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Air pollution and acute respiratory illness in five german communities
ENVIRONMENTAL RESEARCH 56, 1-14 (1991)
Air Pollution and Acute Respiratory Illness in Five German Communities J. SCHWARTZ,* C. SeIx,t
H . E . WICHMANN,'~ AND E . M A L I N ~
*U.S. Environmental Protection Agency, PM221, ,#01 M Street S.W., Washington, D.C. 20460; TDepartment of Labor Safety and Environmental Medicine, University of Wuppertal, 5600 Wuppertal 1, Wuppertal, Federal Republic of Germany; and SMedical Institute for Environmental Hygiene, University of Dusseldorf, Dusseldorf, Federal Republic of Germany Received January 30, 1991 To assess the impact of short-term exposure to air pollution on respiratory illness in children we recruited pediatricians and hospitals in five German cities to report daily counts of children's visits for croup symptoms and obstructive bronchitis. Data were collected for at least 2 years in each location. These symptoms are predominantly found in very young children, with the croup reporting peaking at 2 years of age and obstructive bronchitis at 1 year. Attacks of croup and obstructive bronchitis were relatively rare events: the mean number of cases of croup per day in each city ranged from 0.5 to 3, and obstructive bronchitis was even less frequent. A total of 6330 cases of croup and 4755 cases of obstructive bronchitis were observed during the study. The distributions of these events were quite skewed and were modeled as a Poisson process. To focus the analysis on short-term correlations and avoid seasonal confounding, biannual, annual (seasonal), and six shorter term cycles were controlled for in the regression models. After controlling for short-term weather factors, total suspended particulate matter (TSP) and nitrogen dioxide ( N O 2 ) w e r e associated with croup cases. An increase in TSP levels from 10 ixg/m3 to 70 p~g/m3 was associated with a 27% increase in cases of croup; the same increase in N O 2 levels resulted in a 28% increase in cases. No pollutant was associated with dally cases of obstructive bronchitis. © 1991 Academic Press, Inc.
INTRODUCTION Cross-sectional analyses of differences in the prevalence rates of symptoms and illnesses, or of differences in lung function from predicted values, across areas with different long-term averages in air pollution have been conducted in the last 30 years (Detels et al., 1981; Lunn et al., 1967; Bouhuys et al., 1978; Ferris et al., 1971; Sawicki and Lawrence, 1977). More recently, attention has focused on longitudinal studies of possible associations between air pollution and respiratory outcomes. Longitudinal studies are attractive because the populations studied serve as their own control, eliminating a potential source of bias in cross-sectional studies. Diary studies have examined daily fluctuations in respiratory symptoms (Korn and Whittemore, 1979; Lebowitz et al., 1985; Schwartz and Zeger, 1990; Schwartz et al., 1989; Franke et al., in press). In general these studies have found significant associations between relatively low concentrations of air pollution and reports of respiratory symptoms. These symptoms have been either self-reported or reported by parents. Daily mortality has also been correlated with air pollution (Martin and Bradley, 1960; Mazumdar et al., 1982; Schwartz and Marcus, 1990; Hatzakis et al., 1986; Ozkaynak et al., 1986; Schwartz and Dockery, 1991). Lon-
0013-9351/91 $3.00 Copyright © 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.
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SCHWARTZ ET AL.
gitudinai studies during air pollution episodes have also examined short-term decrements in lung function (Lioy et al., 1985; Spektor et al., 1988; Dassen et al., 1986; Kinney et al., 1989; Dockery et al., 1982; Wichmann et al., 1988) and mortality (Wichmann et al., 1989). While diary studies provide excellent control for individual risk factors within the longitudinal framework, they suffer from the classic difficulty of prospective cohort studies when the outcomes are quite rare. The size of the sample needed to reliably study the outcome can become prohibitive. In such instances a population-based study has considerable attractiveness. Bates and Sizto have used this approach to examine the correlation between hospital admissions (1987) and emergency room visits (1990) and air pollution, for example. If the association between air pollution and respiratory symptoms that has been reported in the literature is a causal one, one would expect a similar association with physiciandiagnosed respiratory illness, which is a more objectively determined outcome. We recruited hospitals and pediatricians in five areas of Germany to participate in a longitudinal study of air pollution and the incidence of croup and obstructive bronchitis in preschool children. The study design was longitudinal, with each community representing its own control, but the data collected did not allow the analysis of individual time-invariant risk factors. This prevents the search for interactive effects between air pollution and such risk factors. An identification of potentially sensitive subgroups was therefore not possible. However, this design allowed a test for a possible association between rare acute respiratory illnesses and air pollution from a population of approximately 2.5 million without crosssectional confounding. The patterns of croup and bronchitis in preschool children have been reported on previously (McConnochie et al., 1988), but their possible association with air pollution was not explored in that study. MATERIAL AND METHODS
Study Design Children's hospitals, pediatrics departments of general hospitals, and all pediatricians in each study area were asked to participate in the study on a voluntary basis. Participation was about 50%. For each child the doctor filled in a short questionnaire per visit, which included disease (croup or obstructive bronchitis), time and date of attack, place of attack, whether the attack was mild, medium, or severe, whether it was the first or a recurrent attack, with or without an infection, and with or without fever. These were aggregated to give daily counts of attacks in each study area for each disease which is referred to as cases per day. A diagnosis of croup was defined as acute stenotic subglottic laryngotracheitis; typical symptoms are hoarseness and barking cough, inspiratory stridor, dyspnea, and a sudden onset. The most important factor in the etiology are parainfluenza viruses. Obstructive bronchitis applies to the lower airways, where an inflammatory swelling of the mucosa and increased secretion lead to an obstruction of the bronchioles. The most important symptoms is exspiratory dyspnea. It is also usually the result of a viral infection. We assume that a fraction of the cases diagnosed as obstructive bronchitis had a bronchiolitis, since it is difficult to
POLLUTION AND RESPIRATORY ILLNESS
3
differentiate between these two diagnoses in very small children. Detailed descriptive statistics for the data by region, severity, hospital versus pediatrician cases, etc., have been reported previously (Wichmann et al., 1990a,b). Both diseases affect mostly preschool children, with the maximum of the age distribution at 2 years and 1 year, respectively. Because croup and obstructive bronchitis show a very notable seasonality and croup shows additionally a 2-year period, all studies ran over at least 2 years. Not all doctors reported for the full 2 years; we observed a loss of roughly 50% over the study period. This loss was modeled in the analysis, as described under the methods section below. All of the air pollution monitors in each study area were averaged to give a complete record of 24-hr measurements. The number of monitoring locations varied by area and pollutant, and is shown in Table 1. For each area, the daily mean temperature and relative humidity were also obtained.
Study Areas, Meteorology, and Pollution Data The areas analyzed here were chosen to cover a range of locations with different degrees of air pollution over the western part of the Federal Republic of Germany (FRG). Two communities were located in highly industrialized areas of Northrhine-Westfalia: in Duisburg (a city of about 550,000 inhabitants, situated north of Kfln in the lower Rhine plain); and Krln (a city of nearly 1,000,000 inhabitants, situated in the Rhine valley, where it opens to the plain). Data were collected from January 1983 to August 1985 in Duisburg and from September 1984 to April 1987 in Kfln. Three of the studied areas were located in South Germany. In each area, data TABLE 1 DISTRIBUTION OF 502, TSP, AND NO 2 24-HR MEASUREMENTSBY STUDY AREA OVER THE STUDY PERIOD
SO2 Duisburg txg/m3 K61n
Stuttgart Tiibingen Freudenstadt TSP Duisburg ~g/m3 K61n
Stuttgart Tiibingen Freudenstadt NO2 Duisburg I~g/m3 K61n
Stuttgart Tiibingen Freudenstadt
Quantiles
No. of days
No. of monitors
Miss.
10%
25%
50%
75%
90%
974 972 730 730 730
3 4 4 zAa zA
0.1 1.3 4.5 16.2 22.1
24 19 8 4 2
32 27 14 8 4
48 37 24 16 9
71 57 42 28 17
113 101 75 59 40
974 972 730 730 365
3 4 4 2A~ 1
0.9 1.8 4.4 15.3 15.3
34 28 11 6 5
42 35 14 10 9
56 48 21 20 17
79 70 33 39 28
118 102 51 69 41
974 972 730 730 730
3 4 4 ~ 2//3a
0.1 1.3 4.7 15.8 28.0
28 34 35 20 6
36 41 44 28 9
44 49 55 41 14
55 59 67 57 21
68 73 84 74 33
Two monitors in 1986, three in 1987.
%
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SCHWARTZ ET AL.
were collected from January 1986 to December 1987. These were: Stuttgart (an industrial city of about 550,000 inhabitants, situated in a bowl surrounded by hills and small mountains); Tiibingen/Reutlingen including 8 surrounding towns and villages (together about 250,000 inhabitants, in a mountainous, mostly rural area, except the big university of Tiibingen and the textile goods industry of Reutlingen; and in Freudenstadt and 16 surrounding towns and villages (together about 100,000 inhabitants, in a mountainous, rural area). NO2 was measured by chemiluminescence and SO 2 by conductometric method, both using a continuous sampler and reporting half hourly. Total suspended particulate matter (TSP) were collected by a low volume sampler using a continuous tape filter, and measured by beta attenuation, reporting every 3 hr. The 24-hr average of each monitor was computed, and the average of all monitors in each area was then taken.
Analytical Metkodology The distribution of daily counts of such rare events as physicians visits for croup symptoms is not Gaussian. Rather it has a low mean (about one to three visits per day in each area) with a long tail. Such skewed distributions of rare events are usually modeled as Poisson processes (McCullagh and Nelder, 1983). We have used Poisson regressions to analyze these data. Our basic strategy was to first fit models that best accounted for seasonal patterns, weather, and other temporal factors. To more conservatively estimate the effect of air pollution, marginally insignificant weather terms were kept in the model. Once the best such model was obtained for each city, air pollution was tested for its association.
Model Specifications Poisson regressions typically assume an exponential relationship between risk factors and the expected number of events (Breslow and Day, 1982). This specification for a categorical variable gives the relative risk for that factor. For a continuous exposure variable it assumes an exponentially increasing response with dose, which is not necessarily the case. Breslow and Day have extensively discussed this issue for prospective studies, and suggest that a logarithmic transformation of the continuous covariates may be appropriate. We have considered such a transformation for both pollution for both pollution and weather terms in our models, as well as the nontransformed variables. There is considerable collinearity between different pollutants. We have approached this problem by examining each pollutant separately to see if an association existed. If an association existed with more than one pollutant, we then considered multiple pollutant models. Current days' pollution, as well as pollution I and 2 clays prior to each reporting day was considered to allow for the possibility of a lag between exposure and response. Temperature and humidity were treated similarly.
Serial Correlation and Temporal Patterns Illness usually varies seasonally, displaying an annual cycle with winter peaks. A 2-year cycle has also been noted in croup data (Wichmann et al., 1990a,b;
POLLUTION AND RESPIRATORY ILLNESS
Franke et al., 1990; Wichmann and Franke, in press). Our hypothesis was that short-term pollution exposure might influence acute respiratory illness. To investigate this it is necessary to remove longer-term fluctuations in the data, so the relationship is not influenced by, e.g., the seasonal differences in pollution and in illness rates. We have done this by including sine and cosine terms for biannual and annual cycles, and for the six additional periods 730/k days, k = 3 to 8. The natural logarithm of the number of reporting physicians was used as an offset in the models for the three South German communities to control for the dropout of physicians over time. These data were not kept in the two Western German communities. To model trends in participation as well as in other factors that might effect respiratory visits, we included a linear term for time trend in every model. A quadratic time term was also included if its t statistic exceeded one. These terms were also included in the models for the South German cities. Day of the week effects were examined using dummy variables for each day. Insignificant daily dummies were dropped. Shorter-term serial correlation may still remain in such a model. We examined the residuals of each model for serial correlation up to a lag of 30 days. Each model was refit using an autoregressive covariance structure, following the approach of Zeger and Liang (1986), which incorporates the serial correlation in the covariance. To be conservative, autoregressive terms were included in the covariance if the model goodness of fit ×z statistic, adjusted for degrees of freedom, improved. This is equivalent to including all terms whose t statistic exceeds one. Random Effects Model Once final regression models were obtained in each study area, the results were combined to yield an overall estimate of pollutant effect and its significance. The classical estimate is simply the mean coefficient, weighted by the inverse of its variance. However, random factors may lead to greater variability between cities than the within city variances would indicate. We have estimated this additional variance using the method of moments, and incorporated it in estimation of the overall mean and its standard error. The effect of this additional variance is to reduce the significance of the pollution variables.
RESULTS Pollution Measurements Table 1 shows the distribution of pollution measurements in the five study areas. Duisburg and K61n, in the industrial western part of the FRG, have generally higher concentrations of particulates and sulfur dioxide in the air. Freudenstadt, in the rural south, had SO 2 levels substantially lower than those of the other southern communities. Nitrogen dioxide levels were more equal, except in the rural area of Freudenstadt. Even the more polluted communities of Duisberg and K61n had pollution levels that were low compared to the U.S. ambient air quality standards. The 90th percentiles for TSP and SO 2 were less than half the 24-hr standards, for instance.
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SCHWARTZ ET AL. TABLE 2 STUDY PARTICIPATION AND COUNTS OF GROUP AND OBSTRUCTIVE BRONCHITIS PER AREA
Obstructive bronchitis
Croup Hospitals
Pediatricians
Cases
Mean (day)
Max (day)
2 3 1 2 1 9
20 67 35 39 31 192
1095 2916 1099 876 344 6330
1.1 2.9 1.5 1.2 0.5 --
11 19 11 7 4 --
Duisburg K61n Stuttgart Tfibingen Freudenstadt Total
1666 1896 703 120 370 4755
Cases mean (day)
Max (day)
1.7 1.9 1.0 0.2 0.5 --
15 I0 10 6 4
Disease Counts Table 2 shows the daily and total counts of croup and obstructive bronchitis in the five study areas. Most of the cases were mild or medium and about half of them occurred while the child had an infection or fever. Nearly twice as many boys than girls were reported. The hospitals had a slightly different clientele than the private pediatricians, with more first cases and more severe cases. Most of the attacks on Mondays were reported by pediatricians. Hospitals received more cases during the weekend. There was a clear autumn-winter peak in all time series, with the autumn peak being smaller every second year. Figure 1 shows the frequency distributions of croup cases per day in K61n during the study. It is clearly not normally distributed, with a pronounced skewness to the right.
Regression Results After filtering out seasonal and other cyclical patterns, today's, yesterday's, and two day's prior temperature and humidity, and their logarithms, were not significant predictors of croup symptoms in any study area. To obtain more conservative estimates of the pollution effects, the most significant weather variable in each city was included in subsequent models that tested pollution variables. A quadratic time term was included in the model in all of the cities except Duisburg, where it decreased the goodness of fit. For TSP, the logarithmic transform provided a better fit to the data. For nitrogen dioxide and sulfur dioxide the results were less clear, but the fit was somewhat better using the untransformed variable. The pollution on the concurrent day was always the best predictor. Table 3 shows the pollution regression results. TSP, NO2, and SO2 all showed significant associations with croup cases, with the strongest association with particulates and the weakest with SO 2. Air pollution levels were quite low in all five locations during the warmer months, and measurement error was a more important part of their variance. To ensure that neither measurement error nor the seasonal differences in pollution and illness affected our results, we repeated the regression models using only data from October to March. These results are shown in Table 4. The estimated coefficients for the three pollutants are essentially identical to those in Table 3.
POLLUTION AND RESPIRATORY ILLNESS 200 .
180
t
160. 140 >~ O ¢-
120 100
t~" q}
aO 60 40 20
0 0
1
2
3
4
5
6
7
8
9
10 11 12 15 14 15 1G 17 18 19
cases per day FIG. 1. Distribution of the daily number of cases of croup in K61n during the study period. Note the skewed, nonnormal distribution.
The serial correlation in the residuals was quite small and autoregressive parameters only improved some models. The impact on the pollution relationships of incorporating these parameters was minor. In two pollutant models, the collinearity between the pollution measures resulted in both pollutants being insignificant when both particulates (t = 1.44) and TABLE 3 REGRESSION RESULTS: ALL DAYS Regression coefficient (Standard error) Pollutant
Stuttgart
Duisburg
Kfln
Tfibingen
Freudenstadt
Overall
log TSP (100 Ixg/m3)
0.1372"* (---.0649)
0.2302*** (-+.0765)
0.0475 (---.0505)
0.1152"* (---.0485)
0.2839** (-+.1185)
0.1244"** (-+.0309)
NO2 (100 ~g/m 3
0.557*** (---.165)
0.520*** (-+.193)
0.0602 (---.141)
0.393* (---.206)
1.221" (-+.638)
0.416"** (-+.156)
SO2 (100 ixg/m3)
0.130 (-+.0930)
0.042 (-+.0712)
0.104"* (-+.0495)
-0.020 (-+.134)
0.080 (-+.189)
0.0831"* (---.0352)
* P < 0.10. ** P < 0.05. *** P < 0.01.
SCHWARTZ ET AL. TABLE 4 REGRESSIONRESULTS: OCTOBERTO MARCH ONLY Regression coefficient (Standard error) Pollutant
Stuttgart
Duisburg
K61n
Tiibingen
Freudenstadt
Overall
log TSP (100 i~g/m3)
0.0853 (-+0.0800)
0.3044*** (-+0.0113)
0.0789 0.1263"* (---0.0621) (+0.0618)
0.1980 (---0.1391)
0.1255"** (-+0.0351)
NO2 (100 izg/m3)
0.291 (---0.194)
0.493* (-+0.269)
0.169 (-+0.166)
0.411" (-+0.236)
1.255 (---0.778)
0.336*** (-+0.127)
SO 2 (100 ixg/m3)
0.122 (-+0.0995)
0.0177 (-+0.0867)
0.109"* (+0.0545)
0.0135 (---0.145)
0.0467 (-+0.229)
0.0830** (-+0.0396)
* P < 0.10. ** P < 0.05. *** P < 0.01.
N O 2 (t = 1.06) were together in a model. Particulates were significant (t = 2.80) and N O 2 marginally insignificant (t = 1.83) in models that also included SO2, which was insignificant (Itl < 1) in these cases. To illustrate the exposure-response relationship, regressions for each city were repeated using quintiles of nitrogen dioxide and TSP level (separately) within each city. This gives relative risks for four quintiles of exposure in each city relative to the lowest quintile in that city. To put these predictions on a comparable basis, the overall mean regression coefficients (0.1244 for TSP and 0.416 for NO2, as per Table 3) were used to compute the relative risk for the lowest quintile in each city relative to the lowest quintile in Freudenstadt. The relative risks for the exposure quintiles in all five cities were then plotted versus the mean pollution level in each quintile. The results are shown in Figs. 2 (TSP) and 3 (NO2). For comparison, the regression results in Table 3 indicate that a change in the daily pollution concentration from 10 izg/m 3 to 70 ixg/m3 would result in a relative risk of 1.28 using NO2 as the exposure measure, and 1.27 using TSP. In contrast to the results for croup no evidence of an association between air pollution and obstructive bronchitis was found. The coefficients of pollution were always insignificant and were negative about half of the time (results not shown).
DISCUSSION A significant relationship between short-term fluctuations in air pollution and short-term fluctuations in medical visits for croup symptoms was found in this study. The association holds after removing seasonal and even shorter-term variations, and controlling for weather. Similar results were found in four of the five areas, with a different pattern in KOln. The results were similar when the analysis was restricted to the cold months when both illness rates and air pollution are higher, except that the results for K61n became more similar to those of the other cities. In single pollutant models, the strongest relationship was found for particulates and the weakest for sulfur dioxide. In two pollutant models, SO2 was insignificant
POLLUTION AND RESPIRATORY ILLNESS
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25 50 75 IO0 total suspended particulates/.tg/m3
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.... Stuttgart oo, Tuebingen
ooo Duisburg e e e Freudenstadt
&z~ K~ln
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FIG. 2. Relative risk of croup syndrome at different levels of total suspended particulates in five German communities. Each point represents the relative risk of croup for a quintile of particulate exposure in one of the communities, after adjusting by regression for weather and the trigonometric terms for seasonal and other fluctuations.
when either TSP o r NO 2 was in the model, and the other pollutant was significant (TSP) or marginally insignificant ( N O 2 ) . Moreover the regression coefficient of SO2 was much lower in the two pollutant models. This suggests that the association between SO2 and croup syndrome primarily reflects its correlation with other pollutants. When particulates and N O 2 w e r e considered together in a model, the significance levels of both pollutants were diminished. TSP remained slightly more significant (t -- 1.44 vs t = 1.06 for NO2). Taken together with the greater significance of TSP in the single pollutant models and in models with SO2 this suggests that particulates may be the more likely pollutant of interest for this outcome. However, the high degree of collinearity between these pollutants makes this conclusion tentative. Croup attacks are usually the product of viral infections. Most relevant are parainfluenza viruses types 1-3, but influenza viruses type A or B and respiratory syncytial (RS) virus may also lead to croup attack (Denny et al., 1983). McConnochie et al. (1988) reporting on 152 cases of croup in a pediatric practice found 27% associated with parainfluenza I and 3; 20% with RS; and 17% with influenza A. Air pollution might play a role in the number of physicians visits for these conditions by increasing the risk of infection, for example, by modulating the
10
SCHWARTZ
ET AL.
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ICITY .... Stuttgart
o~o Tuebingen
ooo Duisburg
eee Freudenstadt
7o
~K~ln
no
90
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FI~. 3. Relative risk of croup syndrome at differentlevels of nitrogen dioxide in five German communities.Each point represents the relativerisk of croup syndromefor a quintileof NO2 exposure in one of the communities,after adjustingby regressionfor weather and the trigonometricterms for seasonal and other fluctuations. immune system in the lung through physical irritation or other processes. High levels of NO 2 have been associated with reduced immunoresponse to infective agents in animal models (Parken et al., 1989). Three hours of exposure of human subjects to 0.60 ppm NO2 has been associated with reduced ability to inactivate influenzea virus in vitro by human alveolar macrophages obtained by bronchoaveolar lavage (Frampton et al., 1989). Continuous exposure was more potent than the equivalent average dose delivered in short-term peaks. Whether longerterm exposure to lower doses is similarly active is not known. The doses in these studies were much higher than those observed in this study. The better correlation with current day's exposure than with previous day's pollution suggests a rapid mechanism of action if this association is causal. The average of today's plus yesterday's pollution had as much predictive power as current days' pollution, however (results not shown). Given the high correlation between the two measures, it is not possible to distinguish in this study whether the 24- or 48-hr average is the better predictor. As reported earlier (Wichmann et al., 1990a,b) croup attacks are more frequently observed on wet days with temperatures above 0°C in autumn and winter, compared to dry and very cold days. Although there is no significant influence of temperature and humidity in the current analysis, in most cities the regression
P O L L U T I O N AND RESPIRATORY ILLNESS
11
coefficient of both is positive, suggesting a small contribution of wet mild weather to the number of daily attacks. It remains open whether this is a direct effect of weather, or whether the conditions for the spread of the relevant viruses are better. The overall result of the regression analysis (relative risks of 1.28 or 1.27 for a 70 ~g/m3 increase in NO2 or TSP) is larger than the observed increase in croup cases during a 7-day smog episode that occurred in Duisburg and Kfln during the study period. TSP concentrations averaged several hundred micrograms per cubic meter higher during the episode, and NO2 was elevated by over a hundred micrograms per cubic meter. Cases of croup increased by 31% in Krln and 40% in Duisburg during the episode. This may be due to the extreme cold weather during the period, or to normal sample variability, given the small number of cases per day for this outcome. Short-term exposure to particulates has been linked to increased reporting of both lower respiratory symptoms and cough in grade school children (Schwartz et al., 1989). This association, like the one seen in our study, occurred at concentrations below the current U.S. ambient air quality standards. TSP has also been associated with respiratory symptoms in a diary study of preschool children in Switzerland (Braun-F~ihrlander et al., 1990). Again the concentrations were quite low. Daily hospital admissions for respiratory conditions have been associated with PM10 concentrations in both Utah and Salt Lake counties in Utah by Pope (1989, 1991), again at concentrations similar to those seen in our study. In a subsequent study, PM10 was associated with both peak flow decrements and increased symptoms in a diary study of mildly asthmatic children (Pope, 1991; Pope et al., in press). Bates and Sizto (1987) have reported a strong association between sulfate particulate concentration and hospital admissions for respiratory conditions in 79 hospitals in Southern Ontario. TSP and respirable particles were associated with emergency room visits in a study in Israel (Gross et al., 1984). Acute respiratory symptoms in adults have been associated with particulates in analyses of the Health Interview Survey by Ostro and Rothschild (1989). Studies of chronic exposure to air pollution are of less direct relevance to our findings of acute effects, but are useful in documenting the association between particulates and respiratory health. Dockery et al. (1989) have recently reported a strong association between annual average PMI5 concentrations and acute bronchitis in school children in the Harvard Six City Study. Long-term exposure to TSP has also been associated with respiratory symptoms and bronchitis in a prospective followup of Seventh Day Adventists (Euler et al., 1988). Children living in areas with higher exposure to particulates and SO2 have been shown to have a higher prevalence of bronchial secretion during colds than children in less exposed areas, after controlling for personal risk factors and other exposures (Spinaci et al., 1985). In summary, an impressive body of literature has been developing associating long-term and short-term exposure to particulates with respiratory conditions. Some of these conditions are primarily infectious, and the role of particulates presumably is to either enhance infectivity or exacerbate symptoms. Others may represent a direct irritant effect. Nitrogen dioxide exposure has also been linked to reporting of sore throat and coughing with phlegm in a diary study of student nurses (Schwartz and Zeger,
12
SCHWARTZ ET AL.
1990). However the latter study did not have daily measurements of particulates, so the possibility of confounding with TSP, as seen in this study, could not be examined. The Swiss diary study (Braun-Fahrl~inder et al., 1990) also reported an association with NO 2 and particulates, with the particulate association the stronger one. A considerable body of literature has examined the association of either gas stove use, as a proxy for indoor NO2 exposure, or NO2 measurements directly, and respiratory health. The literature has been reviewed and summarized by Samet and colleagues (1987), and presents a mixed picture, with weak evidence for any effect. A recent large study using passive NO2 samplers found no association with chronic respiratory conditions (Dijkstra et al., 1990). Acute effects were not assessed. One recent discovery of possible relevance to the indoor studies is the recent discovery (Bult et al., 1990) that NO is a nonadrenergic noncholinergic neurotransmitter leading to smooth muscle relaxation, including in lung tissue. NO is produced by the same processes as NO2, but is rapidly converted to NO2 in the outdoor air. The situation may be different in the indoor environment, however, which may tend to supress any NO2 effects. Hence the situation is more mixed for NO2 than for particles. While the association we found may be due to confounding with particles, this study has been unable to separate the effects. Again, several studies have now reported associations between NO2 exposure and respiratory symptoms, and despite the confounding with particulate matter these associations deserve to be taken seriously.
ACKNOWLEDGMENTS Dr. Schwartz was supported in part by a travel grant from the DAAD. This study was supported in part by the European Research Program on Measures for Air Pollution Control and the Ministry for Environment, Land Use Planning, and Agriculture of the State of North Rhine-Westphalia, FRG.
REFERENCES Bates, D. V., and Sizto, R. (1987). Hospital admissions and air pollutants in Southern Ontario: The acid summer haze effect. Environ. Res. 43, 317-331. Bates, D. V., Baker-Anderson, M. Sizto, R. (1990). Asthma attack periodicity: A study of hospital emergency visits in Vancouver. Environ. Res. 51, 51-70. Bouhuys, A., Beck, G. J., and Schoenberg, J. B. (1978). Do present levels of air pollution affect respiratory health? Nature (London) 276, 464. Braun-Fahrl~inder, C., Ackermann-Liebrich, U., Schwartz, J., Grehm, H. P., Rutishauser, M., and Wanner, H. U. (1990). Air pollution and respiratory symptoms in pre-school children. Am. Rev. Respir. Dis., Abstract. Breslow, N. E., and Day, N. E. (1982). Statistical methods in cancer Research II: The Design and analysis of cohort studies. IARC, Lyon, France. Bult, H., Boeckxstaens, G. E., Pelckmans, P. A., Jordaens, F. H., Van Maercke, Y. M., and Herman, A. G. (1990). Nitric oxide as an inhibitory non-adrenergic non-cholenergic neurotransmitter. Nature 345, 346-347. Dassen, W., Brunekreef, B., Hoek, G., et al. (1986). Decline in children's pulmonary function during an air pollution episode. JAPCA 36, 1233. Denny, F. W., Murphy, T. F., Clyde, W. A., Collier, A. M., and Henderson, F. W. (1983). Croup: A 11 year study in a pediatric practice. Pediatrics 71, 871-876. Detels, R., Sayre, J. W., Coulson, A. H., Rokaw, S. N., Massey, F. J., Jr., Tashking, D. P., and Wu,
POLLUTION AND RESPIRATORY ILLNESS
13
M. (1981). Respiratory effect on long term exposure to two mixes of air pollutants in Los Angeles County. Chest 80, 275. Dijkstra, L., Houthuijs, D., Brunekreef, B., Akkerman, I., and Boleij, J. S. M, (1990). Respiratory health effects of the indoor environmentin a population of Dutch Children. Am. Rev. Respir. Dis. 142, 1172-1178. Dockery, D. W., Ware, J. H., Ferris, B. G. Jr., Speizer, F. E., Cook, N. R., and Hermann, S. M. (1982). Change in pulmonary function in children associated with air pollution episodes. JAPCA 32, 937--42. Dockery, D. W., Speizer, F. E,, Strata, D. O., Ware, J. H., Spengler, J. D., and Ferris, B. G., Jr. (1989). Effects of inhaled particles on respiratory health of children. Am. Rev. Respir. Dis. 39, 587-594. Euler, G. L., Sbbey, D. E., Hodgkin, J. E., and Magie, A. R. (1988). Chronic obstructive pulmonary disease symptom effects of long term cumulative exposure to ambient levels of total oxidants and nitrogen dioxide in California Seventh-Day adventist residents. Arch. Environ. Health, 43, 279285. Ferris, B. G., Jr., Higgins, J, T. T., Higgins, M. W., Peters, J. M., Van Gunse, W. F., and Goldman, M. D. (1971). Chronic non-specific respiratory disease, Berlin, New Hampshire, 1961-1967. A cross sectional study. Am. Rev. Respir. Dis. 104, 232. Frampton, M. W., Smeglin, A. M., Roberts, N. J. Jr., Finkelstein, J. N., Morrow, P. E., Vtell, M. J. (1989). Nitrogen dioxide exposure in vivo and human alveolar macrophage inactivation of influenza virus in vitro. Environ. Res. 48, 179-192. Franke, H., and Wichmann, H. E. (In press). Mathematical model of parainfluenza virus type 1 infections. In "Advances in Systems Analysis" (D. Mrller, Ed.), Vol. 3. Vieweg Braunschweig, FRG. Franke, K., Wichmann, H. E., Boeriu, A. et al. (In press). A 3 year cohort study on short term effects of air pollution in the FRG. 1. Influence of medication and season. Environ. Health Perspect. Gross, J., Goldsmith, J. R., Zangwill, L., and Lerman, S. (1984). Monitoring of hospital emergency room visits as a method for detecting health effects of environmental exposures. Sci. Total Environ. 32, 289-302. Hatzakis, A., Katsouyanni, K., Kalandidi, A., Day, N., and Trichopoulos, D. (1986). Short term effects of air pollution on mortality in Athens. Int. J. Epidemiol. 15, 73-81. Kinney, P., Ware, J. H., Spengler, J. D., Dockery, D. W., Speizer, F. E., and Ferris, B. G., Jr. (1989). Short term pulmonary function change in association with ozone levels. Am. Rev. Respir. Dis. 139, 56--61. Korn, E. L., and Whittemore, A. S. (1979) Methods of analyzing panel studies of acute health effects of air pollution. Biometrics 35, 745--802. Lebowitz, M. D., Holberg, C. J., Boyer, B., and Hayes, C. 0985). Respiratory symptoms and peakflow associated with indoor and outdoor pollutants in the South West. JAPCA 35, 1154-1158 Lioy, P. J., Vollmuth, T., and Lippmann, M. (1985). Persistence of peak flow decrements following ozone exposure exceeding the national ambient air quality standards. JAPCA 35, 1068. Lunn, J. E., Knowelden, J., and Roe, J. W. (1967). Patterns of respiratory illness in Sheffield school children. Br. J. Prey. Soc. Med. 21, 7-16. Martin, A. E., and Bradley, W. H. (1960). Mortality, fog and atmospheric pollution: An investigation during the winter of 1958-59. Monthly Bull. Min. Health Public Health Lab. Set. 19, 56-72. Mazumdar, S., Schimmel, H., and Higgens, I. T. T. (1982). Relation of daily mortality to air pollution: An analysis of 14 London Winters 1958/59-1971/72.Arch. Environ. Health 37, 213-20. McConnochie, K. M., Hall, C. B., Barker, W. H. (1988). Lower respiratory tract illness in the first two years of life: Epidemiologic patterns and costs in a suburban pediatric practice, Am. J. Publ. Health 78(1), 34-9. McCullagh, D., and Nelder, J. A. (1983). "Generalized Linear Models." Chapman and Hall, London. Ostro, B. D., and Rothschild, S. (1989). Air pollution and acute respiratory morbidity: An observational study of multiple pollutants. Environ. Res. 50, 238-247. Ozkaynak, H., Spengler, J. D., Garsd, A., and Thurston, G. D. (1986). Assessment of population health risks resulting from exposures to airborne particles. In "Aerosols" (S. D. Lee, T. Schneider, L. D. Grant, and P. J. VanKerk, Eds), pp. 1067-1080. Lewis Publishers, Chelsea, MI.
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Parken, R. F., Davis, J. K., Cassell, G. H., White, H., Dziedzic, D., Blalock, D. K., Thorp, R. B., and Simeca, K. W. (1989). Short term exposure to nitrogen dioxide enhances susceptibility to murine respiratory mycoplasmosis and decreased intrapulmonary killing mycoplasma pulmonis. Am. Rev. Respir. Dis. 140, 502-512. Pope, C. A. (1989). Respiratory disease associated with community air pollution and a steel mill, Utah Valley. Am. J. Publ. Health 79, 623-628. Pope, C. A. (1991). Respiratory hospital admissions associated with PM10 pollution in Utah, Salt Lake, and Cache Counties. Arch. Environ. Health 46, 90-97. Pope, C. A., Dockery, D. W., Spengler, J. D., and Raizenne, M. E. (In press). Respiratory health and PM10 pollution: A daily time series analysis. Am. Rev. Respir. Dis. Samet, J. M., Marbury, M. C., and Spengler, J. D. (1987). Health effects and sources of indoor air pollution, I. Am. Rev. Respir. Dis. 136, 1486-1508. Sawicki, F., and Lawrence, P. S. (1977). "Chronic Non-specific Lung Disease in the City of Crackow." National Institute of Hygiene, Warsaw, Poland. Schwarz, J., Dockery, D. W., Ware, J. H., Spengler, J. D., Wypij, D., Koutrakis, P., Speizer, F. E., and Ferris, B. J., Jr. (1989). Acute effects of acid aerosols on respiratory symptom reporting in children. Air Pollution Control Assoc. 89, 92.1. Schwartz, J., and Marcus, A. (1990). Mortality and air pollution in London: A time series analysis. Am. J. Epidemiol. 131, 185-194. Schwartz, J., and Zeger, S. L. (1990). Passive smoking, air pollution and acute respiratory symptoms in a diary study of students nurses. Am. Rev. Respir. Dis. 141, 62-67. Schwartz, J., and Dockery, D. W., Particulate air pollution and daily mortality in Steubenville, Ohio. (In press). A m J. Epidemiol. Spektor, M., Lippmann, M., Lioy, P. J., et al. (1988). Effects of ambient ozone on respiratory function in active normal children. Am. Rev. Respir. Dis. 137, 313. Spinaci, S., Arossa, W., Bugiani, M., Natale, P., Bucca, C., and de Candussio, G. (1985). The effects of air pollution on the respiratory health of children: A cross-sectional study. Pediatr. Pulmonol. 1, 262-266. Wichmann, H. E., Mueller, W., Allhoff, P., Beckmann, M., Bocter, N., Csicsaky, M. J., Jung, M., Molik, B., and Schoeneberg, G. (1989). Health effects during a smog-episode in West Germany in 1985. Environ. Health Perspect. 79, 89-99. Wichmann, H. E., Malin, E., Huebner, H. R., and Schlipkoeter, H. W. (1990a). Zusammenfassende Bewertung der "Pseudokrupp-Studien" in Baden-Wfirttemberg und Nordrhein-Westfalen. KfKPEF64, pp. 1-125. Wichmann, H. E., and SchlipkOter, H. W. (1990b). Klndliche Atemsegserkrankungen und Lufschadstoffe--Ergebnisse der loordinierten Psuedokruppstidien. Deutsches Arzteblatt 87, 1533-1546. Wichmann, H. E., and Franke, H. (In press). Croup syndrome and parainfluenza virus type 1 infections--A model analysis. In "Advances in Systems Analysis" (D. Mfller, Ed.), Vol. 3. Vieweg Braunschweg, FRG. Wichmann, H. E., Sugiri, D., Islam, M. S., Haake, D., and Roscovanu, A. (1988). Lungenfunktion und carboxyh~imoglobin in der smogsituation des Januar 1987. ZbL Bakt. Hyg. B 187, 31-43. Zeger, S. L., and Liang, K.-Y. (1986) Longitudinal data analysis for discrete and continuous outcomes. Biometrics 42, 121-130.
Air Pollution and Acute Respiratory Illness in Five German Communities J. SCHWARTZ,* C. SeIx,t
H . E . WICHMANN,'~ AND E . M A L I N ~
*U.S. Environmental Protection Agency, PM221, ,#01 M Street S.W., Washington, D.C. 20460; TDepartment of Labor Safety and Environmental Medicine, University of Wuppertal, 5600 Wuppertal 1, Wuppertal, Federal Republic of Germany; and SMedical Institute for Environmental Hygiene, University of Dusseldorf, Dusseldorf, Federal Republic of Germany Received January 30, 1991 To assess the impact of short-term exposure to air pollution on respiratory illness in children we recruited pediatricians and hospitals in five German cities to report daily counts of children's visits for croup symptoms and obstructive bronchitis. Data were collected for at least 2 years in each location. These symptoms are predominantly found in very young children, with the croup reporting peaking at 2 years of age and obstructive bronchitis at 1 year. Attacks of croup and obstructive bronchitis were relatively rare events: the mean number of cases of croup per day in each city ranged from 0.5 to 3, and obstructive bronchitis was even less frequent. A total of 6330 cases of croup and 4755 cases of obstructive bronchitis were observed during the study. The distributions of these events were quite skewed and were modeled as a Poisson process. To focus the analysis on short-term correlations and avoid seasonal confounding, biannual, annual (seasonal), and six shorter term cycles were controlled for in the regression models. After controlling for short-term weather factors, total suspended particulate matter (TSP) and nitrogen dioxide ( N O 2 ) w e r e associated with croup cases. An increase in TSP levels from 10 ixg/m3 to 70 p~g/m3 was associated with a 27% increase in cases of croup; the same increase in N O 2 levels resulted in a 28% increase in cases. No pollutant was associated with dally cases of obstructive bronchitis. © 1991 Academic Press, Inc.
INTRODUCTION Cross-sectional analyses of differences in the prevalence rates of symptoms and illnesses, or of differences in lung function from predicted values, across areas with different long-term averages in air pollution have been conducted in the last 30 years (Detels et al., 1981; Lunn et al., 1967; Bouhuys et al., 1978; Ferris et al., 1971; Sawicki and Lawrence, 1977). More recently, attention has focused on longitudinal studies of possible associations between air pollution and respiratory outcomes. Longitudinal studies are attractive because the populations studied serve as their own control, eliminating a potential source of bias in cross-sectional studies. Diary studies have examined daily fluctuations in respiratory symptoms (Korn and Whittemore, 1979; Lebowitz et al., 1985; Schwartz and Zeger, 1990; Schwartz et al., 1989; Franke et al., in press). In general these studies have found significant associations between relatively low concentrations of air pollution and reports of respiratory symptoms. These symptoms have been either self-reported or reported by parents. Daily mortality has also been correlated with air pollution (Martin and Bradley, 1960; Mazumdar et al., 1982; Schwartz and Marcus, 1990; Hatzakis et al., 1986; Ozkaynak et al., 1986; Schwartz and Dockery, 1991). Lon-
0013-9351/91 $3.00 Copyright © 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.
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SCHWARTZ ET AL.
gitudinai studies during air pollution episodes have also examined short-term decrements in lung function (Lioy et al., 1985; Spektor et al., 1988; Dassen et al., 1986; Kinney et al., 1989; Dockery et al., 1982; Wichmann et al., 1988) and mortality (Wichmann et al., 1989). While diary studies provide excellent control for individual risk factors within the longitudinal framework, they suffer from the classic difficulty of prospective cohort studies when the outcomes are quite rare. The size of the sample needed to reliably study the outcome can become prohibitive. In such instances a population-based study has considerable attractiveness. Bates and Sizto have used this approach to examine the correlation between hospital admissions (1987) and emergency room visits (1990) and air pollution, for example. If the association between air pollution and respiratory symptoms that has been reported in the literature is a causal one, one would expect a similar association with physiciandiagnosed respiratory illness, which is a more objectively determined outcome. We recruited hospitals and pediatricians in five areas of Germany to participate in a longitudinal study of air pollution and the incidence of croup and obstructive bronchitis in preschool children. The study design was longitudinal, with each community representing its own control, but the data collected did not allow the analysis of individual time-invariant risk factors. This prevents the search for interactive effects between air pollution and such risk factors. An identification of potentially sensitive subgroups was therefore not possible. However, this design allowed a test for a possible association between rare acute respiratory illnesses and air pollution from a population of approximately 2.5 million without crosssectional confounding. The patterns of croup and bronchitis in preschool children have been reported on previously (McConnochie et al., 1988), but their possible association with air pollution was not explored in that study. MATERIAL AND METHODS
Study Design Children's hospitals, pediatrics departments of general hospitals, and all pediatricians in each study area were asked to participate in the study on a voluntary basis. Participation was about 50%. For each child the doctor filled in a short questionnaire per visit, which included disease (croup or obstructive bronchitis), time and date of attack, place of attack, whether the attack was mild, medium, or severe, whether it was the first or a recurrent attack, with or without an infection, and with or without fever. These were aggregated to give daily counts of attacks in each study area for each disease which is referred to as cases per day. A diagnosis of croup was defined as acute stenotic subglottic laryngotracheitis; typical symptoms are hoarseness and barking cough, inspiratory stridor, dyspnea, and a sudden onset. The most important factor in the etiology are parainfluenza viruses. Obstructive bronchitis applies to the lower airways, where an inflammatory swelling of the mucosa and increased secretion lead to an obstruction of the bronchioles. The most important symptoms is exspiratory dyspnea. It is also usually the result of a viral infection. We assume that a fraction of the cases diagnosed as obstructive bronchitis had a bronchiolitis, since it is difficult to
POLLUTION AND RESPIRATORY ILLNESS
3
differentiate between these two diagnoses in very small children. Detailed descriptive statistics for the data by region, severity, hospital versus pediatrician cases, etc., have been reported previously (Wichmann et al., 1990a,b). Both diseases affect mostly preschool children, with the maximum of the age distribution at 2 years and 1 year, respectively. Because croup and obstructive bronchitis show a very notable seasonality and croup shows additionally a 2-year period, all studies ran over at least 2 years. Not all doctors reported for the full 2 years; we observed a loss of roughly 50% over the study period. This loss was modeled in the analysis, as described under the methods section below. All of the air pollution monitors in each study area were averaged to give a complete record of 24-hr measurements. The number of monitoring locations varied by area and pollutant, and is shown in Table 1. For each area, the daily mean temperature and relative humidity were also obtained.
Study Areas, Meteorology, and Pollution Data The areas analyzed here were chosen to cover a range of locations with different degrees of air pollution over the western part of the Federal Republic of Germany (FRG). Two communities were located in highly industrialized areas of Northrhine-Westfalia: in Duisburg (a city of about 550,000 inhabitants, situated north of Kfln in the lower Rhine plain); and Krln (a city of nearly 1,000,000 inhabitants, situated in the Rhine valley, where it opens to the plain). Data were collected from January 1983 to August 1985 in Duisburg and from September 1984 to April 1987 in Kfln. Three of the studied areas were located in South Germany. In each area, data TABLE 1 DISTRIBUTION OF 502, TSP, AND NO 2 24-HR MEASUREMENTSBY STUDY AREA OVER THE STUDY PERIOD
SO2 Duisburg txg/m3 K61n
Stuttgart Tiibingen Freudenstadt TSP Duisburg ~g/m3 K61n
Stuttgart Tiibingen Freudenstadt NO2 Duisburg I~g/m3 K61n
Stuttgart Tiibingen Freudenstadt
Quantiles
No. of days
No. of monitors
Miss.
10%
25%
50%
75%
90%
974 972 730 730 730
3 4 4 zAa zA
0.1 1.3 4.5 16.2 22.1
24 19 8 4 2
32 27 14 8 4
48 37 24 16 9
71 57 42 28 17
113 101 75 59 40
974 972 730 730 365
3 4 4 2A~ 1
0.9 1.8 4.4 15.3 15.3
34 28 11 6 5
42 35 14 10 9
56 48 21 20 17
79 70 33 39 28
118 102 51 69 41
974 972 730 730 730
3 4 4 ~ 2//3a
0.1 1.3 4.7 15.8 28.0
28 34 35 20 6
36 41 44 28 9
44 49 55 41 14
55 59 67 57 21
68 73 84 74 33
Two monitors in 1986, three in 1987.
%
4
SCHWARTZ ET AL.
were collected from January 1986 to December 1987. These were: Stuttgart (an industrial city of about 550,000 inhabitants, situated in a bowl surrounded by hills and small mountains); Tiibingen/Reutlingen including 8 surrounding towns and villages (together about 250,000 inhabitants, in a mountainous, mostly rural area, except the big university of Tiibingen and the textile goods industry of Reutlingen; and in Freudenstadt and 16 surrounding towns and villages (together about 100,000 inhabitants, in a mountainous, rural area). NO2 was measured by chemiluminescence and SO 2 by conductometric method, both using a continuous sampler and reporting half hourly. Total suspended particulate matter (TSP) were collected by a low volume sampler using a continuous tape filter, and measured by beta attenuation, reporting every 3 hr. The 24-hr average of each monitor was computed, and the average of all monitors in each area was then taken.
Analytical Metkodology The distribution of daily counts of such rare events as physicians visits for croup symptoms is not Gaussian. Rather it has a low mean (about one to three visits per day in each area) with a long tail. Such skewed distributions of rare events are usually modeled as Poisson processes (McCullagh and Nelder, 1983). We have used Poisson regressions to analyze these data. Our basic strategy was to first fit models that best accounted for seasonal patterns, weather, and other temporal factors. To more conservatively estimate the effect of air pollution, marginally insignificant weather terms were kept in the model. Once the best such model was obtained for each city, air pollution was tested for its association.
Model Specifications Poisson regressions typically assume an exponential relationship between risk factors and the expected number of events (Breslow and Day, 1982). This specification for a categorical variable gives the relative risk for that factor. For a continuous exposure variable it assumes an exponentially increasing response with dose, which is not necessarily the case. Breslow and Day have extensively discussed this issue for prospective studies, and suggest that a logarithmic transformation of the continuous covariates may be appropriate. We have considered such a transformation for both pollution for both pollution and weather terms in our models, as well as the nontransformed variables. There is considerable collinearity between different pollutants. We have approached this problem by examining each pollutant separately to see if an association existed. If an association existed with more than one pollutant, we then considered multiple pollutant models. Current days' pollution, as well as pollution I and 2 clays prior to each reporting day was considered to allow for the possibility of a lag between exposure and response. Temperature and humidity were treated similarly.
Serial Correlation and Temporal Patterns Illness usually varies seasonally, displaying an annual cycle with winter peaks. A 2-year cycle has also been noted in croup data (Wichmann et al., 1990a,b;
POLLUTION AND RESPIRATORY ILLNESS
Franke et al., 1990; Wichmann and Franke, in press). Our hypothesis was that short-term pollution exposure might influence acute respiratory illness. To investigate this it is necessary to remove longer-term fluctuations in the data, so the relationship is not influenced by, e.g., the seasonal differences in pollution and in illness rates. We have done this by including sine and cosine terms for biannual and annual cycles, and for the six additional periods 730/k days, k = 3 to 8. The natural logarithm of the number of reporting physicians was used as an offset in the models for the three South German communities to control for the dropout of physicians over time. These data were not kept in the two Western German communities. To model trends in participation as well as in other factors that might effect respiratory visits, we included a linear term for time trend in every model. A quadratic time term was also included if its t statistic exceeded one. These terms were also included in the models for the South German cities. Day of the week effects were examined using dummy variables for each day. Insignificant daily dummies were dropped. Shorter-term serial correlation may still remain in such a model. We examined the residuals of each model for serial correlation up to a lag of 30 days. Each model was refit using an autoregressive covariance structure, following the approach of Zeger and Liang (1986), which incorporates the serial correlation in the covariance. To be conservative, autoregressive terms were included in the covariance if the model goodness of fit ×z statistic, adjusted for degrees of freedom, improved. This is equivalent to including all terms whose t statistic exceeds one. Random Effects Model Once final regression models were obtained in each study area, the results were combined to yield an overall estimate of pollutant effect and its significance. The classical estimate is simply the mean coefficient, weighted by the inverse of its variance. However, random factors may lead to greater variability between cities than the within city variances would indicate. We have estimated this additional variance using the method of moments, and incorporated it in estimation of the overall mean and its standard error. The effect of this additional variance is to reduce the significance of the pollution variables.
RESULTS Pollution Measurements Table 1 shows the distribution of pollution measurements in the five study areas. Duisburg and K61n, in the industrial western part of the FRG, have generally higher concentrations of particulates and sulfur dioxide in the air. Freudenstadt, in the rural south, had SO 2 levels substantially lower than those of the other southern communities. Nitrogen dioxide levels were more equal, except in the rural area of Freudenstadt. Even the more polluted communities of Duisberg and K61n had pollution levels that were low compared to the U.S. ambient air quality standards. The 90th percentiles for TSP and SO 2 were less than half the 24-hr standards, for instance.
6
SCHWARTZ ET AL. TABLE 2 STUDY PARTICIPATION AND COUNTS OF GROUP AND OBSTRUCTIVE BRONCHITIS PER AREA
Obstructive bronchitis
Croup Hospitals
Pediatricians
Cases
Mean (day)
Max (day)
2 3 1 2 1 9
20 67 35 39 31 192
1095 2916 1099 876 344 6330
1.1 2.9 1.5 1.2 0.5 --
11 19 11 7 4 --
Duisburg K61n Stuttgart Tfibingen Freudenstadt Total
1666 1896 703 120 370 4755
Cases mean (day)
Max (day)
1.7 1.9 1.0 0.2 0.5 --
15 I0 10 6 4
Disease Counts Table 2 shows the daily and total counts of croup and obstructive bronchitis in the five study areas. Most of the cases were mild or medium and about half of them occurred while the child had an infection or fever. Nearly twice as many boys than girls were reported. The hospitals had a slightly different clientele than the private pediatricians, with more first cases and more severe cases. Most of the attacks on Mondays were reported by pediatricians. Hospitals received more cases during the weekend. There was a clear autumn-winter peak in all time series, with the autumn peak being smaller every second year. Figure 1 shows the frequency distributions of croup cases per day in K61n during the study. It is clearly not normally distributed, with a pronounced skewness to the right.
Regression Results After filtering out seasonal and other cyclical patterns, today's, yesterday's, and two day's prior temperature and humidity, and their logarithms, were not significant predictors of croup symptoms in any study area. To obtain more conservative estimates of the pollution effects, the most significant weather variable in each city was included in subsequent models that tested pollution variables. A quadratic time term was included in the model in all of the cities except Duisburg, where it decreased the goodness of fit. For TSP, the logarithmic transform provided a better fit to the data. For nitrogen dioxide and sulfur dioxide the results were less clear, but the fit was somewhat better using the untransformed variable. The pollution on the concurrent day was always the best predictor. Table 3 shows the pollution regression results. TSP, NO2, and SO2 all showed significant associations with croup cases, with the strongest association with particulates and the weakest with SO 2. Air pollution levels were quite low in all five locations during the warmer months, and measurement error was a more important part of their variance. To ensure that neither measurement error nor the seasonal differences in pollution and illness affected our results, we repeated the regression models using only data from October to March. These results are shown in Table 4. The estimated coefficients for the three pollutants are essentially identical to those in Table 3.
POLLUTION AND RESPIRATORY ILLNESS 200 .
180
t
160. 140 >~ O ¢-
120 100
t~" q}
aO 60 40 20
0 0
1
2
3
4
5
6
7
8
9
10 11 12 15 14 15 1G 17 18 19
cases per day FIG. 1. Distribution of the daily number of cases of croup in K61n during the study period. Note the skewed, nonnormal distribution.
The serial correlation in the residuals was quite small and autoregressive parameters only improved some models. The impact on the pollution relationships of incorporating these parameters was minor. In two pollutant models, the collinearity between the pollution measures resulted in both pollutants being insignificant when both particulates (t = 1.44) and TABLE 3 REGRESSION RESULTS: ALL DAYS Regression coefficient (Standard error) Pollutant
Stuttgart
Duisburg
Kfln
Tfibingen
Freudenstadt
Overall
log TSP (100 Ixg/m3)
0.1372"* (---.0649)
0.2302*** (-+.0765)
0.0475 (---.0505)
0.1152"* (---.0485)
0.2839** (-+.1185)
0.1244"** (-+.0309)
NO2 (100 ~g/m 3
0.557*** (---.165)
0.520*** (-+.193)
0.0602 (---.141)
0.393* (---.206)
1.221" (-+.638)
0.416"** (-+.156)
SO2 (100 ixg/m3)
0.130 (-+.0930)
0.042 (-+.0712)
0.104"* (-+.0495)
-0.020 (-+.134)
0.080 (-+.189)
0.0831"* (---.0352)
* P < 0.10. ** P < 0.05. *** P < 0.01.
SCHWARTZ ET AL. TABLE 4 REGRESSIONRESULTS: OCTOBERTO MARCH ONLY Regression coefficient (Standard error) Pollutant
Stuttgart
Duisburg
K61n
Tiibingen
Freudenstadt
Overall
log TSP (100 i~g/m3)
0.0853 (-+0.0800)
0.3044*** (-+0.0113)
0.0789 0.1263"* (---0.0621) (+0.0618)
0.1980 (---0.1391)
0.1255"** (-+0.0351)
NO2 (100 izg/m3)
0.291 (---0.194)
0.493* (-+0.269)
0.169 (-+0.166)
0.411" (-+0.236)
1.255 (---0.778)
0.336*** (-+0.127)
SO 2 (100 ixg/m3)
0.122 (-+0.0995)
0.0177 (-+0.0867)
0.109"* (+0.0545)
0.0135 (---0.145)
0.0467 (-+0.229)
0.0830** (-+0.0396)
* P < 0.10. ** P < 0.05. *** P < 0.01.
N O 2 (t = 1.06) were together in a model. Particulates were significant (t = 2.80) and N O 2 marginally insignificant (t = 1.83) in models that also included SO2, which was insignificant (Itl < 1) in these cases. To illustrate the exposure-response relationship, regressions for each city were repeated using quintiles of nitrogen dioxide and TSP level (separately) within each city. This gives relative risks for four quintiles of exposure in each city relative to the lowest quintile in that city. To put these predictions on a comparable basis, the overall mean regression coefficients (0.1244 for TSP and 0.416 for NO2, as per Table 3) were used to compute the relative risk for the lowest quintile in each city relative to the lowest quintile in Freudenstadt. The relative risks for the exposure quintiles in all five cities were then plotted versus the mean pollution level in each quintile. The results are shown in Figs. 2 (TSP) and 3 (NO2). For comparison, the regression results in Table 3 indicate that a change in the daily pollution concentration from 10 izg/m 3 to 70 ixg/m3 would result in a relative risk of 1.28 using NO2 as the exposure measure, and 1.27 using TSP. In contrast to the results for croup no evidence of an association between air pollution and obstructive bronchitis was found. The coefficients of pollution were always insignificant and were negative about half of the time (results not shown).
DISCUSSION A significant relationship between short-term fluctuations in air pollution and short-term fluctuations in medical visits for croup symptoms was found in this study. The association holds after removing seasonal and even shorter-term variations, and controlling for weather. Similar results were found in four of the five areas, with a different pattern in KOln. The results were similar when the analysis was restricted to the cold months when both illness rates and air pollution are higher, except that the results for K61n became more similar to those of the other cities. In single pollutant models, the strongest relationship was found for particulates and the weakest for sulfur dioxide. In two pollutant models, SO2 was insignificant
POLLUTION AND RESPIRATORY ILLNESS
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FIG. 2. Relative risk of croup syndrome at different levels of total suspended particulates in five German communities. Each point represents the relative risk of croup for a quintile of particulate exposure in one of the communities, after adjusting by regression for weather and the trigonometric terms for seasonal and other fluctuations.
when either TSP o r NO 2 was in the model, and the other pollutant was significant (TSP) or marginally insignificant ( N O 2 ) . Moreover the regression coefficient of SO2 was much lower in the two pollutant models. This suggests that the association between SO2 and croup syndrome primarily reflects its correlation with other pollutants. When particulates and N O 2 w e r e considered together in a model, the significance levels of both pollutants were diminished. TSP remained slightly more significant (t -- 1.44 vs t = 1.06 for NO2). Taken together with the greater significance of TSP in the single pollutant models and in models with SO2 this suggests that particulates may be the more likely pollutant of interest for this outcome. However, the high degree of collinearity between these pollutants makes this conclusion tentative. Croup attacks are usually the product of viral infections. Most relevant are parainfluenza viruses types 1-3, but influenza viruses type A or B and respiratory syncytial (RS) virus may also lead to croup attack (Denny et al., 1983). McConnochie et al. (1988) reporting on 152 cases of croup in a pediatric practice found 27% associated with parainfluenza I and 3; 20% with RS; and 17% with influenza A. Air pollution might play a role in the number of physicians visits for these conditions by increasing the risk of infection, for example, by modulating the
10
SCHWARTZ
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FI~. 3. Relative risk of croup syndrome at differentlevels of nitrogen dioxide in five German communities.Each point represents the relativerisk of croup syndromefor a quintileof NO2 exposure in one of the communities,after adjustingby regressionfor weather and the trigonometricterms for seasonal and other fluctuations. immune system in the lung through physical irritation or other processes. High levels of NO 2 have been associated with reduced immunoresponse to infective agents in animal models (Parken et al., 1989). Three hours of exposure of human subjects to 0.60 ppm NO2 has been associated with reduced ability to inactivate influenzea virus in vitro by human alveolar macrophages obtained by bronchoaveolar lavage (Frampton et al., 1989). Continuous exposure was more potent than the equivalent average dose delivered in short-term peaks. Whether longerterm exposure to lower doses is similarly active is not known. The doses in these studies were much higher than those observed in this study. The better correlation with current day's exposure than with previous day's pollution suggests a rapid mechanism of action if this association is causal. The average of today's plus yesterday's pollution had as much predictive power as current days' pollution, however (results not shown). Given the high correlation between the two measures, it is not possible to distinguish in this study whether the 24- or 48-hr average is the better predictor. As reported earlier (Wichmann et al., 1990a,b) croup attacks are more frequently observed on wet days with temperatures above 0°C in autumn and winter, compared to dry and very cold days. Although there is no significant influence of temperature and humidity in the current analysis, in most cities the regression
P O L L U T I O N AND RESPIRATORY ILLNESS
11
coefficient of both is positive, suggesting a small contribution of wet mild weather to the number of daily attacks. It remains open whether this is a direct effect of weather, or whether the conditions for the spread of the relevant viruses are better. The overall result of the regression analysis (relative risks of 1.28 or 1.27 for a 70 ~g/m3 increase in NO2 or TSP) is larger than the observed increase in croup cases during a 7-day smog episode that occurred in Duisburg and Kfln during the study period. TSP concentrations averaged several hundred micrograms per cubic meter higher during the episode, and NO2 was elevated by over a hundred micrograms per cubic meter. Cases of croup increased by 31% in Krln and 40% in Duisburg during the episode. This may be due to the extreme cold weather during the period, or to normal sample variability, given the small number of cases per day for this outcome. Short-term exposure to particulates has been linked to increased reporting of both lower respiratory symptoms and cough in grade school children (Schwartz et al., 1989). This association, like the one seen in our study, occurred at concentrations below the current U.S. ambient air quality standards. TSP has also been associated with respiratory symptoms in a diary study of preschool children in Switzerland (Braun-F~ihrlander et al., 1990). Again the concentrations were quite low. Daily hospital admissions for respiratory conditions have been associated with PM10 concentrations in both Utah and Salt Lake counties in Utah by Pope (1989, 1991), again at concentrations similar to those seen in our study. In a subsequent study, PM10 was associated with both peak flow decrements and increased symptoms in a diary study of mildly asthmatic children (Pope, 1991; Pope et al., in press). Bates and Sizto (1987) have reported a strong association between sulfate particulate concentration and hospital admissions for respiratory conditions in 79 hospitals in Southern Ontario. TSP and respirable particles were associated with emergency room visits in a study in Israel (Gross et al., 1984). Acute respiratory symptoms in adults have been associated with particulates in analyses of the Health Interview Survey by Ostro and Rothschild (1989). Studies of chronic exposure to air pollution are of less direct relevance to our findings of acute effects, but are useful in documenting the association between particulates and respiratory health. Dockery et al. (1989) have recently reported a strong association between annual average PMI5 concentrations and acute bronchitis in school children in the Harvard Six City Study. Long-term exposure to TSP has also been associated with respiratory symptoms and bronchitis in a prospective followup of Seventh Day Adventists (Euler et al., 1988). Children living in areas with higher exposure to particulates and SO2 have been shown to have a higher prevalence of bronchial secretion during colds than children in less exposed areas, after controlling for personal risk factors and other exposures (Spinaci et al., 1985). In summary, an impressive body of literature has been developing associating long-term and short-term exposure to particulates with respiratory conditions. Some of these conditions are primarily infectious, and the role of particulates presumably is to either enhance infectivity or exacerbate symptoms. Others may represent a direct irritant effect. Nitrogen dioxide exposure has also been linked to reporting of sore throat and coughing with phlegm in a diary study of student nurses (Schwartz and Zeger,
12
SCHWARTZ ET AL.
1990). However the latter study did not have daily measurements of particulates, so the possibility of confounding with TSP, as seen in this study, could not be examined. The Swiss diary study (Braun-Fahrl~inder et al., 1990) also reported an association with NO 2 and particulates, with the particulate association the stronger one. A considerable body of literature has examined the association of either gas stove use, as a proxy for indoor NO2 exposure, or NO2 measurements directly, and respiratory health. The literature has been reviewed and summarized by Samet and colleagues (1987), and presents a mixed picture, with weak evidence for any effect. A recent large study using passive NO2 samplers found no association with chronic respiratory conditions (Dijkstra et al., 1990). Acute effects were not assessed. One recent discovery of possible relevance to the indoor studies is the recent discovery (Bult et al., 1990) that NO is a nonadrenergic noncholinergic neurotransmitter leading to smooth muscle relaxation, including in lung tissue. NO is produced by the same processes as NO2, but is rapidly converted to NO2 in the outdoor air. The situation may be different in the indoor environment, however, which may tend to supress any NO2 effects. Hence the situation is more mixed for NO2 than for particles. While the association we found may be due to confounding with particles, this study has been unable to separate the effects. Again, several studies have now reported associations between NO2 exposure and respiratory symptoms, and despite the confounding with particulate matter these associations deserve to be taken seriously.
ACKNOWLEDGMENTS Dr. Schwartz was supported in part by a travel grant from the DAAD. This study was supported in part by the European Research Program on Measures for Air Pollution Control and the Ministry for Environment, Land Use Planning, and Agriculture of the State of North Rhine-Westphalia, FRG.
REFERENCES Bates, D. V., and Sizto, R. (1987). Hospital admissions and air pollutants in Southern Ontario: The acid summer haze effect. Environ. Res. 43, 317-331. Bates, D. V., Baker-Anderson, M. Sizto, R. (1990). Asthma attack periodicity: A study of hospital emergency visits in Vancouver. Environ. Res. 51, 51-70. Bouhuys, A., Beck, G. J., and Schoenberg, J. B. (1978). Do present levels of air pollution affect respiratory health? Nature (London) 276, 464. Braun-Fahrl~inder, C., Ackermann-Liebrich, U., Schwartz, J., Grehm, H. P., Rutishauser, M., and Wanner, H. U. (1990). Air pollution and respiratory symptoms in pre-school children. Am. Rev. Respir. Dis., Abstract. Breslow, N. E., and Day, N. E. (1982). Statistical methods in cancer Research II: The Design and analysis of cohort studies. IARC, Lyon, France. Bult, H., Boeckxstaens, G. E., Pelckmans, P. A., Jordaens, F. H., Van Maercke, Y. M., and Herman, A. G. (1990). Nitric oxide as an inhibitory non-adrenergic non-cholenergic neurotransmitter. Nature 345, 346-347. Dassen, W., Brunekreef, B., Hoek, G., et al. (1986). Decline in children's pulmonary function during an air pollution episode. JAPCA 36, 1233. Denny, F. W., Murphy, T. F., Clyde, W. A., Collier, A. M., and Henderson, F. W. (1983). Croup: A 11 year study in a pediatric practice. Pediatrics 71, 871-876. Detels, R., Sayre, J. W., Coulson, A. H., Rokaw, S. N., Massey, F. J., Jr., Tashking, D. P., and Wu,
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M. (1981). Respiratory effect on long term exposure to two mixes of air pollutants in Los Angeles County. Chest 80, 275. Dijkstra, L., Houthuijs, D., Brunekreef, B., Akkerman, I., and Boleij, J. S. M, (1990). Respiratory health effects of the indoor environmentin a population of Dutch Children. Am. Rev. Respir. Dis. 142, 1172-1178. Dockery, D. W., Ware, J. H., Ferris, B. G. Jr., Speizer, F. E., Cook, N. R., and Hermann, S. M. (1982). Change in pulmonary function in children associated with air pollution episodes. JAPCA 32, 937--42. Dockery, D. W., Speizer, F. E,, Strata, D. O., Ware, J. H., Spengler, J. D., and Ferris, B. G., Jr. (1989). Effects of inhaled particles on respiratory health of children. Am. Rev. Respir. Dis. 39, 587-594. Euler, G. L., Sbbey, D. E., Hodgkin, J. E., and Magie, A. R. (1988). Chronic obstructive pulmonary disease symptom effects of long term cumulative exposure to ambient levels of total oxidants and nitrogen dioxide in California Seventh-Day adventist residents. Arch. Environ. Health, 43, 279285. Ferris, B. G., Jr., Higgins, J, T. T., Higgins, M. W., Peters, J. M., Van Gunse, W. F., and Goldman, M. D. (1971). Chronic non-specific respiratory disease, Berlin, New Hampshire, 1961-1967. A cross sectional study. Am. Rev. Respir. Dis. 104, 232. Frampton, M. W., Smeglin, A. M., Roberts, N. J. Jr., Finkelstein, J. N., Morrow, P. E., Vtell, M. J. (1989). Nitrogen dioxide exposure in vivo and human alveolar macrophage inactivation of influenza virus in vitro. Environ. Res. 48, 179-192. Franke, H., and Wichmann, H. E. (In press). Mathematical model of parainfluenza virus type 1 infections. In "Advances in Systems Analysis" (D. Mrller, Ed.), Vol. 3. Vieweg Braunschweig, FRG. Franke, K., Wichmann, H. E., Boeriu, A. et al. (In press). A 3 year cohort study on short term effects of air pollution in the FRG. 1. Influence of medication and season. Environ. Health Perspect. Gross, J., Goldsmith, J. R., Zangwill, L., and Lerman, S. (1984). Monitoring of hospital emergency room visits as a method for detecting health effects of environmental exposures. Sci. Total Environ. 32, 289-302. Hatzakis, A., Katsouyanni, K., Kalandidi, A., Day, N., and Trichopoulos, D. (1986). Short term effects of air pollution on mortality in Athens. Int. J. Epidemiol. 15, 73-81. Kinney, P., Ware, J. H., Spengler, J. D., Dockery, D. W., Speizer, F. E., and Ferris, B. G., Jr. (1989). Short term pulmonary function change in association with ozone levels. Am. Rev. Respir. Dis. 139, 56--61. Korn, E. L., and Whittemore, A. S. (1979) Methods of analyzing panel studies of acute health effects of air pollution. Biometrics 35, 745--802. Lebowitz, M. D., Holberg, C. J., Boyer, B., and Hayes, C. 0985). Respiratory symptoms and peakflow associated with indoor and outdoor pollutants in the South West. JAPCA 35, 1154-1158 Lioy, P. J., Vollmuth, T., and Lippmann, M. (1985). Persistence of peak flow decrements following ozone exposure exceeding the national ambient air quality standards. JAPCA 35, 1068. Lunn, J. E., Knowelden, J., and Roe, J. W. (1967). Patterns of respiratory illness in Sheffield school children. Br. J. Prey. Soc. Med. 21, 7-16. Martin, A. E., and Bradley, W. H. (1960). Mortality, fog and atmospheric pollution: An investigation during the winter of 1958-59. Monthly Bull. Min. Health Public Health Lab. Set. 19, 56-72. Mazumdar, S., Schimmel, H., and Higgens, I. T. T. (1982). Relation of daily mortality to air pollution: An analysis of 14 London Winters 1958/59-1971/72.Arch. Environ. Health 37, 213-20. McConnochie, K. M., Hall, C. B., Barker, W. H. (1988). Lower respiratory tract illness in the first two years of life: Epidemiologic patterns and costs in a suburban pediatric practice, Am. J. Publ. Health 78(1), 34-9. McCullagh, D., and Nelder, J. A. (1983). "Generalized Linear Models." Chapman and Hall, London. Ostro, B. D., and Rothschild, S. (1989). Air pollution and acute respiratory morbidity: An observational study of multiple pollutants. Environ. Res. 50, 238-247. Ozkaynak, H., Spengler, J. D., Garsd, A., and Thurston, G. D. (1986). Assessment of population health risks resulting from exposures to airborne particles. In "Aerosols" (S. D. Lee, T. Schneider, L. D. Grant, and P. J. VanKerk, Eds), pp. 1067-1080. Lewis Publishers, Chelsea, MI.
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Parken, R. F., Davis, J. K., Cassell, G. H., White, H., Dziedzic, D., Blalock, D. K., Thorp, R. B., and Simeca, K. W. (1989). Short term exposure to nitrogen dioxide enhances susceptibility to murine respiratory mycoplasmosis and decreased intrapulmonary killing mycoplasma pulmonis. Am. Rev. Respir. Dis. 140, 502-512. Pope, C. A. (1989). Respiratory disease associated with community air pollution and a steel mill, Utah Valley. Am. J. Publ. Health 79, 623-628. Pope, C. A. (1991). Respiratory hospital admissions associated with PM10 pollution in Utah, Salt Lake, and Cache Counties. Arch. Environ. Health 46, 90-97. Pope, C. A., Dockery, D. W., Spengler, J. D., and Raizenne, M. E. (In press). Respiratory health and PM10 pollution: A daily time series analysis. Am. Rev. Respir. Dis. Samet, J. M., Marbury, M. C., and Spengler, J. D. (1987). Health effects and sources of indoor air pollution, I. Am. Rev. Respir. Dis. 136, 1486-1508. Sawicki, F., and Lawrence, P. S. (1977). "Chronic Non-specific Lung Disease in the City of Crackow." National Institute of Hygiene, Warsaw, Poland. Schwarz, J., Dockery, D. W., Ware, J. H., Spengler, J. D., Wypij, D., Koutrakis, P., Speizer, F. E., and Ferris, B. J., Jr. (1989). Acute effects of acid aerosols on respiratory symptom reporting in children. Air Pollution Control Assoc. 89, 92.1. Schwartz, J., and Marcus, A. (1990). Mortality and air pollution in London: A time series analysis. Am. J. Epidemiol. 131, 185-194. Schwartz, J., and Zeger, S. L. (1990). Passive smoking, air pollution and acute respiratory symptoms in a diary study of students nurses. Am. Rev. Respir. Dis. 141, 62-67. Schwartz, J., and Dockery, D. W., Particulate air pollution and daily mortality in Steubenville, Ohio. (In press). A m J. Epidemiol. Spektor, M., Lippmann, M., Lioy, P. J., et al. (1988). Effects of ambient ozone on respiratory function in active normal children. Am. Rev. Respir. Dis. 137, 313. Spinaci, S., Arossa, W., Bugiani, M., Natale, P., Bucca, C., and de Candussio, G. (1985). The effects of air pollution on the respiratory health of children: A cross-sectional study. Pediatr. Pulmonol. 1, 262-266. Wichmann, H. E., Mueller, W., Allhoff, P., Beckmann, M., Bocter, N., Csicsaky, M. J., Jung, M., Molik, B., and Schoeneberg, G. (1989). Health effects during a smog-episode in West Germany in 1985. Environ. Health Perspect. 79, 89-99. Wichmann, H. E., Malin, E., Huebner, H. R., and Schlipkoeter, H. W. (1990a). Zusammenfassende Bewertung der "Pseudokrupp-Studien" in Baden-Wfirttemberg und Nordrhein-Westfalen. KfKPEF64, pp. 1-125. Wichmann, H. E., and SchlipkOter, H. W. (1990b). Klndliche Atemsegserkrankungen und Lufschadstoffe--Ergebnisse der loordinierten Psuedokruppstidien. Deutsches Arzteblatt 87, 1533-1546. Wichmann, H. E., and Franke, H. (In press). Croup syndrome and parainfluenza virus type 1 infections--A model analysis. In "Advances in Systems Analysis" (D. Mfller, Ed.), Vol. 3. Vieweg Braunschweg, FRG. Wichmann, H. E., Sugiri, D., Islam, M. S., Haake, D., and Roscovanu, A. (1988). Lungenfunktion und carboxyh~imoglobin in der smogsituation des Januar 1987. ZbL Bakt. Hyg. B 187, 31-43. Zeger, S. L., and Liang, K.-Y. (1986) Longitudinal data analysis for discrete and continuous outcomes. Biometrics 42, 121-130.