Effects of Ambient Ozone on Respiratory Function and Symptoms in Mexico City Schoolchildren 1 - 4
MARGARITA CASTILLEJOS, DIANE R. GOLD, DOUGLAS DOCKERY, TOR TOSTESON, TIMOTHY BAUM, and FRANK E. SPEIZER
Introduction
Residents of Mexico City, an urban area with more than 20 million inhabitants, are chronically exposed to concentrations of ambient ozone (03 ) and other ambient pollutants above the World Health Organization (WHO) recommended standards of 80 ppb for 1 h. Almost 3 million vehicles are driven daily within the city, which is also the site for almost 40070 of the country's industrial production (1, 2). The mountains surrounding the city trap the ambient pollution, including 0 3 , within the city's valley basin. Based on data obtained in summer camp studies in the United States, Spektor and colleagues (3) suggest that 0 3 exposure causes decrements in lung function that may be greater under ambient conditions than under conditions created in chamber exposure studies (4, 5). In the camp studies maximum hourly 0 3 concentrations wereall less than the U.S. National Ambient Air Quality Standard 1 h concentration of 120 ppb, and the frequency of even these episodes was low. Hackney and colleagues suggest that subjects chronically exposed to 0 3 may have a reduced physiologic and clinical response to acute increases in 0 3 levels (6). This study evaluates the effects of ambient 0 3 on respiratory function and symptoms reporting of children in a community in the Mexico City basin, where daily maximum levels frequently exceed 120 ppb, Methods The study population (table I) consisted of 148 7- to 9-yr-old children (83 boys and 65 girls) of upper-class professionals in Pedregal. Pedregal is located in the residential southwest of Mexico City, where, because of prevailing northerly winds, 0 3 levels were reported to be the highest in the city, and particulate and sulfur dioxide levels werereported to be lowrelativeto the industrialized north of the city. To monitor the 0 3 levels in the south of the city, the Mexican environmental monitoring agency, Secretaria de Desarrollo Urbano y Ecologia (SEDUE) had given the 276
SUMMARY The effecta of ambIent ozone (0,) on respiratory functIon and acute respIratory symptoms wele evaluated In 1437-to g-yr·old schoolchlldlen followed longitudinally at 1-to 2-wk Intervals over a period of 6 months at thlee schools In Pedregal. Mexico City. The maximum 0, level exceeded the World Health Organization guideline of 80 ppb and the U.S. standard of 120 ppb In every week. For an Increase from lowest to highest In the mean 0 3 level during the 48 hr befole spirometry (53 ppb), logistic regression estimated relative odds of 1.7 for a child Ieportlng cough/phlegm on the day of spirometry. For the full popUlation, the mean 0 3 level during the hour befole spirometry, not adjusted for temperature and humidity, predicted a significant decrement In FVCbut not In FEV1 or FEF2 . - 75 • In contrast, the mean 0, level during the previous 24-, 48-, and 168-h periods pledlcted significant decrements In FEV, and FEF2 . _ 75 but not In FVC. Ozone was consistently associated with a gleater declement In lung function for the 15 chlldlen with chronic phlegm as com paled with the children without chronic cough, chronic phlegm, or wheeze. Ozone In the previous 24-, 48-, and 168-h periods predicted declements In FEV, for chlldlen of mothers Who ~Ie current or former smokers, but not for children of mothers who ~re never smokers. Many of these effects were reduced In multiple Iegresslon analyses Including temperatule and humidity, a8 temperature and 0, wele highly corlelated. In univariate analy,es, for the full popUlation, a 53 ppb rise In mean 48-h 0, level predicted a 2% decrement In FEV, and a 7.4%decrement In FEF2 . _ 75 • These decrements In FEV, and FEF.._75 may reflect an Inflammatory process In the airways that differs from the acute physiologic response to 0 3 associated with a decrement In FVC and the Inability to take a deep bleath. These results also suggest that children with a history of chronic phlegm production or passive smoke exposure may be more susceptible to respiratory Irritants. AM REV RESPIR DIS 1992; 145:276-282
Pedregal monitoring station special attention and resources to optimize the capture and quality of ozone data. For the purposes of this study, sufficient data were not available for respirableparticulate matter and other ambient pollutants in Pedregal. The study subjects were selected from the first and second grade of three private schools that were each located within 5 km of a government pollution monitoring station. Children of the appropriate grade were excluded from the study only if they lived farther than within 5 km of the monitoring station, so that the ozone exposure data from the monitoring station was more likely to reflect outdoor exposures not only at school, but also at home. The schools had no air conditioning or heating systems; classroom windows were often open to the outside and children walked outside to move from one classroom to another. The enrolled study group included 91 students from School I (all eligible students), 43 students from School 2 (all eligible students), and 16students from School 3 (these additional students were selected according to the same geographic selection criteria to
reach a target goal of enrolling approximately 150participants). Tho children did not participate. For each child, informed consent was obtained from either a parent or a guardian who completed a standardized questionnaire,
(Received in original form February 12, 1991 and in revised form September 6, 1991) , From EI Colegio de Mexico and the Universidad Autonoma Metropolitana-X, MexicoCity,Mexico; the Channing Laboratory, Brigham and Women's Hospital, Harvard M~dical School and the Environmental Epidemiolcgy Program, Harvard School of Public Health, Boston, Massachusetts. 1 Supported in part by Cooperative Agreement No. CR811650from the U.S. Environmental Protection Agency Health Effects Research Laboratory and by Grant No. ES-0002 from the National Institute of Environmental Health Sciences. 3 Presented in part at the annual meeting of the American Thoracic Society,Cincinnati, Ohio, May 1989. 4 Correspondence and requests for reprints should be addressed to Dr. Diane Gold, Channing Laboratory, Brigham and Women's Hospital, 180 Longwood Avenue, Boston, MA 02115.
277
EFFECT OF AMBIENT 0, ON SCHOOLCHILDREN
TABLE 1 BASELINE CHARACTERISTICS OF THE CHILDREN AGED 7 TO 9 YR OF PEDREGAL, MEXICO CITY
Sex Male Female Chronic cough Chronic phlegm Wheeze Wheeze with colds Persistent wheeze Ever doctor's diagnosis of asthma Current doctor's diagnosis of asthma Bronchitis, past year Respiratory illness before study Bronchitis Croup Pneumonia Respiratory illness before 2 yr of age Bronchitis Croup Pneumonia Severe chest illness before 2 yr of age Hospitalized for chest illness before 2 yr of age
translated into Spanish, on parental smoking, demographics, and the health history of the child. Chronic cough was defined as usually coughing for at least 3 months of the year in the past year. Chronic phlegm consisted of usually bringing up phlegm for at least 3 months of the year in the past year. Children had wheeze if their parents stated that their chest had ever sounded wheezy or whistling. Persistent wheeze was defined as wheeze apart from colds on most days and nights. The study was conducted over a 6-month period between January and June 1988. Children with and without a history of chronic respiratory symptoms were included. At the beginning and conclusion of the study, each child's height and weight were measured in stocking feet. Measurements of FEV, were made every other week (10measurements) on the children at their respective schools. An additional two measurements were performed on approximately 100 of the children after days that SEDUE declared as "pollution episodes," with 0 3 levelsexceeding 250 ppb. Each of the three schools was surveyed on different days of the week. There were a total of 40 days of testing. The measurements were performed within the schools between 8 A.M. and 2 P.M., i.e., regular school hours, although the time of testing for each child varied from day to day. The varied timing of the administration of spirometry increased the variability of ozone exposure (highest between 12 P.M. and 2 P.M.) and the availability of the children. On each day of testing, each child was asked about respiratory illness in the week preceding the test and current symptoms of cough or phlegm from the chest, and then a pulmonary function test was performed on an 8-L Collins portable recording spirometer (Warren E. Collins, Braintree, MA) in a sitting position without a noseclip. At each of
n
%
83 65 14 16
56.1 43.9 9.5 10.8 23.0 21.0 4.8 2.7 1.4 9.5
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4.8 1.4 1.4 7.5 2.0
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each examination was linearly interpolated between the initial and final height measurements to calculate the predicted lung function values. For each child, linear regressions were calculated between the residuals of lung function and the 0 3 concentration in various specific time periods (e.g., 1,2,24,48, or 168 h [7 days)) preceding the measurement of function for each child. The weighted mean slope and standard error (SE) were calculated for the entire population and for specific subgroups (e.g., boys, girls, chronic phlegm, wheeze).The child-specificslopes wereweighted by the inverse variance of the regression coefficient for that child, as follows:
~ =
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~i
1
n
:E ...../:E 0 i
i = 1
i" I
"2' 0 i
n
the examinations except the first, 10 to 20% of the participants complained of current cough with phlegm, but these children were not eliminated from the spirometric testing. One of two trained technicians supervised the spirometric tests. Spirometer temperature and time of day were recorded for each test. Atmospheric pressure was obtained from the National Meterological Institute. Children performed a minimum of six and a maximum of eight forced expiratory maneuvers. Each of the accepted tracings were digitized (7) at the Harvard School of Public Health (Cambridge, MA). The FVC, FEV" and FEF2 5- 75 for each test were calculated from the acceptable tracings according to the method outlined by O'Donnell and colleagues (7). All expiratory volumes and flows were standardized to BTPS (8). SEDUE collected hourly mean values for ambient temperature, relative humidity, and 0 3 concentration. Quality assurance audits were performed internally by SEDUE and through the U.S. Environmental Protection Agency. The field technicians performing spirometry did not know what the ozone levels were on the days of testing, but on the 2 days following "pollution episodes," they had been told that the previous day's levels had been high. Of the 148children who participated in the study, 143children had seven or more examinations with acceptable FEV, and were included in the analyses examining lung function. Residual lung function values (observedpredicted) were calculated for each child for each examination using prediction equations for Mexican-American children (9) and separately for white American children (l0). Creation of observed-predicted lung function values made it possible to adjust for growth during the 6-month study period. Height at
SE = 1/ ~ "" _1 "2 j;;;;
I
a
i
where Pi is the estimated slope for child i, Oi is the variance of the regression coefficient for child i, 13 is the weighted mean slope over all children, and SE is the standard error of the weighted mean. To identify outliers that might be unduly influencing the means, the range of the slopes was also examined. The relationships between ambient temperature, relative humidity, and 0 3 also were examined, as were the effects of the addition of relative humidity and ambient temperature to the regressions examining the relationship between 0 3 and lung function. Logistic regression was used to examine the relationship between 0 3 and the child's selfreport of cough/phlegm. The proportion of other children reporting cough or phlegm each day of testing was included to adjust for the effect of epidemics of respiratory illness on symptom reporting. The total number of other times the child reported cough or phlegm was included as a predictor of the child's report of cough or phlegm on the day of testing to adjust for heterogeneity of response between children.
Results
Study Population Of the 148children, 14(10%) had chronic cough, 16(11 %) had chronic phlegm, and 34 (23070) had a history of wheeze, 32 of whom had wheezed within the past year (table 1). Nine children reported chronic phlegm and current wheeze. Only 2 (1.4070) children were reported currently to have a doctor's diagnosis of asthma. Of the mothers, 33.8% were never smokers, 21.6% were former smokers, and 44.6% werecurrent smokers. The mothers of the children with chronic phlegm included five never-smokers, four former smokers, and seven current smokers. When compared with other populations of children (Texas Mexican-Americans [9] [table 2], another sample of Mexico City
278
CASTILLEJOS, GOLD, DOCKERY, TOSTESON, BAUM, AND SPEIZER
TABLE 2 MEAN OBSERVED AND MEAN PERCENT PREDICTED FVC, FEV, , AND FEF..-7' IN MEXICO CITY CHILDREN, USING TEXAS MEXICAN-AMERICAN PREDICTION EQUATIONSt Mean % Predicted (Sf)
Observed Mean (Sf) Boys (n ~ 82) FVC (L) FEV, (LJ FEF 2I - 70 (LIs) Girls (n ~ 65) FVC (L) FEV, (L) FEF 20-70 (LIs)
1.87 (0.03)
99.48 (0.98)
1.64 (0.03)
95.60 (1.11) 96.99 (2.78)
2.10 (0.06)
99.65 (1.34) 97.37 (1.44) 94.71 (3.07)
1.74 (0.04) 1.56 (0.03)
2.11 (0.06)
• Initial baseline values. Data from reference 9.
t
children [11], and a white American cohort (10)), on average the children from Pedregal did not have significantly lower initial FEV l '
Exposure Data Maximum daily l-h ozone levels are illustrated in figure 1. Ozone levels were calculated for 24-h periods, with no more than 3 h missing in each of two 12-h periods (e.g., 9 AM to 9 PM, and 9 PM to 9 AM). Hourly average 0 3 level data were unavailable primarily when telephone lines between the monitoring station in Pedregal and the central agency headquarters went down during rainy periods or when the 0 3 monitor was being calibrated.
The maximum l-h ozone level exceeded the U.S. standard of 120 ppb on 74070 of the days and was frequently> 240 ppb. The average diurnal pattern for 0 3 is demonstrated in figure 2. The pattern for January to March was not substantially different from the pattern in April to June. In Pedregal average concentrations peaked at approximately 1 PM at 140ppb, with concentrations> 120 ppb between 11:30AM and 1 PM and> 80 ppb between 11 AM and 5 PM. To estimate personal ozone exposure, the time each child performed spirometry was used as the reference time for that child. The average of the maximum l-h ozone levels in the 24 h before the time of spirometric measurement was 182ppb (table 3), with an average of the mean exposure levels in the 24 h before spirometric measurement of 59 ppb (table 3). For the periods 24, 48, and 168 h before spirometry, the percent of missing ozone data was 1.5, 6.2, and 18.7070, respectively. For the 48- and 168-h periods, if any 24 hour period was missing, the entire period was missing, The mean ambient temperature at the time of spirometry was 16.6° C (range 3.9 to 27.8° C, median 16.7° C) and varied with time of day. Relative humidity varied between 18.9 and 92.30/0, with a mean of 43.3070. For the times when spirometry was performed, ambient temperature and 0 3 were correlated (r = 0.61), as was ambient temperature with spirometer temperature (r = 0.72), and
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O\----..-------r--r---r-----,-------,Ot/Oll.. 02/28/. . OllO/. . 0 .. /22/. . DB/17/. . 011/20/" 03/25/"
DATE Fig. 1. Daily maximum t-h ozone levels measured at the SEDUE monitoring station in Pedregal, Mexico City, between January 1 and June 30, 1988. Circles represent maximum levels on days of spirometry testing. Crosses represent maximum levels on other days. Maximum levels exceeded the U.S. standard of 120 ppb on 74% of days in the 6-month period.
relative humidity with 0 3 (r = -0.56). In addition, ambient temperature at the time of spirometry was correlated with the mean 0 3 levels at 1,24, 48, and 168 h before spirometry (range of correlation coefficients 0.51 to 0.65).
Regressions of Symptoms with Ambient 0 3 Concentrations Mean 0 3 in the previous 48 h was associated with a child's report of cough or phlegm on the day of spirometry. Mean 0 3 at 1,2,4,24, and 168 h before spirometry did not predict cough or phlegm. Dividing the days into tertiles of 48-h mean 0 3 concentrations (29 to 52,52 to 65.6, and 65.7 to 82.3 ppb), the proportion of children reporting cough or phlegm was respectively 13.6,17.1, and 18.5070. An increase in 48-h mean 0 3 concentration by 53 ppb (the range of values) was associated with an increased relative odds of reporting cough or phlegm of 1.70 (95070 confidence interval [CI] 0.98, 2.93). Adjustment for the proportion of other children with cough or phlegm on the day of spirometry (epidemic effects) reduced the estimate to 1.62 (95070 CI 0.95,2.77). Adjustment for both epidemic effects and the total number of times the child reported cough or phlegm increased the relative odds to 1.88 (95070 CI 1.07, 3.30). The proportion of other children with cough or phlegm on the day of spirometry was itself associated with an increase in symptoms reporting (p < 0.001), as was the total number of times the child reported cough or phlegm (p < 0.001). Wheeze, chronic phlegm, and passive smoking reported in the parentcompleted questionnaire before the study did not predict the child's report of cough or phlegm on a given exam day. Regressions of Spirometric Measurements with Ambient 0 3 Concentrations The mean 0 3 level during the hour before spirometry was associated with a significant decrement in FVC, but not in FEV 1 or FEF2 5 - 75 (table 4). In contrast, the mean 0 3 levelduring the previous 24-, 48-, and 168-h periods was associated with significant decrements in FEV 1 and FEF2 5 - 75 , but not in FVC (table 4). The geometric mean ofthe r2 for the individual regressions suggested that the mean 48-h 0 3 level explained 3.8070 (95070 CI 2.4070, 6.0070) of the variance in residual FEYI' Children of mothers who were current smokers had a significant decrement in FVC associated with the mean l-h 0 3 lev-
279
EFFECT OF AMBIENT 0, ON SCHOOLCHILDREN .80 170
.60
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- - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - - + - -
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Fig. 2. Average24-h pattern for ozone between January and June, 1988.
90 80
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TABLE 3 OZONE EXPOSURES FOR THE PERIODS 1, 2, 4, 24, 48, AND 168 H BEFORE SPIROMETRY No. of Hours Before Spirometry
0, Exposure
Mean 0, Level (ppb)
Median O. Level (ppb)
Range (high-low) (ppb)
99 87 65 59 60 59
93 76 49 58 61 60
14-287 (273) 13-269 (256) 12-233 (221) 25-94 (69) 29-82 (53) 39-75 (36)
182
179
51-287 (236)
1 2 4 24
Mean level
48 168 (7 days) Maximum 1-h average
24
TABLE 4 REGRESSION SLOPES FOR FULL DATA SET (143 SUBJECTS) BY VARIOUS MEASURES OF OZONE EXPOSURE No. of Hours Before Spirometry
0, Exposure
1 2 4 24 48 168 (7 days)
Mean level
Maximum t-h average •p
24
FVC (mUppb 0.) - 0.059 ± - 0.031 ± 0.005 ± 0.044 ± -0.063 ± -0.189 ±
0.023" 0.024 0.031 0.101 0.115 0.136
-0.112 ± 0.035'
FEF.._7• (mllslppb)
FEV, (mUppb) - 0.032 - 0.031 - 0.030 - 0.323 -0.592 - 0.692
± 0.022 ± 0.024 ± 0.029 lI: 0.094'
± 0.109' ± 0.124'
-0.120 ± 0.032'
0.122 0.106 0.043 -1.228 - 2.805 -3.711
TABLE 5 REGRESSION SLOPES (± SE) FOR VARIOUS SUBGROUPS BY MEAN OZONE CONCENTRATIONS IN PREVIOUS 1 H
sex Male Female Chronic symptoms Nonet Wheeze Chronic phlegm Maternal smoking Never Former Current
FVC (mllppb 0.)
FEV, (mllppb)
FEF.._15 (mllslppb)
63
- 0.076 ± 0.029' - 0.031 ± 0.038
-0.070 ± 0.028' 0.034 ± 0.037
-0.009 ± 0.117 0.255 ± 0.118'
101 32 15
- 0.086 ± 0.026' 0.014 ± 0.053 -0.123 ± 0.075
- 0.035 ± 0.025 -0,019 ± 0.048 - 0.054 ± 0.084
0.105 ± 0.097 0.283 ± 0.184 0.045 ± 0.293
48 32 63
0.023 ± 0.045 - 0.064 ± 0.054 - 0.095 ± 0.031'
-0.038 ± 0.046 - 0.017 ± 0.044 -0.037 ± 0.031
0.160 ± 0.164 0.285 ± 0.175 0.031 ± 0.116
n
80
• p < 0.05. No parental report of chronic cough, chronic phlegm, or wheeze.
t
± 0.345' ± 0.392' ± 0.461'
-0.135 ± 0.118
< 0.05.
SUbgroup
± 0.083 ± 0.087 ± 0.111
el, whereas children of never smokers did not (table 5). Compared with the subgroup with no symptoms, the children with chronic phlegm had greater mean decrements in both FEVland FEF 25-75 associated with mean 0 3 levelin the 48 h before spirometry (table 6). There was overlap, however, between the 95010 CI for the mean decrements in lung function of the asymptomatic and symptomatic children. Children of mothers who were former smokers and current smokers had significant and similar decrements in FEV 1 associated with mean 0 3 in the previous 48 h, whereas children of never smokers did not. These changes weresmaller in magnitude than the decrement in FEV 1 for the group of children with chronic phlegm. The estimated decrement in FEF25-75 associated with mean 0 3 in the previous 48 h was similar for children with and without exposure to passive smoke (table 6). Taking into account paternal smoking patterns did not significantly modify the associations between decrements in lung function and maternal smoking. Similar associations to those found in regressions with mean 0 3 in the previous 48 h were found in regressions with the mean 0 3 levelin the 24- and 168-h periods before spirometry. No systematic changes in the direction or magnitude of the slopes were noted after excluding the observations during the 2 days after air pollution episodes, after excluding the initial spirometric measurements, or when using a lessstringent rule for missing 0 3 data, requiring 18h of data per 24-h period (thus including more observations, particularly in the 168-h analysis). Adjustment for ambient temperature and relative humidity, which werehighly colinear with 0 3 , reduced the effect of 0 3 , The parameter estimate, however,remained significant for the mean l-h 0 3 and FVC, the maximum 24-h 0 3 , FVC, and FEV h and the mean 48-h 0 3 and FEV 1 (table 7). After adjustment for 0 3 and relative humidity at the time of spirometry, temperature at the time of spirometry was not a significant predictor of decline in lung function for each measure of 0 3 tested. The predicted decrement in lung function for a given rise in 0 3 was calculated using the parameter estimates from the regressions not including temperature. Decrements in FEV l and FEF 2 5 - 75 were estimated for a child with average (for the Pedregal population) levelof pulmonary function if the child were to be exposed to an increase in 0 3 equivalent to the range of 0 3 concentration (highest-
280
CASTILLEJOS. GOLD, DOCKERY, TOSTESON, RAUM. AND SPEIZER
tion for children with chronic phlegm and children without chronic symptoms. For the children with chronic phlegm, the model predicts a 4.3% decrement in FEV 1 and a 14.5% decrement in FEF zs - 7s , with a 53 ppb rise in the mean 0 3 in the previous 48 h.
TABLE 6 REGRESSION SLOPES (± SE) FOR VARIOUS SUBGROUPS BY MEAN OZONE CONCENTRATIONS IN PREVIOUS 48 H
Subgroup Sex Male Female Chronic symptoms Nonet Wheeze Chronic phlegm Maternal smoking Never Former Current • p
n
FVC (ml/ppb 0.)
FEV, (mllppb)
FEF2 . _, . (mllslppb)
80 63
0.052 ± 0.149 -0.232 ± 0.181
-0.495:!: 0.138- 0.752 :t 0.177-
- 3.087 ± 0.526- 2.454 ± 0.587-
101 32 15
-0.012 ± 0.140 -0.110 ± 0.221 -0.736 ± 0.351-
-0.476 :!: 0.128- 0.893 :t 0.220- 1.261 :t 0.379-
- 2.466 ± 0.457- 3.405 ± 0.890- 5.465 ± 1.228-
50 32 66
0.589 ± 0.210- 1.210 ± 0.266' -0.026 ± 0.161
-0.082:t: 0.206 -0.793 ± 0.225-0.787 ± 0.155-
-2.641 ± 0.732-3.336 ± 0.872-2.687 ± 0.548-
Discussion
< 0.05.
t No parental report of chronic cough, chronic phlegm, or wheeze.
TABLE 7 REGRESSION SLOPES FOR FULL DATA SET (143 SUBJECrS) BY VARIOUS MEASURES OF OZONE EXPOSURE, ADJUSTING FOR OUTDOOR TEMPERATURE AND RELATIVE HUMIDITY No. of Hours Before Spirometry
O. Exposure
1 24 48 168 (7 days)
Mean level
- 0.069 0.135 -0.103 - 0.242
24
Maximum t-h average 'p
FVC (mllppb 0.)
± 0.029± 0.123 ± 0.163
± 0.207
- 0.097 ± 0.038'
FEV, (ml/ppb)
0.067 -0.014 -0.488 -0.092
± 0.028± 0.110
± 0.160-
± 0.189
-0.127 ± 0.035-
FEF25- , . (mllslppb)
0.222 0.331 - 0.442 2.571
± ± ± ±
0.102' 0.404 0.569 0.712'
-0.009 ± 0.126
< 0.05.
in a 1.6% decrement in FEV 1 and a 2% decrement in FEFl s - 7s ; a 53 ppb rise in mean 48-h 0 3 level would lead to a 2% decrement in FEV 1 and a 7.4% decrement in FEF 1s - 7s • Figure 3 compares the projected decrement in pulmonary func-
lowest) observed in the 6 months of the study. The model predicts that 273 ppb increasein Os.would result in only a 0.90/0 decrement in FVC in the following hour. A 255 ppb increase in the maximum 0 3 level in the previous 24 h would result
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Fig. 3. Estimated percentage decrement in FEV, and FEF2. _, . for a given rise in mean or maximum O.levels within a specified period before spirometry. The rise in O. is the difference between the highest and the lowest value experienced by the Pedregal, Mexico City, population. Bars represent ± , .96 (SE). The point estimate for the decrement in lung function was always greater for those with chronic phlegm (n = 15)(stifr pled circles) than for those without chronic symptoms (n = 101) (solid circles).
These data suggest that for the schoolchildren of Pedregal, Mexico City, a rise in 0 3 levels is associated with a decline in pulmonary function and a rise in respiratory symptom reporting. Adjusted analyses suggest that a portion of the effect of ozone on lung function might be explained by temperature. Physiologic data on the effects of temperature on lung function do not support this interpretation. Deal and colleagues demonstrated that while extremes of hot dry air (> 37° C) were associated with increased bronchospasm in exercising asthmatic subjects, airways reactivity fell as air temperature was increased from -11 to + 37° C and humidity was held constant (12).Fewdata are available about the interactive effects of temperature and 0 3 on lung function, but Linn and colleagues demonstrated that high temperature and high humidity tended to mitigate the bronchoconstriction produced by 0.6 ppm SOl exposure in exercising asthmatic subjects (13). Within the indoor temperature ranges experienced by the children, it is unlikelythat higher temperature itself led to significant decrements in lung function. It is more likely that temperature is, in great part, a surrogate for ozone. On average the 0 3 levels in Pedregal, Mexico City, were higher than 120 ppb between 11:30 AM and 1 PM from January through June 1988. Data from this study support the suggestion by Lippmann (5) that mean 0 3 levelsover a period of time may be as important as hourly maximum 0 3 levels in communities where levels are elevated for more than 1 or 2 h a day. The strongest effects on FEV 1 relate not to the 0 3 levels during the day of testing, but to the mean levels during the previous 24, 48, and 168 h. In chamber studies of vigorously excercising children living in areas free of chronic exposure to high ozone concentrations, McDonnell and colleagues found decrements in FVC and FEV 1 in response to 2 h of 0 3 at a level of 120 ppb; the effects on FEV 1 persisted for 16 to 20 h (4). It is possible that in the setting of chronic exposure to high levels of ozone the subacute effects of 0 3 in the previous week may modify acute ef-
281
EFFECT OF AMBIENT 0, ON SCHOOLCHILDREN
fects of 0 3 on the day of spirometry. This may be the case, particularly when the children are in school and are therefore more sedentary than the children in chamber or summer camp studies. For the children of Pedregal, the predicted declines in FVC, FEV 10 and FEF25-75 for a maximum 0 3 level of 120 ppb at 24 h before testing were smaller (e.g.,0.8% for FVC, 0.9070 for FEV 1) than might be expected from the regression slopes of Spektor and colleagues (3). Their analyses predict that FVC would decline by 4.9070 for 0 3 1 h before spirometric testing at the current ambient standard of 120 ppb, compared with a predicted decline in FVC of 0.4070 in this study. This difference in magnitude of effect may relate to the higher activity pattern of the children in the summer camps as compared with the schoolchildren in Pedregal. Other U.S. studies examining the effect of 0 3 on children with a low level of activity have found similarly small changes per ppb 0 3 (14). The response to a given level of 0 3 is related to the amount of exercise performed, as increasing VE through exercise increases the total dose of 0 3 , In chamber studies, Folinsbee and colleagues suggest that the "effective dose" of ozone can be estimated, using the product of ozone concentration X ventilation x duration of exercise (15). The dose of 0 3 received by sedentary children at altitude may be underestimated in that resting VE increases with altitude. On the other hand, the dose may be overestimated by the use of a dimensionless measure (ppb), because at sea level 120 ppb 0 3 is equivalent to 235 ug/m", but at the altitude of Mexico City 120 ppb 0 3 is equivalent to 178 ug/m". Variable overestimation of exposure may also have occurred in that spirometry was administered indoors and a proportion of the child's day was spent indoors, where levelsof 0 3 werelikely to have been lower. Not only differences in the dose of 0 3 reaching the lung, but also acquired "tolerance" to 0 3 may explain the differences between this study and the Spektor study in the magnitude of decline in lung function. Hackney and colleagues found that Los Angeles residents showed only minimal clinical physiologic responses to 0 3 whereas new arrivals showed significant losses in pulmonary function and a tendency toward increased symptoms (6). In exercising subjects exposed to 5 consecutive days of 0 3 , Horvath and colleagues found that the greatest decrement in FEV 1 occurred on
the second day and that response to 0 3 was reduced on subsequent days of exposure (16). Linn and colleagues also found a seasonal variation in response to 0 3 among Los Angeles residents; this variability in response paralleled the variability in mean ambient seasonal 0 3 levels (17). Tolerance may also involve physiologic adaptation or maladaptation in the form of an ongoing chronic inflammatory process. Inflammation in the bronchial tree may be reflected more in a decrement in FEV 1 and FEF 25-75, as opposed to a drop in FVC. In these data, the children without chronic symptoms and the children with chronic phlegm experienced a significant change in FVC similar to the percent change in FEV h only in relation to the 24-h maximum 0 3 levels. In contrast, the mean exposures to 0 3 at 48 and 168 h appear to affect the FEV 1 more than the FVC. This may reflect a different physiologic response to exposure over a period of days (a "subacute" response) compared with the response to 0 3 in the immediate period before spirometry which appears in part to be neurologically mediated, possibly via the C-fiber system (18). Tyler and colleagues found that in monkeys chronic exposure to 250 ppb 0 3 for 8 h/day led to a respiratory bronchiolitis (19). Some investigators have suggested that chronic phlegm may be protective against some of the effects of pollutants, particularly S02 (20). Among the Pedregal schoolchildren, phlegm did not appear to be protective against 0 3 , In comparison with the children with no symptoms, the children with chronic phlegm had a larger mean decrement in FEV 1 in response to 0 3 at 24 to 168 h before spirometry, though the differences in response between the two groups were not usually statistically significant. The children of current and past smokers had a greater mean decrement in FEV 1 in relation to 0 3 compared with children of mothers who had never smoked. For groups with and without a history of smoking, the effect of 0 3 on FEF25-75was similar. Changes in both FEV land FEF25-75 may represent a more widespread effect of ozone on the airways than changes in FEF25-75 alone. If this is the case, then these data suggest a possible interaction between passive smoking and ozone effect. It is possible that other unmeasured ambient pollutants modified the effect of ozone at this site or that other unmeasured pollutants had independent effects on the pulmonary function of these chil-
dren. Ambient air pollution data were not available to test these hypotheses. In analyses examining associations between 0 3 and lung function, this study used a parent-completed standardized questionnaire for definition of subgroups of children with passive smoke exposure or chronic symptoms. Analyses examining associations between 0 3 and acute symptoms used the child's self-report of symptoms. The analyses suggesting a relationship between mean 0 3 in the 48 h before spirometry and acute cough or phlegm on the day of spirometry should be interpreted with caution. It is an isolated finding that was not reflected in the other timed exposure analyses, and the reliability of the symptom reporting by children of this age could be questioned. A parent's report that the child had chronic phlegm did not predict whether a child would report cough or phlegm on the day of spirometry. These analyses may be overadjusted by taking into account the proportion of other children with cough or phlegm as this proportion may increase as 0 3 increases. In sensitive individuals, acute 0 3 exposure is believed to result in the neurologically mediated inability to take a deep breath, reflected in a decline of the FVC as demonstrated by Hazucha and colleagues (18) and as seen in this study. These Mexico City data suggest that subacute exposure may result in an inflammatory process reflected in a decline of the FEV l and FEF25-75. Certain subgroups of children may be particularly sensitive to the effects of subacute 0 3 on pulmonary function. More study of both acute and chronic exposure to 0 3 are needed to better define the adverse effects of this ambient pollutant at levels that are generally not encountered elsewhere in North America. Acknowledgment The writers are indebted to the teachers, parents, and children of the schools in Pedregal, Mexico City, whose enthusiastic cooperation made this study possible; to the Secretaria de Desarrollo Urbano y Ecologia of Mexico for maintenance and operation of the monitoring instruments and provision of the monitoring data; to Ms. Leonora Rojas for assistance in collecting and analyzing the spirometry and questionnaire data; to Mr. Francisco Ortega for assistance in analyzing the spirograms; to Dr. Mauricio Hernandez-Avila for careful review of the manuscript and for assistance in data management; to Dr. Carl Hayes for his assistance in establishing this collaboration between U.S. and Mexican scientists; to Ms. Martha Fay for her assistance ~ data management; to Ms. I. Zhao for assistance In pro-
282
CASTILlEJOS, GOLD, DOCKERY, TOSTESON, BAUM, AND SPEIZER
gramming; and to Ms. D. Bramble for secretarial assistance.
References 1. Sanchez V, Castillejos M, Rojas L. Poblacion, recursos y medio ambiente en Mexico. Mexico: Editorial Fundacion Universo Veintiuno, 1989. 2. Schteingart M. The environmental problems associated with urban development in Mexico City. Environ Urbanization 1989; 1:41-50. 3. Spektor DM, Lippmann M, Lioy PJ, et al. Effects of ambient ozone on respiratory function in active normal children. Am Rev Respir Dis 1988; 137:313-20. 4. McDonnell WF 1lI, Chapman RS, Leigh MW, Strope GL, Collier AM. Respiratory responses of vigorously exercising children to 0.12 ppm ozone exposure. Am Rev Respir Dis 1985; 132:875-9. 5. Lippmann M. Health effects of ozone, a critical review. J Air Pollut Control Assoc 1989; 39: 673-95. 6. Hackney JD, Linn WS, Buckley RD, Hislop HJ. Studies in adaption to ambient oxidant air pollution: effects of ozone exposure in Los Angeles residents vs. new arrivals. Environ Health Perspect 1976; 18:141-6. 7. O'Donnell CR, Sneddon SL, Schenker M, Gar-
shick E, Speizer FE, Mead J. Accuracy of spirometric and flow-volume indices obtained bY digitizing volume-time tracings. Am Rev Respir Dis 1987; 136:108-12. 8. Cotes JE. Lung function assessment and application in medicine. Philadelphia: F. A. Davis Company, 1968; 19-21. 9. Hsu KHK, Jenkins DE, Hsi BP, et al. Ventilatory functions of normal children and young adultsMexican-American, white, and black. 1. Spirometry. J Pediatr 1979; 95:14-23. 10. Dockery DW, Berkey CS, Ware JH, Speizer FE, Ferris BG Jr. Distribution of forced vital capacity and forced expiratory volume in one second in children 6 to 11 years of age. Am Rev Respir Dis 1983; 128:405-12. 11. Namihira D, Strope GL, Helms RW, Pekow P, Bojalil BM, Fernandez F. A study of spirometry in children from Mexico City. Pediatr Pulmonol 1986; 2:337-43. 12. Deal EC Jr, McFaddenER Jr, Ingram RH Jr, Strauss RH, Jauger JJ. Role of respiratory heat exchange in production of exercise-induced asthma. J Appl Physiol 1979; 46:467-75. 13. Linn WS, Shamoo DA, Anderson KR, Whynot JD, Avol EL, Hackney JD. Effects of heat and humidity on the responses of exercising asthmatics to sulfur dioxide exposure. Am Rev Respir Dis 1985;
131:221-5. 14. Lioy PJ, Vollmuth TA, Lippmann M. Persistence of peak flow decrement in children following ozone exposures exceeding the national ambient air quality standard. J Air Pollut Control Assoc 1985; 35:1068-71. 15. Folinsbee LJ, McDonnell WF, Horstman DH. Pulmonary function and symptom responses after 6.6-hour exposure to 0.12 ppm ozone with moderate exercise. J Air Pollut Control Assoc 1988; 38:28-35. 16. Horvath SM, Gliner JA, Folinsbee LJ. Adaptation to ozone: duration of effect. Am Rev Respir Dis 1981; 123:496-9. 17. Linn WS, Avol EL, Shamoo DA, et al. Repeated laboratory ozone exposures of volunteer Los Angeles residents: an apparent seasonal variation in response. Toxicol Ind Health 1988; 4:505-20. 18. Hazucha M, Bates DV, Bromberg P. Mechanism of action of ozone on the human lung. J Appl Physiol 1989; 67:1535-41. 19. Tyler WS, Tyler NK, Last JA, Gillespie MJ, Barstow TJ. Comparison of daily and seasonal exposures of young monkeys to ozone. Toxicology 1988; 50:131-44. 20. Shore SA, Kariya ST,Anderson K, et al. Sulfurdioxide-induced bronchitis in dog. Am Rev Respir Dis 1987; 135:840-7.
MARGARITA CASTILLEJOS, DIANE R. GOLD, DOUGLAS DOCKERY, TOR TOSTESON, TIMOTHY BAUM, and FRANK E. SPEIZER
Introduction
Residents of Mexico City, an urban area with more than 20 million inhabitants, are chronically exposed to concentrations of ambient ozone (03 ) and other ambient pollutants above the World Health Organization (WHO) recommended standards of 80 ppb for 1 h. Almost 3 million vehicles are driven daily within the city, which is also the site for almost 40070 of the country's industrial production (1, 2). The mountains surrounding the city trap the ambient pollution, including 0 3 , within the city's valley basin. Based on data obtained in summer camp studies in the United States, Spektor and colleagues (3) suggest that 0 3 exposure causes decrements in lung function that may be greater under ambient conditions than under conditions created in chamber exposure studies (4, 5). In the camp studies maximum hourly 0 3 concentrations wereall less than the U.S. National Ambient Air Quality Standard 1 h concentration of 120 ppb, and the frequency of even these episodes was low. Hackney and colleagues suggest that subjects chronically exposed to 0 3 may have a reduced physiologic and clinical response to acute increases in 0 3 levels (6). This study evaluates the effects of ambient 0 3 on respiratory function and symptoms reporting of children in a community in the Mexico City basin, where daily maximum levels frequently exceed 120 ppb, Methods The study population (table I) consisted of 148 7- to 9-yr-old children (83 boys and 65 girls) of upper-class professionals in Pedregal. Pedregal is located in the residential southwest of Mexico City, where, because of prevailing northerly winds, 0 3 levels were reported to be the highest in the city, and particulate and sulfur dioxide levels werereported to be lowrelativeto the industrialized north of the city. To monitor the 0 3 levels in the south of the city, the Mexican environmental monitoring agency, Secretaria de Desarrollo Urbano y Ecologia (SEDUE) had given the 276
SUMMARY The effecta of ambIent ozone (0,) on respiratory functIon and acute respIratory symptoms wele evaluated In 1437-to g-yr·old schoolchlldlen followed longitudinally at 1-to 2-wk Intervals over a period of 6 months at thlee schools In Pedregal. Mexico City. The maximum 0, level exceeded the World Health Organization guideline of 80 ppb and the U.S. standard of 120 ppb In every week. For an Increase from lowest to highest In the mean 0 3 level during the 48 hr befole spirometry (53 ppb), logistic regression estimated relative odds of 1.7 for a child Ieportlng cough/phlegm on the day of spirometry. For the full popUlation, the mean 0 3 level during the hour befole spirometry, not adjusted for temperature and humidity, predicted a significant decrement In FVCbut not In FEV1 or FEF2 . - 75 • In contrast, the mean 0, level during the previous 24-, 48-, and 168-h periods pledlcted significant decrements In FEV, and FEF2 . _ 75 but not In FVC. Ozone was consistently associated with a gleater declement In lung function for the 15 chlldlen with chronic phlegm as com paled with the children without chronic cough, chronic phlegm, or wheeze. Ozone In the previous 24-, 48-, and 168-h periods predicted declements In FEV, for chlldlen of mothers Who ~Ie current or former smokers, but not for children of mothers who ~re never smokers. Many of these effects were reduced In multiple Iegresslon analyses Including temperatule and humidity, a8 temperature and 0, wele highly corlelated. In univariate analy,es, for the full popUlation, a 53 ppb rise In mean 48-h 0, level predicted a 2% decrement In FEV, and a 7.4%decrement In FEF2 . _ 75 • These decrements In FEV, and FEF.._75 may reflect an Inflammatory process In the airways that differs from the acute physiologic response to 0 3 associated with a decrement In FVC and the Inability to take a deep bleath. These results also suggest that children with a history of chronic phlegm production or passive smoke exposure may be more susceptible to respiratory Irritants. AM REV RESPIR DIS 1992; 145:276-282
Pedregal monitoring station special attention and resources to optimize the capture and quality of ozone data. For the purposes of this study, sufficient data were not available for respirableparticulate matter and other ambient pollutants in Pedregal. The study subjects were selected from the first and second grade of three private schools that were each located within 5 km of a government pollution monitoring station. Children of the appropriate grade were excluded from the study only if they lived farther than within 5 km of the monitoring station, so that the ozone exposure data from the monitoring station was more likely to reflect outdoor exposures not only at school, but also at home. The schools had no air conditioning or heating systems; classroom windows were often open to the outside and children walked outside to move from one classroom to another. The enrolled study group included 91 students from School I (all eligible students), 43 students from School 2 (all eligible students), and 16students from School 3 (these additional students were selected according to the same geographic selection criteria to
reach a target goal of enrolling approximately 150participants). Tho children did not participate. For each child, informed consent was obtained from either a parent or a guardian who completed a standardized questionnaire,
(Received in original form February 12, 1991 and in revised form September 6, 1991) , From EI Colegio de Mexico and the Universidad Autonoma Metropolitana-X, MexicoCity,Mexico; the Channing Laboratory, Brigham and Women's Hospital, Harvard M~dical School and the Environmental Epidemiolcgy Program, Harvard School of Public Health, Boston, Massachusetts. 1 Supported in part by Cooperative Agreement No. CR811650from the U.S. Environmental Protection Agency Health Effects Research Laboratory and by Grant No. ES-0002 from the National Institute of Environmental Health Sciences. 3 Presented in part at the annual meeting of the American Thoracic Society,Cincinnati, Ohio, May 1989. 4 Correspondence and requests for reprints should be addressed to Dr. Diane Gold, Channing Laboratory, Brigham and Women's Hospital, 180 Longwood Avenue, Boston, MA 02115.
277
EFFECT OF AMBIENT 0, ON SCHOOLCHILDREN
TABLE 1 BASELINE CHARACTERISTICS OF THE CHILDREN AGED 7 TO 9 YR OF PEDREGAL, MEXICO CITY
Sex Male Female Chronic cough Chronic phlegm Wheeze Wheeze with colds Persistent wheeze Ever doctor's diagnosis of asthma Current doctor's diagnosis of asthma Bronchitis, past year Respiratory illness before study Bronchitis Croup Pneumonia Respiratory illness before 2 yr of age Bronchitis Croup Pneumonia Severe chest illness before 2 yr of age Hospitalized for chest illness before 2 yr of age
translated into Spanish, on parental smoking, demographics, and the health history of the child. Chronic cough was defined as usually coughing for at least 3 months of the year in the past year. Chronic phlegm consisted of usually bringing up phlegm for at least 3 months of the year in the past year. Children had wheeze if their parents stated that their chest had ever sounded wheezy or whistling. Persistent wheeze was defined as wheeze apart from colds on most days and nights. The study was conducted over a 6-month period between January and June 1988. Children with and without a history of chronic respiratory symptoms were included. At the beginning and conclusion of the study, each child's height and weight were measured in stocking feet. Measurements of FEV, were made every other week (10measurements) on the children at their respective schools. An additional two measurements were performed on approximately 100 of the children after days that SEDUE declared as "pollution episodes," with 0 3 levelsexceeding 250 ppb. Each of the three schools was surveyed on different days of the week. There were a total of 40 days of testing. The measurements were performed within the schools between 8 A.M. and 2 P.M., i.e., regular school hours, although the time of testing for each child varied from day to day. The varied timing of the administration of spirometry increased the variability of ozone exposure (highest between 12 P.M. and 2 P.M.) and the availability of the children. On each day of testing, each child was asked about respiratory illness in the week preceding the test and current symptoms of cough or phlegm from the chest, and then a pulmonary function test was performed on an 8-L Collins portable recording spirometer (Warren E. Collins, Braintree, MA) in a sitting position without a noseclip. At each of
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each examination was linearly interpolated between the initial and final height measurements to calculate the predicted lung function values. For each child, linear regressions were calculated between the residuals of lung function and the 0 3 concentration in various specific time periods (e.g., 1,2,24,48, or 168 h [7 days)) preceding the measurement of function for each child. The weighted mean slope and standard error (SE) were calculated for the entire population and for specific subgroups (e.g., boys, girls, chronic phlegm, wheeze).The child-specificslopes wereweighted by the inverse variance of the regression coefficient for that child, as follows:
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the examinations except the first, 10 to 20% of the participants complained of current cough with phlegm, but these children were not eliminated from the spirometric testing. One of two trained technicians supervised the spirometric tests. Spirometer temperature and time of day were recorded for each test. Atmospheric pressure was obtained from the National Meterological Institute. Children performed a minimum of six and a maximum of eight forced expiratory maneuvers. Each of the accepted tracings were digitized (7) at the Harvard School of Public Health (Cambridge, MA). The FVC, FEV" and FEF2 5- 75 for each test were calculated from the acceptable tracings according to the method outlined by O'Donnell and colleagues (7). All expiratory volumes and flows were standardized to BTPS (8). SEDUE collected hourly mean values for ambient temperature, relative humidity, and 0 3 concentration. Quality assurance audits were performed internally by SEDUE and through the U.S. Environmental Protection Agency. The field technicians performing spirometry did not know what the ozone levels were on the days of testing, but on the 2 days following "pollution episodes," they had been told that the previous day's levels had been high. Of the 148children who participated in the study, 143children had seven or more examinations with acceptable FEV, and were included in the analyses examining lung function. Residual lung function values (observedpredicted) were calculated for each child for each examination using prediction equations for Mexican-American children (9) and separately for white American children (l0). Creation of observed-predicted lung function values made it possible to adjust for growth during the 6-month study period. Height at
SE = 1/ ~ "" _1 "2 j;;;;
I
a
i
where Pi is the estimated slope for child i, Oi is the variance of the regression coefficient for child i, 13 is the weighted mean slope over all children, and SE is the standard error of the weighted mean. To identify outliers that might be unduly influencing the means, the range of the slopes was also examined. The relationships between ambient temperature, relative humidity, and 0 3 also were examined, as were the effects of the addition of relative humidity and ambient temperature to the regressions examining the relationship between 0 3 and lung function. Logistic regression was used to examine the relationship between 0 3 and the child's selfreport of cough/phlegm. The proportion of other children reporting cough or phlegm each day of testing was included to adjust for the effect of epidemics of respiratory illness on symptom reporting. The total number of other times the child reported cough or phlegm was included as a predictor of the child's report of cough or phlegm on the day of testing to adjust for heterogeneity of response between children.
Results
Study Population Of the 148children, 14(10%) had chronic cough, 16(11 %) had chronic phlegm, and 34 (23070) had a history of wheeze, 32 of whom had wheezed within the past year (table 1). Nine children reported chronic phlegm and current wheeze. Only 2 (1.4070) children were reported currently to have a doctor's diagnosis of asthma. Of the mothers, 33.8% were never smokers, 21.6% were former smokers, and 44.6% werecurrent smokers. The mothers of the children with chronic phlegm included five never-smokers, four former smokers, and seven current smokers. When compared with other populations of children (Texas Mexican-Americans [9] [table 2], another sample of Mexico City
278
CASTILLEJOS, GOLD, DOCKERY, TOSTESON, BAUM, AND SPEIZER
TABLE 2 MEAN OBSERVED AND MEAN PERCENT PREDICTED FVC, FEV, , AND FEF..-7' IN MEXICO CITY CHILDREN, USING TEXAS MEXICAN-AMERICAN PREDICTION EQUATIONSt Mean % Predicted (Sf)
Observed Mean (Sf) Boys (n ~ 82) FVC (L) FEV, (LJ FEF 2I - 70 (LIs) Girls (n ~ 65) FVC (L) FEV, (L) FEF 20-70 (LIs)
1.87 (0.03)
99.48 (0.98)
1.64 (0.03)
95.60 (1.11) 96.99 (2.78)
2.10 (0.06)
99.65 (1.34) 97.37 (1.44) 94.71 (3.07)
1.74 (0.04) 1.56 (0.03)
2.11 (0.06)
• Initial baseline values. Data from reference 9.
t
children [11], and a white American cohort (10)), on average the children from Pedregal did not have significantly lower initial FEV l '
Exposure Data Maximum daily l-h ozone levels are illustrated in figure 1. Ozone levels were calculated for 24-h periods, with no more than 3 h missing in each of two 12-h periods (e.g., 9 AM to 9 PM, and 9 PM to 9 AM). Hourly average 0 3 level data were unavailable primarily when telephone lines between the monitoring station in Pedregal and the central agency headquarters went down during rainy periods or when the 0 3 monitor was being calibrated.
The maximum l-h ozone level exceeded the U.S. standard of 120 ppb on 74070 of the days and was frequently> 240 ppb. The average diurnal pattern for 0 3 is demonstrated in figure 2. The pattern for January to March was not substantially different from the pattern in April to June. In Pedregal average concentrations peaked at approximately 1 PM at 140ppb, with concentrations> 120 ppb between 11:30AM and 1 PM and> 80 ppb between 11 AM and 5 PM. To estimate personal ozone exposure, the time each child performed spirometry was used as the reference time for that child. The average of the maximum l-h ozone levels in the 24 h before the time of spirometric measurement was 182ppb (table 3), with an average of the mean exposure levels in the 24 h before spirometric measurement of 59 ppb (table 3). For the periods 24, 48, and 168 h before spirometry, the percent of missing ozone data was 1.5, 6.2, and 18.7070, respectively. For the 48- and 168-h periods, if any 24 hour period was missing, the entire period was missing, The mean ambient temperature at the time of spirometry was 16.6° C (range 3.9 to 27.8° C, median 16.7° C) and varied with time of day. Relative humidity varied between 18.9 and 92.30/0, with a mean of 43.3070. For the times when spirometry was performed, ambient temperature and 0 3 were correlated (r = 0.61), as was ambient temperature with spirometer temperature (r = 0.72), and
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DATE Fig. 1. Daily maximum t-h ozone levels measured at the SEDUE monitoring station in Pedregal, Mexico City, between January 1 and June 30, 1988. Circles represent maximum levels on days of spirometry testing. Crosses represent maximum levels on other days. Maximum levels exceeded the U.S. standard of 120 ppb on 74% of days in the 6-month period.
relative humidity with 0 3 (r = -0.56). In addition, ambient temperature at the time of spirometry was correlated with the mean 0 3 levels at 1,24, 48, and 168 h before spirometry (range of correlation coefficients 0.51 to 0.65).
Regressions of Symptoms with Ambient 0 3 Concentrations Mean 0 3 in the previous 48 h was associated with a child's report of cough or phlegm on the day of spirometry. Mean 0 3 at 1,2,4,24, and 168 h before spirometry did not predict cough or phlegm. Dividing the days into tertiles of 48-h mean 0 3 concentrations (29 to 52,52 to 65.6, and 65.7 to 82.3 ppb), the proportion of children reporting cough or phlegm was respectively 13.6,17.1, and 18.5070. An increase in 48-h mean 0 3 concentration by 53 ppb (the range of values) was associated with an increased relative odds of reporting cough or phlegm of 1.70 (95070 confidence interval [CI] 0.98, 2.93). Adjustment for the proportion of other children with cough or phlegm on the day of spirometry (epidemic effects) reduced the estimate to 1.62 (95070 CI 0.95,2.77). Adjustment for both epidemic effects and the total number of times the child reported cough or phlegm increased the relative odds to 1.88 (95070 CI 1.07, 3.30). The proportion of other children with cough or phlegm on the day of spirometry was itself associated with an increase in symptoms reporting (p < 0.001), as was the total number of times the child reported cough or phlegm (p < 0.001). Wheeze, chronic phlegm, and passive smoking reported in the parentcompleted questionnaire before the study did not predict the child's report of cough or phlegm on a given exam day. Regressions of Spirometric Measurements with Ambient 0 3 Concentrations The mean 0 3 level during the hour before spirometry was associated with a significant decrement in FVC, but not in FEV 1 or FEF2 5 - 75 (table 4). In contrast, the mean 0 3 levelduring the previous 24-, 48-, and 168-h periods was associated with significant decrements in FEV 1 and FEF2 5 - 75 , but not in FVC (table 4). The geometric mean ofthe r2 for the individual regressions suggested that the mean 48-h 0 3 level explained 3.8070 (95070 CI 2.4070, 6.0070) of the variance in residual FEYI' Children of mothers who were current smokers had a significant decrement in FVC associated with the mean l-h 0 3 lev-
279
EFFECT OF AMBIENT 0, ON SCHOOLCHILDREN .80 170
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TABLE 3 OZONE EXPOSURES FOR THE PERIODS 1, 2, 4, 24, 48, AND 168 H BEFORE SPIROMETRY No. of Hours Before Spirometry
0, Exposure
Mean 0, Level (ppb)
Median O. Level (ppb)
Range (high-low) (ppb)
99 87 65 59 60 59
93 76 49 58 61 60
14-287 (273) 13-269 (256) 12-233 (221) 25-94 (69) 29-82 (53) 39-75 (36)
182
179
51-287 (236)
1 2 4 24
Mean level
48 168 (7 days) Maximum 1-h average
24
TABLE 4 REGRESSION SLOPES FOR FULL DATA SET (143 SUBJECTS) BY VARIOUS MEASURES OF OZONE EXPOSURE No. of Hours Before Spirometry
0, Exposure
1 2 4 24 48 168 (7 days)
Mean level
Maximum t-h average •p
24
FVC (mUppb 0.) - 0.059 ± - 0.031 ± 0.005 ± 0.044 ± -0.063 ± -0.189 ±
0.023" 0.024 0.031 0.101 0.115 0.136
-0.112 ± 0.035'
FEF.._7• (mllslppb)
FEV, (mUppb) - 0.032 - 0.031 - 0.030 - 0.323 -0.592 - 0.692
± 0.022 ± 0.024 ± 0.029 lI: 0.094'
± 0.109' ± 0.124'
-0.120 ± 0.032'
0.122 0.106 0.043 -1.228 - 2.805 -3.711
TABLE 5 REGRESSION SLOPES (± SE) FOR VARIOUS SUBGROUPS BY MEAN OZONE CONCENTRATIONS IN PREVIOUS 1 H
sex Male Female Chronic symptoms Nonet Wheeze Chronic phlegm Maternal smoking Never Former Current
FVC (mllppb 0.)
FEV, (mllppb)
FEF.._15 (mllslppb)
63
- 0.076 ± 0.029' - 0.031 ± 0.038
-0.070 ± 0.028' 0.034 ± 0.037
-0.009 ± 0.117 0.255 ± 0.118'
101 32 15
- 0.086 ± 0.026' 0.014 ± 0.053 -0.123 ± 0.075
- 0.035 ± 0.025 -0,019 ± 0.048 - 0.054 ± 0.084
0.105 ± 0.097 0.283 ± 0.184 0.045 ± 0.293
48 32 63
0.023 ± 0.045 - 0.064 ± 0.054 - 0.095 ± 0.031'
-0.038 ± 0.046 - 0.017 ± 0.044 -0.037 ± 0.031
0.160 ± 0.164 0.285 ± 0.175 0.031 ± 0.116
n
80
• p < 0.05. No parental report of chronic cough, chronic phlegm, or wheeze.
t
± 0.345' ± 0.392' ± 0.461'
-0.135 ± 0.118
< 0.05.
SUbgroup
± 0.083 ± 0.087 ± 0.111
el, whereas children of never smokers did not (table 5). Compared with the subgroup with no symptoms, the children with chronic phlegm had greater mean decrements in both FEVland FEF 25-75 associated with mean 0 3 levelin the 48 h before spirometry (table 6). There was overlap, however, between the 95010 CI for the mean decrements in lung function of the asymptomatic and symptomatic children. Children of mothers who were former smokers and current smokers had significant and similar decrements in FEV 1 associated with mean 0 3 in the previous 48 h, whereas children of never smokers did not. These changes weresmaller in magnitude than the decrement in FEV 1 for the group of children with chronic phlegm. The estimated decrement in FEF25-75 associated with mean 0 3 in the previous 48 h was similar for children with and without exposure to passive smoke (table 6). Taking into account paternal smoking patterns did not significantly modify the associations between decrements in lung function and maternal smoking. Similar associations to those found in regressions with mean 0 3 in the previous 48 h were found in regressions with the mean 0 3 levelin the 24- and 168-h periods before spirometry. No systematic changes in the direction or magnitude of the slopes were noted after excluding the observations during the 2 days after air pollution episodes, after excluding the initial spirometric measurements, or when using a lessstringent rule for missing 0 3 data, requiring 18h of data per 24-h period (thus including more observations, particularly in the 168-h analysis). Adjustment for ambient temperature and relative humidity, which werehighly colinear with 0 3 , reduced the effect of 0 3 , The parameter estimate, however,remained significant for the mean l-h 0 3 and FVC, the maximum 24-h 0 3 , FVC, and FEV h and the mean 48-h 0 3 and FEV 1 (table 7). After adjustment for 0 3 and relative humidity at the time of spirometry, temperature at the time of spirometry was not a significant predictor of decline in lung function for each measure of 0 3 tested. The predicted decrement in lung function for a given rise in 0 3 was calculated using the parameter estimates from the regressions not including temperature. Decrements in FEV l and FEF 2 5 - 75 were estimated for a child with average (for the Pedregal population) levelof pulmonary function if the child were to be exposed to an increase in 0 3 equivalent to the range of 0 3 concentration (highest-
280
CASTILLEJOS. GOLD, DOCKERY, TOSTESON, RAUM. AND SPEIZER
tion for children with chronic phlegm and children without chronic symptoms. For the children with chronic phlegm, the model predicts a 4.3% decrement in FEV 1 and a 14.5% decrement in FEF zs - 7s , with a 53 ppb rise in the mean 0 3 in the previous 48 h.
TABLE 6 REGRESSION SLOPES (± SE) FOR VARIOUS SUBGROUPS BY MEAN OZONE CONCENTRATIONS IN PREVIOUS 48 H
Subgroup Sex Male Female Chronic symptoms Nonet Wheeze Chronic phlegm Maternal smoking Never Former Current • p
n
FVC (ml/ppb 0.)
FEV, (mllppb)
FEF2 . _, . (mllslppb)
80 63
0.052 ± 0.149 -0.232 ± 0.181
-0.495:!: 0.138- 0.752 :t 0.177-
- 3.087 ± 0.526- 2.454 ± 0.587-
101 32 15
-0.012 ± 0.140 -0.110 ± 0.221 -0.736 ± 0.351-
-0.476 :!: 0.128- 0.893 :t 0.220- 1.261 :t 0.379-
- 2.466 ± 0.457- 3.405 ± 0.890- 5.465 ± 1.228-
50 32 66
0.589 ± 0.210- 1.210 ± 0.266' -0.026 ± 0.161
-0.082:t: 0.206 -0.793 ± 0.225-0.787 ± 0.155-
-2.641 ± 0.732-3.336 ± 0.872-2.687 ± 0.548-
Discussion
< 0.05.
t No parental report of chronic cough, chronic phlegm, or wheeze.
TABLE 7 REGRESSION SLOPES FOR FULL DATA SET (143 SUBJECrS) BY VARIOUS MEASURES OF OZONE EXPOSURE, ADJUSTING FOR OUTDOOR TEMPERATURE AND RELATIVE HUMIDITY No. of Hours Before Spirometry
O. Exposure
1 24 48 168 (7 days)
Mean level
- 0.069 0.135 -0.103 - 0.242
24
Maximum t-h average 'p
FVC (mllppb 0.)
± 0.029± 0.123 ± 0.163
± 0.207
- 0.097 ± 0.038'
FEV, (ml/ppb)
0.067 -0.014 -0.488 -0.092
± 0.028± 0.110
± 0.160-
± 0.189
-0.127 ± 0.035-
FEF25- , . (mllslppb)
0.222 0.331 - 0.442 2.571
± ± ± ±
0.102' 0.404 0.569 0.712'
-0.009 ± 0.126
< 0.05.
in a 1.6% decrement in FEV 1 and a 2% decrement in FEFl s - 7s ; a 53 ppb rise in mean 48-h 0 3 level would lead to a 2% decrement in FEV 1 and a 7.4% decrement in FEF 1s - 7s • Figure 3 compares the projected decrement in pulmonary func-
lowest) observed in the 6 months of the study. The model predicts that 273 ppb increasein Os.would result in only a 0.90/0 decrement in FVC in the following hour. A 255 ppb increase in the maximum 0 3 level in the previous 24 h would result
;'C
II I
~o
"'.S u,
~
eo
I
u-, I
::i
.c
u
0
~'i
~
t c,
Vj
I 0
'I'
69 ppb Rise in 0 3 {24h mean)
»: Ii: 0 c ~
or
::i
N
I
6 ~) 1" s
~
&
'?
II
II
53 ppb Rise in 03 (4&h mean)
11
36 ppb Rise in 03 (16gh mean)
II
I
I
'1 236 ppb Rise in 03 (24h max)
69 ppb Rise in 03 (24h mean}
53 ppb Rise in 01 (48h mean)
36 ppb Rise in 0 3 «68h mean)
Fig. 3. Estimated percentage decrement in FEV, and FEF2. _, . for a given rise in mean or maximum O.levels within a specified period before spirometry. The rise in O. is the difference between the highest and the lowest value experienced by the Pedregal, Mexico City, population. Bars represent ± , .96 (SE). The point estimate for the decrement in lung function was always greater for those with chronic phlegm (n = 15)(stifr pled circles) than for those without chronic symptoms (n = 101) (solid circles).
These data suggest that for the schoolchildren of Pedregal, Mexico City, a rise in 0 3 levels is associated with a decline in pulmonary function and a rise in respiratory symptom reporting. Adjusted analyses suggest that a portion of the effect of ozone on lung function might be explained by temperature. Physiologic data on the effects of temperature on lung function do not support this interpretation. Deal and colleagues demonstrated that while extremes of hot dry air (> 37° C) were associated with increased bronchospasm in exercising asthmatic subjects, airways reactivity fell as air temperature was increased from -11 to + 37° C and humidity was held constant (12).Fewdata are available about the interactive effects of temperature and 0 3 on lung function, but Linn and colleagues demonstrated that high temperature and high humidity tended to mitigate the bronchoconstriction produced by 0.6 ppm SOl exposure in exercising asthmatic subjects (13). Within the indoor temperature ranges experienced by the children, it is unlikelythat higher temperature itself led to significant decrements in lung function. It is more likely that temperature is, in great part, a surrogate for ozone. On average the 0 3 levels in Pedregal, Mexico City, were higher than 120 ppb between 11:30 AM and 1 PM from January through June 1988. Data from this study support the suggestion by Lippmann (5) that mean 0 3 levelsover a period of time may be as important as hourly maximum 0 3 levels in communities where levels are elevated for more than 1 or 2 h a day. The strongest effects on FEV 1 relate not to the 0 3 levels during the day of testing, but to the mean levels during the previous 24, 48, and 168 h. In chamber studies of vigorously excercising children living in areas free of chronic exposure to high ozone concentrations, McDonnell and colleagues found decrements in FVC and FEV 1 in response to 2 h of 0 3 at a level of 120 ppb; the effects on FEV 1 persisted for 16 to 20 h (4). It is possible that in the setting of chronic exposure to high levels of ozone the subacute effects of 0 3 in the previous week may modify acute ef-
281
EFFECT OF AMBIENT 0, ON SCHOOLCHILDREN
fects of 0 3 on the day of spirometry. This may be the case, particularly when the children are in school and are therefore more sedentary than the children in chamber or summer camp studies. For the children of Pedregal, the predicted declines in FVC, FEV 10 and FEF25-75 for a maximum 0 3 level of 120 ppb at 24 h before testing were smaller (e.g.,0.8% for FVC, 0.9070 for FEV 1) than might be expected from the regression slopes of Spektor and colleagues (3). Their analyses predict that FVC would decline by 4.9070 for 0 3 1 h before spirometric testing at the current ambient standard of 120 ppb, compared with a predicted decline in FVC of 0.4070 in this study. This difference in magnitude of effect may relate to the higher activity pattern of the children in the summer camps as compared with the schoolchildren in Pedregal. Other U.S. studies examining the effect of 0 3 on children with a low level of activity have found similarly small changes per ppb 0 3 (14). The response to a given level of 0 3 is related to the amount of exercise performed, as increasing VE through exercise increases the total dose of 0 3 , In chamber studies, Folinsbee and colleagues suggest that the "effective dose" of ozone can be estimated, using the product of ozone concentration X ventilation x duration of exercise (15). The dose of 0 3 received by sedentary children at altitude may be underestimated in that resting VE increases with altitude. On the other hand, the dose may be overestimated by the use of a dimensionless measure (ppb), because at sea level 120 ppb 0 3 is equivalent to 235 ug/m", but at the altitude of Mexico City 120 ppb 0 3 is equivalent to 178 ug/m". Variable overestimation of exposure may also have occurred in that spirometry was administered indoors and a proportion of the child's day was spent indoors, where levelsof 0 3 werelikely to have been lower. Not only differences in the dose of 0 3 reaching the lung, but also acquired "tolerance" to 0 3 may explain the differences between this study and the Spektor study in the magnitude of decline in lung function. Hackney and colleagues found that Los Angeles residents showed only minimal clinical physiologic responses to 0 3 whereas new arrivals showed significant losses in pulmonary function and a tendency toward increased symptoms (6). In exercising subjects exposed to 5 consecutive days of 0 3 , Horvath and colleagues found that the greatest decrement in FEV 1 occurred on
the second day and that response to 0 3 was reduced on subsequent days of exposure (16). Linn and colleagues also found a seasonal variation in response to 0 3 among Los Angeles residents; this variability in response paralleled the variability in mean ambient seasonal 0 3 levels (17). Tolerance may also involve physiologic adaptation or maladaptation in the form of an ongoing chronic inflammatory process. Inflammation in the bronchial tree may be reflected more in a decrement in FEV 1 and FEF 25-75, as opposed to a drop in FVC. In these data, the children without chronic symptoms and the children with chronic phlegm experienced a significant change in FVC similar to the percent change in FEV h only in relation to the 24-h maximum 0 3 levels. In contrast, the mean exposures to 0 3 at 48 and 168 h appear to affect the FEV 1 more than the FVC. This may reflect a different physiologic response to exposure over a period of days (a "subacute" response) compared with the response to 0 3 in the immediate period before spirometry which appears in part to be neurologically mediated, possibly via the C-fiber system (18). Tyler and colleagues found that in monkeys chronic exposure to 250 ppb 0 3 for 8 h/day led to a respiratory bronchiolitis (19). Some investigators have suggested that chronic phlegm may be protective against some of the effects of pollutants, particularly S02 (20). Among the Pedregal schoolchildren, phlegm did not appear to be protective against 0 3 , In comparison with the children with no symptoms, the children with chronic phlegm had a larger mean decrement in FEV 1 in response to 0 3 at 24 to 168 h before spirometry, though the differences in response between the two groups were not usually statistically significant. The children of current and past smokers had a greater mean decrement in FEV 1 in relation to 0 3 compared with children of mothers who had never smoked. For groups with and without a history of smoking, the effect of 0 3 on FEF25-75was similar. Changes in both FEV land FEF25-75 may represent a more widespread effect of ozone on the airways than changes in FEF25-75 alone. If this is the case, then these data suggest a possible interaction between passive smoking and ozone effect. It is possible that other unmeasured ambient pollutants modified the effect of ozone at this site or that other unmeasured pollutants had independent effects on the pulmonary function of these chil-
dren. Ambient air pollution data were not available to test these hypotheses. In analyses examining associations between 0 3 and lung function, this study used a parent-completed standardized questionnaire for definition of subgroups of children with passive smoke exposure or chronic symptoms. Analyses examining associations between 0 3 and acute symptoms used the child's self-report of symptoms. The analyses suggesting a relationship between mean 0 3 in the 48 h before spirometry and acute cough or phlegm on the day of spirometry should be interpreted with caution. It is an isolated finding that was not reflected in the other timed exposure analyses, and the reliability of the symptom reporting by children of this age could be questioned. A parent's report that the child had chronic phlegm did not predict whether a child would report cough or phlegm on the day of spirometry. These analyses may be overadjusted by taking into account the proportion of other children with cough or phlegm as this proportion may increase as 0 3 increases. In sensitive individuals, acute 0 3 exposure is believed to result in the neurologically mediated inability to take a deep breath, reflected in a decline of the FVC as demonstrated by Hazucha and colleagues (18) and as seen in this study. These Mexico City data suggest that subacute exposure may result in an inflammatory process reflected in a decline of the FEV l and FEF25-75. Certain subgroups of children may be particularly sensitive to the effects of subacute 0 3 on pulmonary function. More study of both acute and chronic exposure to 0 3 are needed to better define the adverse effects of this ambient pollutant at levels that are generally not encountered elsewhere in North America. Acknowledgment The writers are indebted to the teachers, parents, and children of the schools in Pedregal, Mexico City, whose enthusiastic cooperation made this study possible; to the Secretaria de Desarrollo Urbano y Ecologia of Mexico for maintenance and operation of the monitoring instruments and provision of the monitoring data; to Ms. Leonora Rojas for assistance in collecting and analyzing the spirometry and questionnaire data; to Mr. Francisco Ortega for assistance in analyzing the spirograms; to Dr. Mauricio Hernandez-Avila for careful review of the manuscript and for assistance in data management; to Dr. Carl Hayes for his assistance in establishing this collaboration between U.S. and Mexican scientists; to Ms. Martha Fay for her assistance ~ data management; to Ms. I. Zhao for assistance In pro-
282
CASTILlEJOS, GOLD, DOCKERY, TOSTESON, BAUM, AND SPEIZER
gramming; and to Ms. D. Bramble for secretarial assistance.
References 1. Sanchez V, Castillejos M, Rojas L. Poblacion, recursos y medio ambiente en Mexico. Mexico: Editorial Fundacion Universo Veintiuno, 1989. 2. Schteingart M. The environmental problems associated with urban development in Mexico City. Environ Urbanization 1989; 1:41-50. 3. Spektor DM, Lippmann M, Lioy PJ, et al. Effects of ambient ozone on respiratory function in active normal children. Am Rev Respir Dis 1988; 137:313-20. 4. McDonnell WF 1lI, Chapman RS, Leigh MW, Strope GL, Collier AM. Respiratory responses of vigorously exercising children to 0.12 ppm ozone exposure. Am Rev Respir Dis 1985; 132:875-9. 5. Lippmann M. Health effects of ozone, a critical review. J Air Pollut Control Assoc 1989; 39: 673-95. 6. Hackney JD, Linn WS, Buckley RD, Hislop HJ. Studies in adaption to ambient oxidant air pollution: effects of ozone exposure in Los Angeles residents vs. new arrivals. Environ Health Perspect 1976; 18:141-6. 7. O'Donnell CR, Sneddon SL, Schenker M, Gar-
shick E, Speizer FE, Mead J. Accuracy of spirometric and flow-volume indices obtained bY digitizing volume-time tracings. Am Rev Respir Dis 1987; 136:108-12. 8. Cotes JE. Lung function assessment and application in medicine. Philadelphia: F. A. Davis Company, 1968; 19-21. 9. Hsu KHK, Jenkins DE, Hsi BP, et al. Ventilatory functions of normal children and young adultsMexican-American, white, and black. 1. Spirometry. J Pediatr 1979; 95:14-23. 10. Dockery DW, Berkey CS, Ware JH, Speizer FE, Ferris BG Jr. Distribution of forced vital capacity and forced expiratory volume in one second in children 6 to 11 years of age. Am Rev Respir Dis 1983; 128:405-12. 11. Namihira D, Strope GL, Helms RW, Pekow P, Bojalil BM, Fernandez F. A study of spirometry in children from Mexico City. Pediatr Pulmonol 1986; 2:337-43. 12. Deal EC Jr, McFaddenER Jr, Ingram RH Jr, Strauss RH, Jauger JJ. Role of respiratory heat exchange in production of exercise-induced asthma. J Appl Physiol 1979; 46:467-75. 13. Linn WS, Shamoo DA, Anderson KR, Whynot JD, Avol EL, Hackney JD. Effects of heat and humidity on the responses of exercising asthmatics to sulfur dioxide exposure. Am Rev Respir Dis 1985;
131:221-5. 14. Lioy PJ, Vollmuth TA, Lippmann M. Persistence of peak flow decrement in children following ozone exposures exceeding the national ambient air quality standard. J Air Pollut Control Assoc 1985; 35:1068-71. 15. Folinsbee LJ, McDonnell WF, Horstman DH. Pulmonary function and symptom responses after 6.6-hour exposure to 0.12 ppm ozone with moderate exercise. J Air Pollut Control Assoc 1988; 38:28-35. 16. Horvath SM, Gliner JA, Folinsbee LJ. Adaptation to ozone: duration of effect. Am Rev Respir Dis 1981; 123:496-9. 17. Linn WS, Avol EL, Shamoo DA, et al. Repeated laboratory ozone exposures of volunteer Los Angeles residents: an apparent seasonal variation in response. Toxicol Ind Health 1988; 4:505-20. 18. Hazucha M, Bates DV, Bromberg P. Mechanism of action of ozone on the human lung. J Appl Physiol 1989; 67:1535-41. 19. Tyler WS, Tyler NK, Last JA, Gillespie MJ, Barstow TJ. Comparison of daily and seasonal exposures of young monkeys to ozone. Toxicology 1988; 50:131-44. 20. Shore SA, Kariya ST,Anderson K, et al. Sulfurdioxide-induced bronchitis in dog. Am Rev Respir Dis 1987; 135:840-7.
