Protection Agency (EPA) ozone standard (1). In 1997 the EPA tightened the standards for ozone to 0.08 ppm averaged over 8 hr.
It is well known that short-term (2-7 hr) exposures to ozone at 0.08-0.2 ppm in healthy subjects are associated with decreased lung function, pain upon deep breathing, and inflammation of the lung (2,3). Repeated short-term exposure to ozone results in attenuation of pulmonary function effects by the fifth day, indicating that there is a complicated interaction between ozone and human airways (4). A similar tolerance for prolonged ozone exposure was observed in some California residents (5). The physiological basis for this phenomenon and its long-term pattern are not known. It was also shown that young people with asthma in Atlanta, Georgia, were more likely to visit emergency departments for asthma treatment on days following ozone levels that exceeded 0.11 ppm (6). The effects of long-term exposure to ozone on asthma aggravation are not known.
Unlike humans, animals can be used to study prolonged exposure to ozone to examine histopathologic and structural changes. Ozone exposure for 6-12 months induces cell injury, lung edema, and inflammation in a time-dependent fashion (7). Long-term exposure to ozone is associated with fibrotic changes resulting in a smaller, stiffer lung. Structural damage is often seen at the junctions of the terminal airways (7), where the important mucus lining soon disappears altogether. The documentation of structural changes is useful in helping investigators of human effects understand the likely areas of maximal effect within the different parts of the lung. Tolerance (or attenuation of effect) to repeated and continuous ozone exposure has been shown in animal studies as well as in human studies (8).
It is generally agreed that knowledge of the effects of long-term exposure to air pollutants is necessary to develop protective regulatory policies, but relatively little is known about the effects in humans, and especially about the developing lung. Several studies have tracked respiratory symptoms and lung function in adult subjects with varying exposure to ozone (9-11). In general, these studies report reduced lung volumes and increased respiratory symptoms in individuals residing in areas with higher yearly ozone concentrations. Last year Künzli et al. (12) reported the results of a study using a creative new experimental design to evaluate the effects of ozone exposure on the human lung. They enrolled a group of freshmen at the University of California at Berkeley and estimated their lifetime exposure to ozone. They were 18-21 years of age and had no history of respiratory disease. Lung function was measured on two occasions about 1 week apart. The analysis estimated lifetime ozone concentration and several measures of lung function, and indicated that ozone exposure was associated with smaller lung capacities.
In this issue of EHP, Galizia and Kinney present data that expand on the observations of Künzli and associates (12). The Künzli study was restricted to California residents, but the present study included subjects nationwide. The Galizia and Kinney study examines the association between respiratory health status in college freshmen and individual long-term estimates of prior ozone exposures. On average, pulmonary function values in early adulthood were 3-8% lower in the subjects who were categorized as
having resided in high ozone areas as compared with the low exposure group. Thus, this study provides additional data which indicate that exposure to ozone for 10 or more years during early lung development results in a smaller lung capacity. Taken together, these two lifetime exposure studies provide us with extremely important data to help estimate the risk of chronic ozone exposure on the human lung. More and more children grow up in urban or suburban areas with persistent elevated summertime ozone concentrations; thus, these data highlight a pressing public health issue.
As with any study of air pollution epidemiology, there is concern about confounding effects from other air pollutants. However, here is a substantial body of literature from animal toxicology that supports adverse respiratory effects associated with extended exposure to ozone. Children are especially vulnerable to ozone exposure because of their vigorous outdoor summer activities when ozone concentrations are highest. Experimental data from animal and human subjects show that ozone causes decreases in lung function and airway inflammation, which together reduce lung capacity. Future studies should attempt to determine the most vulnerable age ranges that are associated with adverse effects from ozone exposure on the developing human lung, and whether there are threshold concentrations or durations of exposure involved in this end point.
Jane Q. Koenig
Department of Environmental Health
University of Washington
Seattle, Washington
E-mail: jkoenig@u.washington.edu
References and Notes
1. U.S. EPA. National Air Quality and Emissions Trends Report, 1995. EPA 454/R-96-005. Washington, DC:U.S. Environmental Protection Agency, 1996.
2. Horstman DH, Folinsbee LJ, Ives PJ, Abdul-Salaam S, McDonnell WF. Ozone concentration and pulmonary response relationships for 6.6 hour exposures with five hours of moderate exercise to 0.08, 0.10, and 0.12 ppm. Am Rev Respir Dis 142:1158-1163 (1990).
3. Devlin RB, McDonnell WF, Mann R, Becker S, House DE, Schreinemachers D, Koren HS. Exposure of humans to ambient levels of ozone for 6.6 hours causes cellular and biochemical changes in the lung. Am J Respir Cell Mol Biol 4: 72-81 (1991).
4. Horvath SM, Gliner JA, Folinsbee LJ. Adaptation to ozone: duration of effect. Am Rev Respir Dis 123:496-499 (1981).
5. Hackney JD, Linn WS, Shamoo DA, Avol EL. Responses of selected reactive and nonreactive volunteers to ozone exposure in high and low pollution seasons. In: Atmospheric Ozone Research and Its Policy Implications (Schneider T, ed). Amsterdam:Elsevier, 1989;311-318.
6. White MC, Etzel RA, Wilcox WD, Lloyd C. Exacerbations of childhood asthma and ozone pollution in Atlanta. Environ Res 65:56-68 (1994).
7. Chitano P, Hosselet JJ, Mapp CE, Fabbri LM. Effect of oxidant air pollutants on the respiratory system: insights from experimental animal research. Eur Respir J 8:1357-1371 (1995).
8. Nikula KJ, Wilson DW, Dungworth DL, Plopper CG. In vitro evidence of cellular adaptation to ozone toxicity in the rat trachea. Toxicol Appl Pharmacol 93:394-402 (1988).
9. Detels R, Tashkin DP, Sayre JW, Rokaw SN, Coulson AH, Massey FJ Jr, Wegman DH. The UCLA Population Studies of Chronic Obstructive Respiratory Disease: IX: Lung function changes associated with chronic exposure to photochemical oxidants; a cohort study among never smokers. Chest 92:594-603 (1987).
10. Abbey DE, Peterson F, Mills PK, Beeson WL. Long-term ambient concentrations of total suspended particulates, ozone, and sulfur dioxide and respiratory symptoms in a nonsmoking population. Arch Environ Health 48:33-46 (1993).
11. Abbey DE, Burchette RJ, Knutsen SF, McDonnell WF, Lebowitz MD, Enright PL. Long-term particulate and other air pollutants and lung function in nonsmokers. Am J Respir Crit Care Med 158:289-298 (1998).
12. Künzli N, Lurmann F, Segal M, Ngo L, Balmes J, Tager IB. Association between lifetime ambient ozone exposure and pulmonary function in college freshmen--results of a pilot study. Environ Res 72:8-23 (1997).
Last Updated: July 16, 1999
