Chronic Exposure to Fine Particles and Mortality, 1974-2009
Chronic Exposure to Fine Particles and Mortality, 1974-2009
Including more recent observations with PM2.5 exposures down to 8 μg/m, we continued to find a statistically significant association between chronic exposure to PM2.5 and all-cause and cardiovascular mortality. Furthermore, in the present extended follow-up, PM2.5 exposure was also statistically significantly associated with lung-cancer mortality. Our study indicated no sensitivity of the results for all-cause mortality and specific causes of death when we allowed the effects of smoking, education, and sex to vary over time, or when we used age as the time scale instead of follow-up time. Using very flexible modeling assumptions, our results did not show any rationale for change of PM2.5 effect size over the whole study period, as indicated by the adjusted survival curves and the lack of a clear interaction of PM2.5 with the four study periods. The concentration–response relationship was linear without any threshold, even at exposure levels below the U.S. annual 15-μg/m standard (U.S. EPA 1997). Taken together with the results of a previous reanalysis of the Harvard Six Cities study (Krewski et al. 2005b), there is evidence for a robust association between chronic PM2.5 exposure and early mortality.
Our results indicated a statistically significant 14% increase in all-cause mortality for a 10-μg/m annual increase in PM2.5, which is similar to the results of the previous follow-ups (Dockery et al. 1993; Laden et al. 2006). The Netherlands Cohort Study on Diet (NLCS–Air) in Europe (Beelen et al. 2008b), the Adventist Study (McDonnell et al. 2000), and the male Health Professionals Follow-up Study in the United States (Puett et al. 2011) did not show statistically significant associations between PM2.5 and all-cause mortality. However, our current results are consistent with those from the ACS cohort (Pope et al. 2002), the Nurses' Health Study (Puett et al. 2009), and the Medicare cohort (Eftim et al. 2008), which indicated mortality increases ranging from 3–26% per 10-μg/m increase in PM2.5.
The 26% increase in cardiovascular mortality for each 10-μg/m increase in PM2.5 exposure during the previous 3 years estimated in this extended follow-up is similar to the previous estimate (Laden et al. 2006). Although the NLCS–Air study (Beelen et al. 2008b) found no statistically significant association, the magnitude of the estimated effect reported here is between the 12% increase estimated for the ACS cohort (Pope et al. 2004) and the 76% increase estimated for the Women's Health Initiative study (Miller et al. 2007). Puett et al. (2009) also estimated a 100% increase in fatal coronary heart diseases for a 10-μg/m increase in PM2.5 during the prior year. Underlying mechanisms for the effects of PM2.5 on cardiovascular mortality are still poorly understood, but changes in vasoconstriction might explain the associations (Anderson et al. 2011).
The previous extended follow-up of the Harvard Six Cities study showed an elevated, but not statistically significant, risk of lung-cancer mortality (Laden et al. 2006), whereas the present extended follow-up estimated a statistically significant 37% increase in lung-cancer mortality (for each 10-μg/m increase in PM2.5), which is greater than that estimated for both the ACS cohort (14%) (Pope et al. 2002) and a Japanese cohort (27%) (Katanoda et al. 2011). Lungs are one of the organs that are most directly affected by particulate air pollution. Fine particles, which may carry toxic chemicals of carcinogenic potential (Laden et al. 2000), can reach lung alveoli where the clearance is slow (Pinkerton et al. 1995) and induce durable pulmonary and systemic inflammation (Riva et al. 2011). Recent findings in the ACS cohort indicated that a 10-μg/m increase in PM2.5 concentration was associated with a statistically significant 15% to 27% increase in lung-cancer mortality in never smokers (Turner et al. 2011). We did not find such an association in our study, which might be due to a lack of statistical power (350 lung-cancer deaths, 26 among never smokers). However, estimated effects of PM2.5 on all-cause and cardiovascular mortality were also statistically significant (or borderline significant) in never smokers, and higher in current smokers compared to never or former smokers (Table 2).
Regarding COPD mortality, we found a positive but not statistically significant risk of COPD death associated with PM2.5 exposure. In the ACS cohort, Pope et al. (2004) estimated an unexpected inverse association between PM2.5 exposure and COPD mortality, whereas Katanoda et al. (2011) estimated an inverse but not statistically significant association between PM2.5 and COPD in a Japanese cohort.
The central deposition of particles in lungs has been shown to be enhanced in COPD patients (Bennett et al. 1997). Although PM2.5 has been associated with early mortality in COPD patients (Zanobetti et al. 2008), and ozone has been associated with early mortality in susceptible subjects (i.e., with COPD, diabetes, heart failure, or myocardial infarction) (Zanobetti and Schwartz 2011), our results did not indicate stronger associations in participants with such chronic conditions at enrollment compared with the population as a whole,. This might have been due to a lack of statistical power as few participants had COPD (n = 942) or diabetes (n = 563) at enrollment.
Use of outdoor measurements from central monitoring stations as a proxy measure of mean personal exposure to PM2.5 is prone to measurement error because the measures do not capture fine spatial contrasts that may occur within a city, which may bias the results. Recent reanalyses of the ACS cohort using land use regression models showed that the impact on the PM2.5–mortality association was heterogeneous depending on the city (Krewski et al. 2009). However, other recent studies have suggested that considering a more precise exposure model focused on the home address might not improve health effects estimates in terms of bias and variance (Kim et al. 2009; Lepeule et al. 2010; Szpiro et al. 2011). In the Harvard Six Cities study, there were not enough monitors in the cities to implement a land use regression model.
Our results were adjusted for baseline factors, but there is potential for residual confounding for risk factors after enrollment and for unmeasured factors such as occupational exposures or medication use if those factors co-vary with PM2.5. Some other limitations are that we did not measure PM2.5 in the same locations throughout the study period, that death certificates might have listed misclassified specific causes of death, and that hypertension and diabetes were assessed by questionnaire only. An extensive body of methodological work has been performed regarding the sensitivity of estimated associations between long-term exposure to air pollution and mortality, especially for the ACS and Harvard Six Cities study cohorts. More specifically, it has been shown that results were robust to alternative model specifications, alternative metrics of PM2.5, and adjustment for individual and ecological risk factors such as occupational exposures and socioeconomic variables (Krewski et al. 2005a, 2005b). It was also shown that using a spatial covariance structure did not change the results (Pope et al. 2002), but with only six locations, that methodology is not applicable in our study. Whereas the primary analysis from the Harvard Six Cities study (Dockery et al. 1993) estimated associations were based on between–city contrasts in exposure, in the current study, with age used as time scale, the exposure relied on both between– and within–city contrasts, limiting the potential for residual cross-sectional confounding. The strengths of the present study are the randomly sampled participants and its extended follow-up through 2009, which included more observations of participants with lower exposures during recent years and provided more statistical power.
Our results indicated that the best fit moving average for PM2.5 was 1 year for all-cause mortality. For cardiovascular and lung-cancer mortality, no clear pattern was identified because of the high correlation between PM2.5 concentrations in the 5 lagged years tested. These results suggest that PM2.5 exposure can act to promote cardiovascular diseases and lung-cancer growth, although the design of this study precludes us from determining whether PM2.5 initiates these diseases as suggested by other studies (Beelen et al. 2008a; Beeson et al. 1998). These results agree with the literature (Gehring et al. 2006; Krewski et al. 2009; Puett et al. 2009; Schwartz et al. 2008) and suggest that health improvements can be expected almost immediately after a reduction in air pollution. This conclusion should be taken into account for cost–benefit analyses related to air pollution standards.
Although RRs for PM2.5 fluctuated over time, our extended follow-up did not indicate any clear pattern over time during the study period. Between 1979–1988 (Laden et al. 2000) and 2009 (Nehls and Akland 1973), the sulfates/PM2.5 ratio for exposures measured for the Harvard Six Cities study dropped between 13% and 54%, depending on the city. If sulfates are unrelated to mortality, as some have argued (Grahame and Schlesinger 2005), the elimination of a substantial fraction of nontoxic material from PM2.5 mass should result in a substantial increase in the PM2.5 coefficient, which would otherwise have been suppressed by the large fraction of mass that was nontoxic. This was not the case, and hence our results indicate that sulfate particles are about as toxic as the average fine particle. This is consistent with the results of Pope et al. (2007), who found that the 2.5-μg/m decrease in sulfate particle concentrations observed during an 8-month smelters strike were associated with a 2.5% decrease in the number of deaths in the region. In comparison, a 2.5-μg/m decrease in PM2.5 in our follow-up of the Harvard Six Cities study was associated with a 3.5% reduction in all-cause deaths, but that was for reductions in PM2.5 lasting at least a year, not 8 months. Given that there were 2,423,712 deaths in the United States in 2007 (Xu et al. 2010) and that the average PM2.5 level was 11.9 μg/m (U.S. EPA 2011), our estimated association between PM2.5 and all-cause mortality implies that a decrease of 1 μg/m in population-average PM2.5 would result in approximately 34,000 fewer deaths per year.
Discussion
Including more recent observations with PM2.5 exposures down to 8 μg/m, we continued to find a statistically significant association between chronic exposure to PM2.5 and all-cause and cardiovascular mortality. Furthermore, in the present extended follow-up, PM2.5 exposure was also statistically significantly associated with lung-cancer mortality. Our study indicated no sensitivity of the results for all-cause mortality and specific causes of death when we allowed the effects of smoking, education, and sex to vary over time, or when we used age as the time scale instead of follow-up time. Using very flexible modeling assumptions, our results did not show any rationale for change of PM2.5 effect size over the whole study period, as indicated by the adjusted survival curves and the lack of a clear interaction of PM2.5 with the four study periods. The concentration–response relationship was linear without any threshold, even at exposure levels below the U.S. annual 15-μg/m standard (U.S. EPA 1997). Taken together with the results of a previous reanalysis of the Harvard Six Cities study (Krewski et al. 2005b), there is evidence for a robust association between chronic PM2.5 exposure and early mortality.
Consistency of the Results
Our results indicated a statistically significant 14% increase in all-cause mortality for a 10-μg/m annual increase in PM2.5, which is similar to the results of the previous follow-ups (Dockery et al. 1993; Laden et al. 2006). The Netherlands Cohort Study on Diet (NLCS–Air) in Europe (Beelen et al. 2008b), the Adventist Study (McDonnell et al. 2000), and the male Health Professionals Follow-up Study in the United States (Puett et al. 2011) did not show statistically significant associations between PM2.5 and all-cause mortality. However, our current results are consistent with those from the ACS cohort (Pope et al. 2002), the Nurses' Health Study (Puett et al. 2009), and the Medicare cohort (Eftim et al. 2008), which indicated mortality increases ranging from 3–26% per 10-μg/m increase in PM2.5.
The 26% increase in cardiovascular mortality for each 10-μg/m increase in PM2.5 exposure during the previous 3 years estimated in this extended follow-up is similar to the previous estimate (Laden et al. 2006). Although the NLCS–Air study (Beelen et al. 2008b) found no statistically significant association, the magnitude of the estimated effect reported here is between the 12% increase estimated for the ACS cohort (Pope et al. 2004) and the 76% increase estimated for the Women's Health Initiative study (Miller et al. 2007). Puett et al. (2009) also estimated a 100% increase in fatal coronary heart diseases for a 10-μg/m increase in PM2.5 during the prior year. Underlying mechanisms for the effects of PM2.5 on cardiovascular mortality are still poorly understood, but changes in vasoconstriction might explain the associations (Anderson et al. 2011).
The previous extended follow-up of the Harvard Six Cities study showed an elevated, but not statistically significant, risk of lung-cancer mortality (Laden et al. 2006), whereas the present extended follow-up estimated a statistically significant 37% increase in lung-cancer mortality (for each 10-μg/m increase in PM2.5), which is greater than that estimated for both the ACS cohort (14%) (Pope et al. 2002) and a Japanese cohort (27%) (Katanoda et al. 2011). Lungs are one of the organs that are most directly affected by particulate air pollution. Fine particles, which may carry toxic chemicals of carcinogenic potential (Laden et al. 2000), can reach lung alveoli where the clearance is slow (Pinkerton et al. 1995) and induce durable pulmonary and systemic inflammation (Riva et al. 2011). Recent findings in the ACS cohort indicated that a 10-μg/m increase in PM2.5 concentration was associated with a statistically significant 15% to 27% increase in lung-cancer mortality in never smokers (Turner et al. 2011). We did not find such an association in our study, which might be due to a lack of statistical power (350 lung-cancer deaths, 26 among never smokers). However, estimated effects of PM2.5 on all-cause and cardiovascular mortality were also statistically significant (or borderline significant) in never smokers, and higher in current smokers compared to never or former smokers (Table 2).
Regarding COPD mortality, we found a positive but not statistically significant risk of COPD death associated with PM2.5 exposure. In the ACS cohort, Pope et al. (2004) estimated an unexpected inverse association between PM2.5 exposure and COPD mortality, whereas Katanoda et al. (2011) estimated an inverse but not statistically significant association between PM2.5 and COPD in a Japanese cohort.
Chronic Conditions at Enrollment and Mortality
The central deposition of particles in lungs has been shown to be enhanced in COPD patients (Bennett et al. 1997). Although PM2.5 has been associated with early mortality in COPD patients (Zanobetti et al. 2008), and ozone has been associated with early mortality in susceptible subjects (i.e., with COPD, diabetes, heart failure, or myocardial infarction) (Zanobetti and Schwartz 2011), our results did not indicate stronger associations in participants with such chronic conditions at enrollment compared with the population as a whole,. This might have been due to a lack of statistical power as few participants had COPD (n = 942) or diabetes (n = 563) at enrollment.
Exposure Assessment
Use of outdoor measurements from central monitoring stations as a proxy measure of mean personal exposure to PM2.5 is prone to measurement error because the measures do not capture fine spatial contrasts that may occur within a city, which may bias the results. Recent reanalyses of the ACS cohort using land use regression models showed that the impact on the PM2.5–mortality association was heterogeneous depending on the city (Krewski et al. 2009). However, other recent studies have suggested that considering a more precise exposure model focused on the home address might not improve health effects estimates in terms of bias and variance (Kim et al. 2009; Lepeule et al. 2010; Szpiro et al. 2011). In the Harvard Six Cities study, there were not enough monitors in the cities to implement a land use regression model.
Strengths and Limitations
Our results were adjusted for baseline factors, but there is potential for residual confounding for risk factors after enrollment and for unmeasured factors such as occupational exposures or medication use if those factors co-vary with PM2.5. Some other limitations are that we did not measure PM2.5 in the same locations throughout the study period, that death certificates might have listed misclassified specific causes of death, and that hypertension and diabetes were assessed by questionnaire only. An extensive body of methodological work has been performed regarding the sensitivity of estimated associations between long-term exposure to air pollution and mortality, especially for the ACS and Harvard Six Cities study cohorts. More specifically, it has been shown that results were robust to alternative model specifications, alternative metrics of PM2.5, and adjustment for individual and ecological risk factors such as occupational exposures and socioeconomic variables (Krewski et al. 2005a, 2005b). It was also shown that using a spatial covariance structure did not change the results (Pope et al. 2002), but with only six locations, that methodology is not applicable in our study. Whereas the primary analysis from the Harvard Six Cities study (Dockery et al. 1993) estimated associations were based on between–city contrasts in exposure, in the current study, with age used as time scale, the exposure relied on both between– and within–city contrasts, limiting the potential for residual cross-sectional confounding. The strengths of the present study are the randomly sampled participants and its extended follow-up through 2009, which included more observations of participants with lower exposures during recent years and provided more statistical power.
Critical Periods of PM2.5 Exposure
Our results indicated that the best fit moving average for PM2.5 was 1 year for all-cause mortality. For cardiovascular and lung-cancer mortality, no clear pattern was identified because of the high correlation between PM2.5 concentrations in the 5 lagged years tested. These results suggest that PM2.5 exposure can act to promote cardiovascular diseases and lung-cancer growth, although the design of this study precludes us from determining whether PM2.5 initiates these diseases as suggested by other studies (Beelen et al. 2008a; Beeson et al. 1998). These results agree with the literature (Gehring et al. 2006; Krewski et al. 2009; Puett et al. 2009; Schwartz et al. 2008) and suggest that health improvements can be expected almost immediately after a reduction in air pollution. This conclusion should be taken into account for cost–benefit analyses related to air pollution standards.
Role of Sulfates and Public Health Implications
Although RRs for PM2.5 fluctuated over time, our extended follow-up did not indicate any clear pattern over time during the study period. Between 1979–1988 (Laden et al. 2000) and 2009 (Nehls and Akland 1973), the sulfates/PM2.5 ratio for exposures measured for the Harvard Six Cities study dropped between 13% and 54%, depending on the city. If sulfates are unrelated to mortality, as some have argued (Grahame and Schlesinger 2005), the elimination of a substantial fraction of nontoxic material from PM2.5 mass should result in a substantial increase in the PM2.5 coefficient, which would otherwise have been suppressed by the large fraction of mass that was nontoxic. This was not the case, and hence our results indicate that sulfate particles are about as toxic as the average fine particle. This is consistent with the results of Pope et al. (2007), who found that the 2.5-μg/m decrease in sulfate particle concentrations observed during an 8-month smelters strike were associated with a 2.5% decrease in the number of deaths in the region. In comparison, a 2.5-μg/m decrease in PM2.5 in our follow-up of the Harvard Six Cities study was associated with a 3.5% reduction in all-cause deaths, but that was for reductions in PM2.5 lasting at least a year, not 8 months. Given that there were 2,423,712 deaths in the United States in 2007 (Xu et al. 2010) and that the average PM2.5 level was 11.9 μg/m (U.S. EPA 2011), our estimated association between PM2.5 and all-cause mortality implies that a decrease of 1 μg/m in population-average PM2.5 would result in approximately 34,000 fewer deaths per year.
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