Short-Term Effects of Ambient Particles on Cardiovascular and Respiratory Mortality

Analitis, Antonis*; Katsouyanni, Klea*; Dimakopoulou, Konstantina*; Samoli, Evangelia*; Nikoloulopoulos, Aristidis K.*; Petasakis, Yannis*; Touloumi, Giota*; Schwartz, Joel†; Anderson, Hugh Ross‡; Cambra, Koldo§; Forastiere, Francesco∥; Zmirou, Denis¶; Vonk, Judith M.**; Clancy, Luke††; Kriz, Bohumir‡‡; Bobvos, Janos§§; Pekkanen, Juha∥∥

doi: 10.1097/01.ede.0000199439.57655.6b
Brief Report

Background: Particulate air pollution is associated with increased mortality. There is a need for European results from multicountry databases concerning cause-specific mortality to obtain more accurate effect estimates.

Methods: We report the estimated effects of ambient particle concentrations (black smoke and particulate matter less than 10 μm [PM10]) on cardiovascular and respiratory mortality, from 29 European cities, within the Air Pollution and Health: a European Approach (APHEA2) project. We applied a 2-stage hierarchical modeling approach assessing city-specific effects first and then overall effects. City characteristics were considered as potential effect modifiers.

Results: An increase in PM10 by 10 μg/m3 (lag 0 + 1) was associated with increases of 0.76% (95% confidence interval = 0.47 to 1.05%) in cardiovascular deaths and 0.58% (0.21 to 0.95%) in respiratory deaths. The same increase in black smoke was associated with increases of 0.62% (0.35 to 0.90%) and 0.84% (0.11 to 1.57%), respectively.

Conclusions: These effect estimates are appropriate for health impact assessment and standard-setting procedures.

Author Information

From the *Department of Hygiene and Epidemiology, University of Athens Medical School, Athens, Greece; †Harvard School of Public Health, Boston, MA; the ‡Division of Community Health Sciences, St. George's University of London, London, U.K.; the §Department of Health, Basque Government, Vitoria Gasteiz, Spain; the ∥Department of Epidemiology, Roma E Health Authority, Rome, Italy; ¶INSERM Unit ERI n°11 (Assessment and Prevention of Occupational and Environmental Risks), Medical School, Nancy University, Nancy, France; the **Department of Epidemiology and Bioinformatics, University Medical Center Groningen, The Netherlands; ††CResT Directorate, St. James Hospital, Dublin, Ireland; the ‡‡Department of Epidemiology CPL, Charles University, 3rd Medical Faculty, Praha, NIPH, Czech Republic; §§Budapest Institute of the National Public Health and Medical Officer Service, Hungary; and the ∥∥Unit of Environmental Epidemiology, National Public Health Institute, Kuopio, Finland.

Submitted 4 March 2005; accepted 12 October 2005.

Supported by the European Commission Environment and Climate 1994–1998 Program and Key Action 4: Environment and Health, FP5 (contract nos. ENV4-CT97-0534 and QLK4-CT-2001-30055).

Supplemental material for this article is available with the online version of the journal at; click on “Article Plus.”

Correspondence: Klea Katsouyanni, Department of Hygiene and Epidemiology, University of Athens Medical School, 75, Mikras Asias Street, 115 27 Athens, Greece. E-mail:

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Several epidemiologic studies (including multicenter projects) have reported results linking the daily ambient particle concentrations with daily mortality.1–3 Most of the published results concern total mortality from all natural causes. This outcome has the advantage of being completely and accurately recorded. However, it is not specific for air pollution health effects. Respiratory mortality is a more specific outcome because air pollution exposure occurs mainly through inhalation, but several recent studies have also linked particle exposure with mechanisms leading to cardiovascular (CVD) morbidity and mortality.4–6

The APHEA (Air Pollution and Health: a European Approach) project is a large multicenter European project investigating the short-term effects of air pollution on health. Results have been reported from phase 1 of this project.7,8 We report here the estimated effects of ambient particles concentrations on respiratory and CVD mortality from 29 cities taking part in phase 2 of the APHEA project.

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Twenty-nine European cities have provided data on mortality from respiratory (International Classification of Diseases, 9th Revision [ICD-9] 460–519) and cardiovascular (ICD-9 390–459) diseases, as well as daily data on ambient particles concentrations using PM10 (21 cities) and/or black smoke (15 cities). The median daily number of CVD deaths ranged between 2 and 143 and that of respiratory deaths from zero to 31. The median concentrations of PM10 and black smoke (average of 2 consecutive days) ranged from 9 to 64 and from 14 to 166 μg/m3, respectively (Table A1, available with the online version of this article).

We applied a 2-stage hierarchic modeling approach. In the first stage, we analyzed individual city data and obtained city-specific effect estimates, which were then used in a second-stage analysis to provide overall estimates and investigate heterogeneity. Various methods have been used as core and sensitivity analyses. Details about the data and the methods may be found in the online supplement and in the paper by Katsouyanni et al.2 We adjusted for potential confounding effects of seasonality, long-term trends, temperature, humidity, influenza epidemics, other unusual events, day of the week, and holidays. We also adjusted for the daily levels of other pollutants in 2-pollutant models. Because substantial heterogeneity had been observed in city-specific effect parameter estimates,7 we also explored the possible role of several city characteristics as effect modifiers. We report results from random-effects models in the presence of significant heterogeneity (P < 0.05).

In the second-stage analysis, city-specific effect estimates were regressed on city-specific covariates to obtain an overall estimate and to explore heterogeneity across cities (as reported in the online supplement “Methods” section). We explore effect modification only in the presence of significant heterogeneity and display results for those variables that explain more than 10% of the observed heterogeneity.

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Table 1 shows the estimated effects from PM10 and black smoke exposure on CVD and respiratory mortality. The results displayed are from models using penalized splines to adjust for seasonal and long-term effects. An increase of 0.76% and 0.62% in the daily number of CVD deaths is associated with a 10-μg/m3 increase in PM10 and black smoke, respectively. Decreasing the number of degrees of freedom results in increased effects, whereas increasing it results in decreasing the effect estimates (see online supplement Tables A3 and A4). Applying alternative ways to control for seasonality, we get somewhat increased effects using the LOESS smoother and approximately 30% decreased estimates using natural splines. Controlling for ozone, the effect of PM10 remains practically identical, whereas it is decreased to 0.55% (95% confidence interval [CI] = 0.27 to 0.83%) when adjusting for sulfur dioxide (SO2) and to 0.32% (0.05 to 0.59%) when adjusting for nitrogen dioxide (NO2) (see online supplement Table A5). When adjusted for SO2, the black smoke effects slightly decrease; when adjusted for NO2 they decrease substantially to 0.17% (−0.10 to 0.45%), and when adjusted for ozone, they increase somewhat to 0.84% (0.53 to 1.16%) (online supplement Table A6).

An increase of 0.58% and 0.84% in the daily number of respiratory deaths is associated with a 10-μg/m3 increase in PM10 and black smoke, respectively. The estimated effects are larger by the LOESS method and they increase when decreasing the number of degrees of freedom; the opposite is true when the number of degrees of freedom increases (see online supplement Tables A7 and A8). Using natural splines, the PM10 estimates decrease by 46% and those of black smoke by 24%. The estimates of PM10 effects are not confounded by ozone concentrations but decrease substantially when adjusting for SO2 and NO2 (to 0.22% [−0.23 to 0.68%] and 0.20% [−0.29 to 0.69%], respectively) (online supplement Table A9). The estimates for black smoke exposure are confounded by ozone, NO2, and SO2 concentrations. Adjusting for these gaseous pollutants, results in decreasing the black smoke effects by 32% to 56% (online supplement Table A10).

Several effect modifiers explained more than 10% of the heterogeneity of the effects on CVD mortality. There was a larger effect of both PM10 and black smoke in warmer and drier cities, in cities with higher long-term average NO2 concentrations, and in cities with a higher proportion of elderly and a lower age-standardized mortality rate. There was also regional heterogeneity; the increase of the daily number of CVD deaths associated with 10-μg/m3 increase in PM10 was 0.54% in northwestern cities, 1.25% in southern cities, and 0.25% in central–eastern cities, whereas the contrast was somewhat smaller for black smoke (Tables A11 and A12, online supplement). There was no statistically significant heterogeneity in the estimated city-specific respiratory effects from PM10 exposure using the penalized splines method, so the causes of heterogeneity were not further explored. In contrast, there was heterogeneity in the black smoke city-specific effects. We found larger effects in cities with a higher age-adjusted lung cancer mortality rate and in cities with a larger proportion of elderly (Table A13, online supplement).

All of these estimates concern exposure over 2 days (lags zero and one). We also estimated the cumulative effects over 6 days (lags 0–5) for the chosen number of degrees of freedom and the penalized splines method. For PM10 effects on CVD deaths, the increase in the daily number of deaths was 0.90% (95% CI = 0.57 to 1.23%; 18% increase over the zero to one lags estimate); for black smoke effects on CVD deaths, it was 0.80% (0.49 to 1.11; a 29% increase). The corresponding estimates for respiratory deaths are 1.24% (0.49 to 1.99%; a 75% increase over the zero to one lags estimate) for PM10 and 1.61% (0.56 to 2.66%; a 93% increase) for black smoke. In the online supplement figures and tables, the individual city and pooled-effect estimates by both methods can be seen (Figs. A1–A4 and Tables A14–A17, online supplement).

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We report effects of ambient particles exposures on CVD and respiratory mortality using data from 29 cities applying penalized splines to control for seasonality and long-term trends. In sensitivity analyses, larger effects are found using LOESS smoother whereas, in contrast, they are lower when we apply natural splines. CVD and respiratory causes of death are more specific to air pollution exposure than total mortality is. Recently, several reports have indicated mechanisms through which PM exposure can affect the cardiovascular system4–6,9–11 and cause pulmonary inflammation.12,13 Other time-series studies have found results comparable to ours.14–17 The APHEA1 study of 4 Western European cities reported an increase of 0.4% and 0.8% in CVD and respiratory deaths, respectively, for a 10-μg/m3 increase in PM10, whereas no associations were found in 4 Eastern European (Polish) cities, possibly due to modeling problems.18 Strong evidence for the effect of black smoke exposure on the CV system comes from a recent intervention study in which a reduction of black smoke concentrations in Dublin was followed by a substantial reduction in CVD mortality.19

The lag pattern of effects differs between CVD and respiratory deaths; it appears that effects on CVD mortality are more immediate, whereas the effects on respiratory mortality persist for several days.20–22 Our findings are consistent with this result. Adjusting for other pollutants shows that the PM10 effects, on both CVD and respiratory mortality, are independent of the levels of ozone, whereas they are somewhat confounded by SO2 levels and more by NO2. NO2 is an indicator of traffic pollution. Previous reports have shown that particles originating from traffic may be more associated with mortality effects.2 It is not clear whether NO2 is a better indicator than PM10 or black smoke of traffic particles or whether there is a true confounding effect.

We were able to identify effect modifiers for the PM effects on CVD mortality that are consistent with those previously reported for total mortality.2,23 The greatest relative effect modification for PM10 came from mean temperature and city-average NO2 concentrations. Warmer towns with more NO2 showed larger effects. There was less effect modification by NO2 for black smoke than for PM10, which suggests differential effects of traffic particles, for which PM10 is a less good indicator than black smoke. The greater effects in warmer cities may reflect greater ventilation, and hence higher indoor/outdoor pollution concentration ratios in those locations, but this mechanism remains to be confirmed by more detailed studies. The differences in effect modification patterns between cardiovascular and respiratory mortality may be interpreted as a further indication that the mechanisms through which particles affect cause-specific mortality are different for cardiac and respiratory causes. On the other hand, much of the modification of effects in this study is related to differences between Eastern, Northern, and Southern Europe, and we cannot exclude the possibility that other factors that differ across these regions, for which we do not have data, were responsible for the observed differences. In particular, the relative contributions of different sources of particles, and hence their likely physicochemical characteristics, may differ across these regions, and recent studies have suggested these characteristics may modify toxicity.24

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The Air Pollution and Health: a European Approach (APHEA2) collaborative group consists of: K. Katsouyanni, G. Touloumi, E. Samoli, A. Gryparis, Y. Monopolis, E. Aga, D. Panagiotakos, A. Analitis, Y. Petasakis, and K. Dimakopoulou (Greece, coordinating center); C. Spix, A. Zanobetti, and H. E. Wichmann (Germany); H. R. Anderson, R. Atkinson, and J. Ayres (U.K.); S. Medina, A. Le Tertre, P. Quenel, L. Pascale, and A. Boumghar (Paris, France); J. Sunyer, M. Saez, F. Ballester, S. Perez-Hoyos, J. M. Tenias, E. Alonso, K. Kambra, E. Aranguez, A. Gandarillas, I. Galan, and J. M. Ordonez (Spain); M. A. Vigotti, G. Rossi, E. Cadum, G. Costa, L. Albano, D. Mirabelli, P. Natale, L. Bisanti, A. Bellini, M. Baccini, A. Biggeri, P. Michelozzi, V. Fano, A. Barca, and F. Forastiere (Italy); D. Zmirou and F. Balducci (Grenoble, France); J. Schouten and J. Vonk (The Netherlands); J. Pekkanen and P. Tittanen (Finland); L. Clancy and P. Goodman (Ireland); A. Goren and R. Braunstein (Israel); C. Schindler (Switzerland); B. Wojtyniak, D. Rabczenko, and K. Szafraniek (Poland); B. Kriz, M. Celko, and J. Danova (Prague, Czech Republic); A. Paldy, J. Bobvos, A. Vamos, G. Nador, I. Vincze, P. Rudnai, and A. Pinter (Hungary); E. Niciu, V. Frunza, and V. Bunda, (Romania); M. Macarol-Hitti and P. Otorepec (Slovenia); Z. Dor̈tbudak and F. Erkan (Turkey); B. Forsberg and B. Segerstedt (Sweden); andF. Kotesovec and J. Skorkovski (Teplice, Czech Republic).

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