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Effects of nitrogen dioxide on pulmonary function in human subjects: An environmental chamber study
ENVIRONMENTAL
RESEARCH
19,
392-404 (1979)
Effects of Nitrogen Dioxide on Pulmonary Function in Human Subjects: An Environmental Chamber Study’ H. D. KERR, T. J. KULLE,
M. L. MCILHANY,~
AND P. SWIDERSKY~
University of Maryland School of Medicine, Departmenr of Medicine, Division of Pulmonary Diseases, 29 South Greene Street, Baltimore. Maryland 21201 and The Johns Hopkins University. School of Hygiene and Public Health, Department of Environmental Health Sciences, 615 North Wove Street. Baltimore, Maryland 21205
Received November 23, 1978 Twenty human subjects with asthma and chronic bronchitis and 10 normal, healthy adults were exposed to 0.5 ppm of nitrogen dioxide for 2 hr in an environmental chamber. Seven of the 13 subjects with asthma experienced symptoms with exposure, while only one each of the subjects with chronic bronchitis and the healthy, normal group experienced symptoms. Significant pulmonary function changes from control values with exposure to NO, were observed in decreased quasistatic compliance for the 10 normal subjects and the 20 subjects with asthma and chronic bronchitis. In addition, functional residual capacity increased significantly for the 20 subjects with asthma and chronic bronchitis. The subjects with asthma and the subjects with chronic bronchitis as separate groups, however, did not show any significant changes with exposure. With this study we are reasonably confident that exposure of subjects with asthma and chronic bronchitis to 0.5 ppm NO, for 2 hr does not produce a significant decrement in their pulmonary function.
INTRODUCTION
Nitrogen dioxide (NO& levels in urban air pollution episodes in the U.S. (1962- 1968) have been measured between 0.10 and 0.80 parts per million (ppm) as a maximum hourly average with short-term peaks as high as 1.27 ppm (National Air Pollution Control Administration, 1971). The industrial hygiene occupational exposure for nitrogen dioxide is set by the American Conference of Government Industrial Hygienists (ACGIH) at 5 ppm as a ceiling value not to be exceeded (ACGIH, 1977). Limited studies of the toxic effects of NOz in man generally have considered moderate to high exposure levels (1.0 to 5.0 ppm) for periods of time from 10 min to 3 hr. Measurements of pulmonary function have shown conflicting results; in some cases marked increase in pulmonary resistance was observed with exposure, while no change in pulmonary function was reported by other investigators (Suzuki and Ishikawa, 1965; Abe, 1967; Rokaw et al., 1968; Nieding et al., 1973; Hackney et al., 1978). Epidemiologic and pulmonary function studies of children and their families living in neighborhoods with elevated NO, levels (proximity to large TNT plant) have demonstrated diminished pulmonary function (FEV,.,,) and/or an excess of lower respiratory illnesses (Shy et al., 1970a, b; Pearlman et al., 1971). Horvath and Folinsbee (1977) exposed normal human I This study was supported by Environmental Protection Agency Contract No. 68-02-1745. p Present address: Social Security Administration, Baltimore, Maryland 21207. 3 Present address: Borriston Research Laboratories, Temple Hills, Maryland 2003 1. 392 0013-9351/79/040392-13$02.00/O Copyright All rights
0 1979 by Academic Press. Inc. of reproduction in any form reserved.
HUMAN
PULMONARY
FUNCTION
WITH
NO2
EXPOSURE
393
subjects to 0.62 ppm NO, for 2 hr, observing no significant decrement in pulmonary function. Few controlled studies employing specific NO, exposures have been performed on subjects with chronic pulmonary disease (Rokaw er al., 1968; Nieding et al., 1973). The purpose ofthis investigation was to determine if measurable changes in pulmonary function occur breathing 0.5 ppm (940 pg/m3) nitrogen dioxide for 2 hr in subjects with asthma and chronic bronchitis and in normal subjects. MATERIALS
AND METHODS
Test Facility In order to restrict environmental effects to nitrogen dioxide, these experiments were carried out with subjects confined to an environmentally controlled chamber. A more detailed description of the environmental chamber facility is presented in a previously published paper (Kerr, 1973). Temperature was maintained at 24 + 1°C (75 f 2°F) with relative humidity of 45 2 5%. All room air was exhausted to the outside, instead of recirculating it through the conditioning system, enabling precise control of nitrogen dioxide concentration during the exposure phase. A complete room air exchange occurred every 2.5 min. Air entering the 2.1 x 4.3 x 2.4-m (7 x 14 x S-ft) exposure room was passed through highefficiency particulate absolute filters and activated carbon filters approaching class 100 cleanliness (
394
KERR
ET AL.
Nitrogen dioxide monitor strip chart recordings were made during each subject exposure. Means and standard deviations were determined from 3-min data points over the 2-hr exposure period. The means of the various exposures ranged between 0.49 and 0.51 ppm, with the standard deviations ranging from 0.01 to 0.02 ppm. Subjects Thirteen subjects with asthma, seven with chronic bronchitis, and ten normal, healthy subjects, were studied. An individual with asthma is defined as one who has a medical history of episodes of breathlessness, wheezing, and cough lasting for hours to days followed by intervals of complete remission. An individual with chronic bronchitis is defined as one who has a medical history of daily cough with sputum production persisting for 3 or more consecutive months over a period of 2 or more consecutive years. Informed consent was obtained from each subject after the nature of the procedure had been fully explained. Smokers were asked to abstain for 24 hr prior to, and during the 2 days of the research. Twenty-three subjects were male and seven female. Each subject served as his or her own control. The order of subject study in pairs and the sequence of physiological tests were not varied. Physiological Tests A 2-day study procedure was employed; on the first or control day the subjects remained in the exposure room for 2 hr breathing filtered clean air. On the second day, they breathed 0.50 ppm nitrogen dioxide for 2 hr at the same time of the day. Pulmonary function tests were performed in sequence (spirometry, plethysmography, and single breath nitrogen elimination rate) at the beginning and following the 2-hr chamber confinement on both Day 1 and Day 2. The remaining two physiological tests (pulmonary resistance and compliance) were done following the above tests only at the end of the 2-hr confinement on Day 1 and Day 2. Bicycle ergometer exercise at a light-to-moderate work load of 60- 100 W, depending upon the subject’s physical characteristics and tolerance, at 60 rpm for 15 min was performed during the first hour on both Day 1 and Day 2. All pulmonary function tests were performed in a seated position to ensure comparability of lung volumes from the various tests. To assure technically satisfactory subject performance, the subjects repeatedly executed each test, except those requiring the esophageal balloon, during preliminary practice sessions and before confinement on both days. Ventilatory function testing was performed as a single forced vital capacity (FVC) by standard technique employing a waterseal direct writing spirometer. All volumes were expressed in liters at body temperature, pressure, saturated (BTPS). Airway resistance (Raw) and volume of thoracic gas (Vtg) were determined by the whole-body pressure plethysmographic technique of DuBois et al. (1956) with certain technical modifications (Kerr, 1973). Each of 10 panting breaths for Raw and Vtg at functional residual capacity (FRC) were determined by computer analysis of analog tape recording of pressures, flow, and volume. Airway resistance measurements determined a 1 liter/set airflow (0.5 liter/set inspiratory to 0.5
HUMAN
PULMONARY
FUNCTION
WITH
NOz
EXPOSURE
395
liter/set expiratory) were converted to specific airway conductance (SGaw = l/Raw/Vtg), using the Vtg at which each Raw was measured, and expressed as the mean of the 10 panting breaths. Practice sessions enabled most subjects to perform the panting maneuvers of Raw and Vtg at or very close to FRC. Total lung capacity (TLC) was expressed as the sum of FRC and the inspiratory capacity, and residual volume (RV) was expressed as the difference between FRC and the expiratory reserve volume. All lung volumes were expressed in liters and SGaw as l/cm HZ0 x second units. Tests of single breath nitrogen elimination rate were calculated from an XY plot of expired nitrogen concentration vs expired volume from TLC to RV following a full inspiration of 100% oxygen from RV to TLC. Rate of expiration was controlled to not exceed 0.5 liter/set. Phase III was expressed as change in percentage alveolar nitrogen concentration per liter of expired volume, and was determined from the best fit straight line of the alveolar sample mid-portion of the XY plot. Phase IV (“closing volume”) was measured from RV to the Phase III-Phase IV junction (Anthonisen, 1972). One reader performed all the line-fitting procedures. Pulmonary resistance (Rt) and compliance (CL) were determined by the electronic subtractor method of Mead and Whittenberger (1953). In order to stabilize volume history, each subject fully inflated his or her lungs to TLC prior to performing the quasistatic and dynamic compliance maneuvers. Dynamic compliance was performed at frequencies of 16 breaths per minute (C, dyn 16), 32/min and 48/min in rhythm with an audio metronome while maintaining a tidal volume of 1 liter for 8 to 10 breaths at each breathing frequency. To determine CL dyn, a portion of the transpulmonary pressure proportional to airflow was subtracted by manual potentiometer adjustment for the best fit straight line XY oscilloscope display of this resultant pressure vs tidal volume. For R,,, a portion of transpulmonary pressure proportional to volume change was subtracted in a similar fashion with straight line fitting of the XY plot of this pressure vs airflow. All subtractions and readings were performed from playback of analog tape recordings of aifflow, volume change, and transpulmonary pressure. This procedure enabled rereading of the recordings to verify values and also to standardize the length of time each subject performed at the different frequencies, thereby avoiding excessive alveolar ventilation from prolonged measurement. Pulmonary resistance was expressed as cm H,O/liter/sec and was not corrected for the Vtg at which it was measured. All compliance data were expressed as ml/cm H,O. Dura Analysis
There were three subject groups consisting of 10 normals, 7 subjects with chronic bronchitis, and 13 subjects with asthma. Individual subject data were grouped into the appropriate category (Table 1). The group data were compared between control (Day 1) and exposure (Day 2), and the levels of significance determined by t test of paired observations. The effects found were small and there were trends toward significance with some measurements in the group of subjects with asthma and those with chronic bronchitis. In order to provide a greater sensitivity in detecting these changes, the data for the 20 subjects with asthma and chronic bronchitis were combined for analysis.
53 25 30 24
M M M M
13 17 20 21
M M M M M M M M M
2 3 4 5 6 7 10 11 12
44 29 42 63 39 26 28 29 22 23
34.5 12.7
M
1
(years)
Age
SMOKING
Mean SD
Sex
DATA,
No.
Subject
ANTHROPOMETRIC
HISTORY,
171 165 188 175
181.8 6.4
188 175 183 174 173 183 190 183 179 190
Height (cm)
AND
Smoking history”
0 + + +
(pipe)
(pipe)
(n = 7)
3110
(n = 10) + + 0 0 0 0 0 + 0 0
Chronic Bronchitis 86 99 92 75
75.7 8.7
Normal 73 66 77 64 70 70 92 83 79 83
Weight (kg)
I
EXPOSURE TO NITROGEN TO DIAGNOSIS
TABLE SYMPTOMS DURING ACCORDING
DIOXIDE
l/IO
0 0 0 0 0 0
0 0 0 +
(Nasal
discharge)
SUBJECTS
Symptoms during exposureb
OF 30 HUMAN
CLASSIFIED
M M M M M F F M F M M M F
F F F
Sex
26.8 10.0
41 23 30 22 24 19 21 21 38 50 20 20 19
30.3 10.5
32 24 24
Age (years)
’ 0, nonsmoker; +, smoker. ’ 0, no symptoms: C, symptom experienced.
Mean SD
8 9 14 15 16 18 19 22 23 24 25 27 28
Mean SD
26 29 30
No.
Subject
170.5 8.9
161 178 165 164 185 159 166 173 160 175 175 185 171
170.8 8.7
168 168 161
Height (cm)
517
+ 0 +
Smoking history”
I--Conrinued
67.0 7.6
3113
Asthma (n = 13) 68 0 75 0 64 + 65 0 64 + 62 0 62 0 68 0 49 0 80 0 72 0 69 + 73 0
80.6 12.7
75 61 76
Weight (kg)
TABLE
(light)
(former smoker)
(former smoker) (occasional)
7113
0 0 + + 0 + 0 0 + + + + 0
117
+ 0 0
(Chest tightness) (Chest tightness) (Slight burning of eyes) (Dyspnea with exercise)
(Slight burning of eyes)
(Chest tightness) (Slight headache)
(Nasal discharge)
Symptoms during exposure*
398
KERRETAL. RESULTS
The odor of nitrogen dioxide was readily perceptible at the 0.50 ppm concentration, but most subjects reported that they became unaware of the odor after 15 min of exposure. None of the subjects considered the odor to be unpleasant. Subjects were asked to keep note of symptoms they might experience; following the exposure study, they were specifically asked about cough, sputum, irritation of mucous membranes, and chest discomfort. Symptoms reported were in general mild and more frequently reported by subjects with asthma. Only one subject with chronic bronchitis and one normal subject experienced the very mild symptom of slight rhinorrhea (Table I), while more than half (seven of thirteen) subjects with asthma reported some degree of chest tightness, burning of the eyes, headache, or dyspnea with exercise and exposure to NOz. There did not appear to be any relationship between history and symptoms. Although subjects with asthma experienced the most symptoms, no significant changes were observed in any of the parameters of pulmonary function (Tables 2 to 5). With NOt exposure, a significant decrement in quasistatic compliance was seen in normal subjects, while there were no significant changes in dynamic compliance for any subject group (Table 5). Although no significant difference was shown between the control and exposure (2-hr) values, variance in the preexposure (0-hr) values occurred with Phase III nitrogen elimination rate in subjects with chronic bronchitis and with Phase IV nitrogen elimination rate in normals (Table 4). No other significant differences were observed in any of the pulmonary function tests. When the data for all 20 subjects with asthma and chronic bronchitis are considered together, significant increases were noted in FRC and quasistatic compliance as well as TLC and RV on the exposure day (Tables 3 and 5). Variance was also demonstrated in the preexposure (0-hr) TLC and RV values, thus, a significant change with exposure in TLC and RV is questioned. DISCUSSION
The symptoms reported were minimal, did not correlate with functional changes, and are of doubtful significance. Because the odor of NOe is detectable at 0.5 ppm, a double-blind study, though desirable, would not be practical. The results of this investigation are in general negative, which is in itself useful. Although exposure to higher concentrations of NOz have been shown by others to alter function, and very high concentrations to result in significant damage to the respiratory system, it would appear that no significant alteration in pulmonary function is likely to result from a 2-hr exposure to 0.5 ppm NOz alone in normal subjects or subjects with chronic obstructive pulmonary disease. The few significant changes reported here may be due to chance alone. While changes in compliance, distribution of ventilation, and static lung volumes (TLC, FRC, RV) suggest some degree of change in elastic properties, no meaningful change in function can be implied as significant differences in some of these functions also were observed prior to exposure (0-hr). The changes observed showed no consistency between subject groups and did not correlate with the symptoms. There were no significant changes in any of the flow resistance parameters by spirometry, plethysmograph, or esophageal balloon techniques.
4.06 4.10
4.05 4.14
4.91 4.98
9.79 10.00
3.70 3.94
1.84 1.82
FEV, 0-hr 2-hr
MEFR 0-hr 2-hr
MMEF 0-hr 2-hr
ERV 0-hr 2-hr
1.81 1.67
3.69 3.74
9.04 9.55
4.98 4.94
5.29 5.27
Day 2 (Exposure)
5.25 5.30
Day 1 (Control)
FVC 0-hr 2-hr FEV, 0-hr 2-hr
Subject groups
Mean
Normal subjects (n = 10)
MEAN
0.10 0.08
0.10 0.13
0.54 0.42
0.05 0.03
0.05 0.04
0.05 0.03
1.37 1.25
2.51 2.65
5.76 5.93
4.15 4.09
3.15 3.12
4.51 4.42
Day 1 (Control)
OF VENTILATORY
Standard error of difference in means
VALUES
2 DERIVED
1.23 1.24
2.83 2.70
5.85 5.86
4.18 4.07
3.25 3.14
4.49 4.38
Day 2 (Exposure)
Mean
FROM
0.08 0.04
1.63 1.55
3.15 2.71
7.20
0.30 0.18 0.13
8.14
4.47 4.38
3.66 3.50
4.88 4.81
0.27
0.06 0.05
0.07 0.05
0.07 0.05
1.63 1.53
3.02 2.81
7.51
8.07
4.51 4.38
3.64 3.51
4.93 4.82
Day 2 t Exposure)
Mean
0.08 0.07
0.12 0.23
0.47
0.61
0.03 0.06
0.04 0.08
0.04 0.06
Standard error of difference in means
Subjects with chronic bronchitis (II = 7)
Day 1 (Control)
SPIROMETRY
Standard error of difference in means
Subjects with asthma (n = 13)
FUNCTION
TABLE
s
m
3 B
N3
4 5 2 Q =i X
z
% sz z
z
$ z
KERR ET AL.
TABLE MEAN
VALUES
OF TESTS DERIVED
FROM
3 PLETHYSMOGRAPHIC
Normal subjects (n
=
MEASUREMENTS
Subjects with asthma
10)
(n = 13)
Subject groups
Day 1 (Control)
Day 2 (Exposure)
Standard error of difference in means
SGaw 0-hr 2-hr
0.218 0.246
0.219 0.238
0.014 0.014
0.137 0.137
0.136 0.142
0.007 0.012
TLC 0-hr 2-hr
7.24 7.38
7.37 7.44
0.13 0.17
6.47 6.32
6.65 6.49
0.11 0.11
FRC 0-hr 2-hr
3.83 3.91
3.90 3.83
0.10 0.13
3.37 3.19
3.40 3.38
0.09 0.13
RV 0-hr 2-hr
1.99 2.08
2.08 2.16
0.12 0.18
1.96 1.90
2.16 2.11
0.09 0.12
Mean
Day 1 (Control)
Day 2 (Exposure)
Standard error of difference in means
Mean
Subjects with chronic bronchitis
Subjects with asthma and chronic bronchitis (n = 20)
(n = 7)
Subject groups
Day 1 (Control)
Day 2 (Exposure)
Standard error of difference in means
SGaw 0-hr 2-hr
0.196 0.198
0.185 0.180
0.016 0.014
0.158 0.159
0.153 0.156
0.007 0.009
TLC 0-hr 2-hr
6.67 6.63
6.87 6.86
0.11 0.13
6.54 6.44
6.74’* 6.63*
0.08 0.08
FRC 0-hr 2-hr
3.42 3.37
3.57 3.57
0.09 0.13
3.39 3.26
3.46 3.45*
0.07 0.09
RV 0-hr 2-hr
1.79 1.82
1.94 2.04
0.08 0.11
1.90 1.87
2.08*” 2.09**
0.07 0.09
Mean
*P **p
< 0.05. < 0.025.
Day 1 (Control)
Day 2 (Exposure)
Standard error of difference in means
Mean
HUMAN
PULMONARY
FUNCTION
WITH
NO2 EXPOSURE
SINGLE-BREATH
N2 ELIMINATION
TABLE MEAN
VALUES
OF TESTS DERIVED
FROM
4
Normal subjects (n = IO)
Subject groups
Day 1 (Control)
(Exposure)
Day 1 (Control)
Day 2
RATE
Subjects with asthma (n = 13) Standard error of difference in means
Mean
401
Mean Day 2 (Exposure)
Standard error of difference in means
Phase III 0-hr 2-hr
1.15 1.13
1.26 1.08
0.13 0.13
1.42 I .30
1.58 1.41
0.18 0. I I
Phase IV 0-hr 2-hr
0.62 0.54
0.47* 0.65
0.06 0.07
0.44 0.36
0.35 0.39
0.06 0.06
2.61 2.62
2.55 2.81
0.14 0.20
2.44 2.30
2.54 2.54
0.09 0.13
Phase IV +RV 0-hr 2-hr
Subjects with chronic bronchitis (n = 7)
Day 2 (Exposure)
Standard error of difference in means
Mean Subject groups
Day I (Control)
Subjects with asthma and chronic bronchitis (n = 20) Mean Day I (Control)
Day 2 (Exposure)
Standard error of difference in means
Phase III 0-hr 2-hr
1.14 I.15
0.85”* 0.92
0.07 0.10
1.32
1.33
1.28
1.22
0.13 0.07
Phase IV 0-hr 2-hr
0.41 0.48
0.53 0.39
0.13 0.18
0.43 0.41
0.41 0.39
0.06 0.07
Phase IV + RV O-hr 2-hr
2.20 2.30
2.47 2.43
0.15 0.18
2.35 2.30
2.51 2.50
0.08 0.10
* P < 0.05. **P < 0.01.
In a similar study but employing
1.0 ppm NOz using normal subjects, Hackney changes in pulmonary function with the NO2 exposures, except for a marginally decreased FVC (P < 0.05) following the second 2-hr NO2 exposure. The authors emphasized that their study findings applied to healthy human subjects, while individuals with asthma or chronic obstructive lung disease might be more sensitive. The results of our study employing a 0.5 ppm NO, exposure for 2 hr found this not to be the case. The authors also noted that short-term toxicity of NO2 at approximately 1 ppm appears to be substantially less et al. (1978) found no significant
402
KERR ET AL. TABLE MEAN
VALUES
OF TESTS
DERIVED
FROM
5
MEASUREMENTS
OF TRANSPULMONARY
Normal subjects (n = IO) Mean Subject groups
Day I (Control)
Day 2 (Exposure)
PRESSURE
Subjects with asthma (n = 13) Standard error of difference in means
Mean Day I (Control)
Day 2 (Exposure)
Standard error of difference in means
R, 2-hr
2.00
1.94
346
0.10
4.41
4.43
0.19
18
269
253
10
C I. da” I6
2-hr
196
197
12
160
159
6
CL ds” 32 2-hr
190
189
18
137
131
7
C L.d>” 4” 2-hr
194
194
21
121
123
7
Subjects with chronic bronchitis (n = 7) Mean Subject groups
R,.
2-hr
CL !,,a, 2-hr CL dY” Iti
2-hr
CL (1sn 32
Day 1 (Control) 3.23
Day 2 (Exposure) 3.17
Standard error of difference in means 0.11
Subjects with asthma and chronic bronchitis (n = 20) Mean Day 1 (Control) 4.00
Day 2 (Exposure) 3.99
Standard error of difference in means 0.13
366
334
18
303
282**
9
210
207
9
178
176
5
170
8
133
140
6
2-hr
187
CL dY” 48 2-hr
155
*P < 0.025. **p
< 0.05.
than that of ozone in healthy people, but adverse NO2 effects in diseased people or in long-term exposures cannot be ruled out. Nitrogen dioxide is an oxidant gas similar to ozone in its oxidative properties and health effects, but at similar concentrations in animal studies NO2 is less toxic than ozone (Mueller and Hitchcock, 1969; National Research Council, 1977). Of interest is a previously reported 6 hr ozone exposure study with normal human
HUMAN
PULMONARY
FUNCTION
WITH
NO2 EXPOSURE
403
subjects, also conducted in our environmental chamber, using the same 0.5 ppm concentration. Significant decrements in pulmonary function occurred with exposure for the 20 subject group as a whole in SGaw, RL, FVC and FEV1, and Ct+,, with the nonsmoking group of 10 subjects (Kerr et al., 1975). However, the changes in SGaw and in FVC with FEV, reached significance after the first 2 hr of ozone exposure, i.e., at 4 and 6 hr, respectively, of exposure. Subjects, who experienced symptoms, in general, were those who developed objective evidence of decreased pulmonary function. Noting the trends seen with our NO% study, a 0.5 ppm NO, exposure of normal subjects for 6 hr also might produce a significant decrement in pulmonary function. From this study we are reasonably confident that exposure of subjects with asthma and chronic bronchitis to 0.5 ppm NO1 for 2 hr does not produce a significant decrement in their pulmonary function. Exposure of either normal, healthy subjects or subjects with asthma or chronic bronchitis to 0.5 ppm NOz for 6 hr could result in a significant decrement with possible correlation with symptoms. Further studies using increased exposure time appear appropriate. ACKNOWLEDGMENT The authors wish to thank Richard L. Riley, M.D. for guidance in this investigation.
REFERENCES Abe, M. (1967). Effects of mixed NOz-SO, gas on human pulmonary functions. BUN. Tok.ro Med. Dent. Univ. 14, 415-433. American Conference of Government Industrial Hygienists (1977). “Threshold Limit Values for Chemical Substances in Workroom Air: Adopted by ACGIH for 1977,” Cincinnati, Ohio. Anthonisen. N. (1972). “Report of Informal Session on ‘Closing Volume’ Determination.” Fedrration Meetings, Atlantic City, New Jersey. DuBois, A. B., Botelho, S. Y., and Comroe, J. H., Jr. (1956). A new method for measuring airway resistance in man using a body plethysmograph: Values in normal subjects and in patients with respiratory diseases. J. C/in. Invest. 35, 327-335. Hackney, J. D., Thiede, F. C., Linn, W. S., Pedersen, E. E., Spier, C. E., Law, D. C., and Fischer, D. A. (1978). Experimental studies on human health effects of air pollutants. IV. Short-term physiological and clinical effects of nitrogen dioxide exposure. Arch. Environ. Hdth 33, 176- 181. Horvath, S. M., and Folinsbee, L. J. (1977). The effect of NO, on lung function in normal subjects. Report under contract with University of California, EPA No. 68-02-1757. Kerr, H. D. (1973). Diurnal variation of respiratory function independent of air quality: Experience with an environmentally controlled exposure chamber for human subjects. Arch. Environ. Health 26, 144-152. Kerr, H. D., Kulle, T. J., McIlhany, M. L.. and Swidersky, P. (1975). Effects of ozone on pulmonary function in normal subjects-An environmental chamber study. Am~r. Rev. Respir. DI’s. 111, 763-773. Mead, J., and Whittenberger, J. L. (1953). Physical properties of human lungs measured during spontaneous respiration. J. Appl. Physiol. 5, 779-196. Mueller, P. K., and Hitchcock, M. (1969). Air quality criteria-Toxicological appraisal for oxidants. nitrogen oxides, and hydrocarbons. J. Air Pollut. Control Assoc. 19, 670-676. National Air Pollution Control Administration. (1971). “Air Quality Criteria for Nitrogen Oxides.” Publication NO. AP-84, Washington, D.C. National Research Council: Committee on Medical and Bio]ogica] Effects of Environmental Pollutants (1977). “Ozone and Other Photochemical Oxidants,” p. 323. National Academy of Sciences, Washington. Nieding, G. V., Krekeler, H., Fuchs, R., Wagner, M., and Koppenhagen, K. (1973). Studies of the
404
KERR ET AL.
acute effects of NO, on lung function: Influence on diffusion, perfusion and ventilation in the lungs. Int. Arch. Arbeitsmed. 31, 61-72. Pearlman, M. E., Finklea, J. F., Creason, J. P., Shy, C. M., Young, M. M., and Horton, R. V. M. (1971). Nitrogen dioxide and lower respiratory illness. Pediatrics 47, 391-398. Rokaw, S. N. ef al. (1968). Human exposures to single pollutants-NO2 in controlled environment facility (Pre-Print of Presentation at the Ninth AMA Air Pollution Medical Research Conference, Denver). Shy, C. M., Creason, J. P., Pearlman, M. E., McClain, K. E., Benson, F. B., and Young, M. M. (1970a). The Chattanooga school study: Effects of community exposure to nitrogen dioxide, methods, description of pollutant exposure and results of ventilatory function testing. J. Air Pollut. Control Assoc. 20, 539-545. Shy, C. M., Creason, J. P., Pearlman, M. E., McClain, K. E., Benson, F. B., and Young, M. M. (1970b). The Chattanooga school children study: Effects of community exposure to nitrogen dioxide. Incidence of acute respiratory illness. J. Air Pollut. Control Assoc. 20, 582-588. Suzuki, T., and Ishikawa, K. (1965). Research on effect of smog on human body. Research and Report on Air Pollution Prevention No. 2, 199-221 (in Japanese).
RESEARCH
19,
392-404 (1979)
Effects of Nitrogen Dioxide on Pulmonary Function in Human Subjects: An Environmental Chamber Study’ H. D. KERR, T. J. KULLE,
M. L. MCILHANY,~
AND P. SWIDERSKY~
University of Maryland School of Medicine, Departmenr of Medicine, Division of Pulmonary Diseases, 29 South Greene Street, Baltimore. Maryland 21201 and The Johns Hopkins University. School of Hygiene and Public Health, Department of Environmental Health Sciences, 615 North Wove Street. Baltimore, Maryland 21205
Received November 23, 1978 Twenty human subjects with asthma and chronic bronchitis and 10 normal, healthy adults were exposed to 0.5 ppm of nitrogen dioxide for 2 hr in an environmental chamber. Seven of the 13 subjects with asthma experienced symptoms with exposure, while only one each of the subjects with chronic bronchitis and the healthy, normal group experienced symptoms. Significant pulmonary function changes from control values with exposure to NO, were observed in decreased quasistatic compliance for the 10 normal subjects and the 20 subjects with asthma and chronic bronchitis. In addition, functional residual capacity increased significantly for the 20 subjects with asthma and chronic bronchitis. The subjects with asthma and the subjects with chronic bronchitis as separate groups, however, did not show any significant changes with exposure. With this study we are reasonably confident that exposure of subjects with asthma and chronic bronchitis to 0.5 ppm NO, for 2 hr does not produce a significant decrement in their pulmonary function.
INTRODUCTION
Nitrogen dioxide (NO& levels in urban air pollution episodes in the U.S. (1962- 1968) have been measured between 0.10 and 0.80 parts per million (ppm) as a maximum hourly average with short-term peaks as high as 1.27 ppm (National Air Pollution Control Administration, 1971). The industrial hygiene occupational exposure for nitrogen dioxide is set by the American Conference of Government Industrial Hygienists (ACGIH) at 5 ppm as a ceiling value not to be exceeded (ACGIH, 1977). Limited studies of the toxic effects of NOz in man generally have considered moderate to high exposure levels (1.0 to 5.0 ppm) for periods of time from 10 min to 3 hr. Measurements of pulmonary function have shown conflicting results; in some cases marked increase in pulmonary resistance was observed with exposure, while no change in pulmonary function was reported by other investigators (Suzuki and Ishikawa, 1965; Abe, 1967; Rokaw et al., 1968; Nieding et al., 1973; Hackney et al., 1978). Epidemiologic and pulmonary function studies of children and their families living in neighborhoods with elevated NO, levels (proximity to large TNT plant) have demonstrated diminished pulmonary function (FEV,.,,) and/or an excess of lower respiratory illnesses (Shy et al., 1970a, b; Pearlman et al., 1971). Horvath and Folinsbee (1977) exposed normal human I This study was supported by Environmental Protection Agency Contract No. 68-02-1745. p Present address: Social Security Administration, Baltimore, Maryland 21207. 3 Present address: Borriston Research Laboratories, Temple Hills, Maryland 2003 1. 392 0013-9351/79/040392-13$02.00/O Copyright All rights
0 1979 by Academic Press. Inc. of reproduction in any form reserved.
HUMAN
PULMONARY
FUNCTION
WITH
NO2
EXPOSURE
393
subjects to 0.62 ppm NO, for 2 hr, observing no significant decrement in pulmonary function. Few controlled studies employing specific NO, exposures have been performed on subjects with chronic pulmonary disease (Rokaw er al., 1968; Nieding et al., 1973). The purpose ofthis investigation was to determine if measurable changes in pulmonary function occur breathing 0.5 ppm (940 pg/m3) nitrogen dioxide for 2 hr in subjects with asthma and chronic bronchitis and in normal subjects. MATERIALS
AND METHODS
Test Facility In order to restrict environmental effects to nitrogen dioxide, these experiments were carried out with subjects confined to an environmentally controlled chamber. A more detailed description of the environmental chamber facility is presented in a previously published paper (Kerr, 1973). Temperature was maintained at 24 + 1°C (75 f 2°F) with relative humidity of 45 2 5%. All room air was exhausted to the outside, instead of recirculating it through the conditioning system, enabling precise control of nitrogen dioxide concentration during the exposure phase. A complete room air exchange occurred every 2.5 min. Air entering the 2.1 x 4.3 x 2.4-m (7 x 14 x S-ft) exposure room was passed through highefficiency particulate absolute filters and activated carbon filters approaching class 100 cleanliness (
394
KERR
ET AL.
Nitrogen dioxide monitor strip chart recordings were made during each subject exposure. Means and standard deviations were determined from 3-min data points over the 2-hr exposure period. The means of the various exposures ranged between 0.49 and 0.51 ppm, with the standard deviations ranging from 0.01 to 0.02 ppm. Subjects Thirteen subjects with asthma, seven with chronic bronchitis, and ten normal, healthy subjects, were studied. An individual with asthma is defined as one who has a medical history of episodes of breathlessness, wheezing, and cough lasting for hours to days followed by intervals of complete remission. An individual with chronic bronchitis is defined as one who has a medical history of daily cough with sputum production persisting for 3 or more consecutive months over a period of 2 or more consecutive years. Informed consent was obtained from each subject after the nature of the procedure had been fully explained. Smokers were asked to abstain for 24 hr prior to, and during the 2 days of the research. Twenty-three subjects were male and seven female. Each subject served as his or her own control. The order of subject study in pairs and the sequence of physiological tests were not varied. Physiological Tests A 2-day study procedure was employed; on the first or control day the subjects remained in the exposure room for 2 hr breathing filtered clean air. On the second day, they breathed 0.50 ppm nitrogen dioxide for 2 hr at the same time of the day. Pulmonary function tests were performed in sequence (spirometry, plethysmography, and single breath nitrogen elimination rate) at the beginning and following the 2-hr chamber confinement on both Day 1 and Day 2. The remaining two physiological tests (pulmonary resistance and compliance) were done following the above tests only at the end of the 2-hr confinement on Day 1 and Day 2. Bicycle ergometer exercise at a light-to-moderate work load of 60- 100 W, depending upon the subject’s physical characteristics and tolerance, at 60 rpm for 15 min was performed during the first hour on both Day 1 and Day 2. All pulmonary function tests were performed in a seated position to ensure comparability of lung volumes from the various tests. To assure technically satisfactory subject performance, the subjects repeatedly executed each test, except those requiring the esophageal balloon, during preliminary practice sessions and before confinement on both days. Ventilatory function testing was performed as a single forced vital capacity (FVC) by standard technique employing a waterseal direct writing spirometer. All volumes were expressed in liters at body temperature, pressure, saturated (BTPS). Airway resistance (Raw) and volume of thoracic gas (Vtg) were determined by the whole-body pressure plethysmographic technique of DuBois et al. (1956) with certain technical modifications (Kerr, 1973). Each of 10 panting breaths for Raw and Vtg at functional residual capacity (FRC) were determined by computer analysis of analog tape recording of pressures, flow, and volume. Airway resistance measurements determined a 1 liter/set airflow (0.5 liter/set inspiratory to 0.5
HUMAN
PULMONARY
FUNCTION
WITH
NOz
EXPOSURE
395
liter/set expiratory) were converted to specific airway conductance (SGaw = l/Raw/Vtg), using the Vtg at which each Raw was measured, and expressed as the mean of the 10 panting breaths. Practice sessions enabled most subjects to perform the panting maneuvers of Raw and Vtg at or very close to FRC. Total lung capacity (TLC) was expressed as the sum of FRC and the inspiratory capacity, and residual volume (RV) was expressed as the difference between FRC and the expiratory reserve volume. All lung volumes were expressed in liters and SGaw as l/cm HZ0 x second units. Tests of single breath nitrogen elimination rate were calculated from an XY plot of expired nitrogen concentration vs expired volume from TLC to RV following a full inspiration of 100% oxygen from RV to TLC. Rate of expiration was controlled to not exceed 0.5 liter/set. Phase III was expressed as change in percentage alveolar nitrogen concentration per liter of expired volume, and was determined from the best fit straight line of the alveolar sample mid-portion of the XY plot. Phase IV (“closing volume”) was measured from RV to the Phase III-Phase IV junction (Anthonisen, 1972). One reader performed all the line-fitting procedures. Pulmonary resistance (Rt) and compliance (CL) were determined by the electronic subtractor method of Mead and Whittenberger (1953). In order to stabilize volume history, each subject fully inflated his or her lungs to TLC prior to performing the quasistatic and dynamic compliance maneuvers. Dynamic compliance was performed at frequencies of 16 breaths per minute (C, dyn 16), 32/min and 48/min in rhythm with an audio metronome while maintaining a tidal volume of 1 liter for 8 to 10 breaths at each breathing frequency. To determine CL dyn, a portion of the transpulmonary pressure proportional to airflow was subtracted by manual potentiometer adjustment for the best fit straight line XY oscilloscope display of this resultant pressure vs tidal volume. For R,,, a portion of transpulmonary pressure proportional to volume change was subtracted in a similar fashion with straight line fitting of the XY plot of this pressure vs airflow. All subtractions and readings were performed from playback of analog tape recordings of aifflow, volume change, and transpulmonary pressure. This procedure enabled rereading of the recordings to verify values and also to standardize the length of time each subject performed at the different frequencies, thereby avoiding excessive alveolar ventilation from prolonged measurement. Pulmonary resistance was expressed as cm H,O/liter/sec and was not corrected for the Vtg at which it was measured. All compliance data were expressed as ml/cm H,O. Dura Analysis
There were three subject groups consisting of 10 normals, 7 subjects with chronic bronchitis, and 13 subjects with asthma. Individual subject data were grouped into the appropriate category (Table 1). The group data were compared between control (Day 1) and exposure (Day 2), and the levels of significance determined by t test of paired observations. The effects found were small and there were trends toward significance with some measurements in the group of subjects with asthma and those with chronic bronchitis. In order to provide a greater sensitivity in detecting these changes, the data for the 20 subjects with asthma and chronic bronchitis were combined for analysis.
53 25 30 24
M M M M
13 17 20 21
M M M M M M M M M
2 3 4 5 6 7 10 11 12
44 29 42 63 39 26 28 29 22 23
34.5 12.7
M
1
(years)
Age
SMOKING
Mean SD
Sex
DATA,
No.
Subject
ANTHROPOMETRIC
HISTORY,
171 165 188 175
181.8 6.4
188 175 183 174 173 183 190 183 179 190
Height (cm)
AND
Smoking history”
0 + + +
(pipe)
(pipe)
(n = 7)
3110
(n = 10) + + 0 0 0 0 0 + 0 0
Chronic Bronchitis 86 99 92 75
75.7 8.7
Normal 73 66 77 64 70 70 92 83 79 83
Weight (kg)
I
EXPOSURE TO NITROGEN TO DIAGNOSIS
TABLE SYMPTOMS DURING ACCORDING
DIOXIDE
l/IO
0 0 0 0 0 0
0 0 0 +
(Nasal
discharge)
SUBJECTS
Symptoms during exposureb
OF 30 HUMAN
CLASSIFIED
M M M M M F F M F M M M F
F F F
Sex
26.8 10.0
41 23 30 22 24 19 21 21 38 50 20 20 19
30.3 10.5
32 24 24
Age (years)
’ 0, nonsmoker; +, smoker. ’ 0, no symptoms: C, symptom experienced.
Mean SD
8 9 14 15 16 18 19 22 23 24 25 27 28
Mean SD
26 29 30
No.
Subject
170.5 8.9
161 178 165 164 185 159 166 173 160 175 175 185 171
170.8 8.7
168 168 161
Height (cm)
517
+ 0 +
Smoking history”
I--Conrinued
67.0 7.6
3113
Asthma (n = 13) 68 0 75 0 64 + 65 0 64 + 62 0 62 0 68 0 49 0 80 0 72 0 69 + 73 0
80.6 12.7
75 61 76
Weight (kg)
TABLE
(light)
(former smoker)
(former smoker) (occasional)
7113
0 0 + + 0 + 0 0 + + + + 0
117
+ 0 0
(Chest tightness) (Chest tightness) (Slight burning of eyes) (Dyspnea with exercise)
(Slight burning of eyes)
(Chest tightness) (Slight headache)
(Nasal discharge)
Symptoms during exposure*
398
KERRETAL. RESULTS
The odor of nitrogen dioxide was readily perceptible at the 0.50 ppm concentration, but most subjects reported that they became unaware of the odor after 15 min of exposure. None of the subjects considered the odor to be unpleasant. Subjects were asked to keep note of symptoms they might experience; following the exposure study, they were specifically asked about cough, sputum, irritation of mucous membranes, and chest discomfort. Symptoms reported were in general mild and more frequently reported by subjects with asthma. Only one subject with chronic bronchitis and one normal subject experienced the very mild symptom of slight rhinorrhea (Table I), while more than half (seven of thirteen) subjects with asthma reported some degree of chest tightness, burning of the eyes, headache, or dyspnea with exercise and exposure to NOz. There did not appear to be any relationship between history and symptoms. Although subjects with asthma experienced the most symptoms, no significant changes were observed in any of the parameters of pulmonary function (Tables 2 to 5). With NOt exposure, a significant decrement in quasistatic compliance was seen in normal subjects, while there were no significant changes in dynamic compliance for any subject group (Table 5). Although no significant difference was shown between the control and exposure (2-hr) values, variance in the preexposure (0-hr) values occurred with Phase III nitrogen elimination rate in subjects with chronic bronchitis and with Phase IV nitrogen elimination rate in normals (Table 4). No other significant differences were observed in any of the pulmonary function tests. When the data for all 20 subjects with asthma and chronic bronchitis are considered together, significant increases were noted in FRC and quasistatic compliance as well as TLC and RV on the exposure day (Tables 3 and 5). Variance was also demonstrated in the preexposure (0-hr) TLC and RV values, thus, a significant change with exposure in TLC and RV is questioned. DISCUSSION
The symptoms reported were minimal, did not correlate with functional changes, and are of doubtful significance. Because the odor of NOe is detectable at 0.5 ppm, a double-blind study, though desirable, would not be practical. The results of this investigation are in general negative, which is in itself useful. Although exposure to higher concentrations of NOz have been shown by others to alter function, and very high concentrations to result in significant damage to the respiratory system, it would appear that no significant alteration in pulmonary function is likely to result from a 2-hr exposure to 0.5 ppm NOz alone in normal subjects or subjects with chronic obstructive pulmonary disease. The few significant changes reported here may be due to chance alone. While changes in compliance, distribution of ventilation, and static lung volumes (TLC, FRC, RV) suggest some degree of change in elastic properties, no meaningful change in function can be implied as significant differences in some of these functions also were observed prior to exposure (0-hr). The changes observed showed no consistency between subject groups and did not correlate with the symptoms. There were no significant changes in any of the flow resistance parameters by spirometry, plethysmograph, or esophageal balloon techniques.
4.06 4.10
4.05 4.14
4.91 4.98
9.79 10.00
3.70 3.94
1.84 1.82
FEV, 0-hr 2-hr
MEFR 0-hr 2-hr
MMEF 0-hr 2-hr
ERV 0-hr 2-hr
1.81 1.67
3.69 3.74
9.04 9.55
4.98 4.94
5.29 5.27
Day 2 (Exposure)
5.25 5.30
Day 1 (Control)
FVC 0-hr 2-hr FEV, 0-hr 2-hr
Subject groups
Mean
Normal subjects (n = 10)
MEAN
0.10 0.08
0.10 0.13
0.54 0.42
0.05 0.03
0.05 0.04
0.05 0.03
1.37 1.25
2.51 2.65
5.76 5.93
4.15 4.09
3.15 3.12
4.51 4.42
Day 1 (Control)
OF VENTILATORY
Standard error of difference in means
VALUES
2 DERIVED
1.23 1.24
2.83 2.70
5.85 5.86
4.18 4.07
3.25 3.14
4.49 4.38
Day 2 (Exposure)
Mean
FROM
0.08 0.04
1.63 1.55
3.15 2.71
7.20
0.30 0.18 0.13
8.14
4.47 4.38
3.66 3.50
4.88 4.81
0.27
0.06 0.05
0.07 0.05
0.07 0.05
1.63 1.53
3.02 2.81
7.51
8.07
4.51 4.38
3.64 3.51
4.93 4.82
Day 2 t Exposure)
Mean
0.08 0.07
0.12 0.23
0.47
0.61
0.03 0.06
0.04 0.08
0.04 0.06
Standard error of difference in means
Subjects with chronic bronchitis (II = 7)
Day 1 (Control)
SPIROMETRY
Standard error of difference in means
Subjects with asthma (n = 13)
FUNCTION
TABLE
s
m
3 B
N3
4 5 2 Q =i X
z
% sz z
z
$ z
KERR ET AL.
TABLE MEAN
VALUES
OF TESTS DERIVED
FROM
3 PLETHYSMOGRAPHIC
Normal subjects (n
=
MEASUREMENTS
Subjects with asthma
10)
(n = 13)
Subject groups
Day 1 (Control)
Day 2 (Exposure)
Standard error of difference in means
SGaw 0-hr 2-hr
0.218 0.246
0.219 0.238
0.014 0.014
0.137 0.137
0.136 0.142
0.007 0.012
TLC 0-hr 2-hr
7.24 7.38
7.37 7.44
0.13 0.17
6.47 6.32
6.65 6.49
0.11 0.11
FRC 0-hr 2-hr
3.83 3.91
3.90 3.83
0.10 0.13
3.37 3.19
3.40 3.38
0.09 0.13
RV 0-hr 2-hr
1.99 2.08
2.08 2.16
0.12 0.18
1.96 1.90
2.16 2.11
0.09 0.12
Mean
Day 1 (Control)
Day 2 (Exposure)
Standard error of difference in means
Mean
Subjects with chronic bronchitis
Subjects with asthma and chronic bronchitis (n = 20)
(n = 7)
Subject groups
Day 1 (Control)
Day 2 (Exposure)
Standard error of difference in means
SGaw 0-hr 2-hr
0.196 0.198
0.185 0.180
0.016 0.014
0.158 0.159
0.153 0.156
0.007 0.009
TLC 0-hr 2-hr
6.67 6.63
6.87 6.86
0.11 0.13
6.54 6.44
6.74’* 6.63*
0.08 0.08
FRC 0-hr 2-hr
3.42 3.37
3.57 3.57
0.09 0.13
3.39 3.26
3.46 3.45*
0.07 0.09
RV 0-hr 2-hr
1.79 1.82
1.94 2.04
0.08 0.11
1.90 1.87
2.08*” 2.09**
0.07 0.09
Mean
*P **p
< 0.05. < 0.025.
Day 1 (Control)
Day 2 (Exposure)
Standard error of difference in means
Mean
HUMAN
PULMONARY
FUNCTION
WITH
NO2 EXPOSURE
SINGLE-BREATH
N2 ELIMINATION
TABLE MEAN
VALUES
OF TESTS DERIVED
FROM
4
Normal subjects (n = IO)
Subject groups
Day 1 (Control)
(Exposure)
Day 1 (Control)
Day 2
RATE
Subjects with asthma (n = 13) Standard error of difference in means
Mean
401
Mean Day 2 (Exposure)
Standard error of difference in means
Phase III 0-hr 2-hr
1.15 1.13
1.26 1.08
0.13 0.13
1.42 I .30
1.58 1.41
0.18 0. I I
Phase IV 0-hr 2-hr
0.62 0.54
0.47* 0.65
0.06 0.07
0.44 0.36
0.35 0.39
0.06 0.06
2.61 2.62
2.55 2.81
0.14 0.20
2.44 2.30
2.54 2.54
0.09 0.13
Phase IV +RV 0-hr 2-hr
Subjects with chronic bronchitis (n = 7)
Day 2 (Exposure)
Standard error of difference in means
Mean Subject groups
Day I (Control)
Subjects with asthma and chronic bronchitis (n = 20) Mean Day I (Control)
Day 2 (Exposure)
Standard error of difference in means
Phase III 0-hr 2-hr
1.14 I.15
0.85”* 0.92
0.07 0.10
1.32
1.33
1.28
1.22
0.13 0.07
Phase IV 0-hr 2-hr
0.41 0.48
0.53 0.39
0.13 0.18
0.43 0.41
0.41 0.39
0.06 0.07
Phase IV + RV O-hr 2-hr
2.20 2.30
2.47 2.43
0.15 0.18
2.35 2.30
2.51 2.50
0.08 0.10
* P < 0.05. **P < 0.01.
In a similar study but employing
1.0 ppm NOz using normal subjects, Hackney changes in pulmonary function with the NO2 exposures, except for a marginally decreased FVC (P < 0.05) following the second 2-hr NO2 exposure. The authors emphasized that their study findings applied to healthy human subjects, while individuals with asthma or chronic obstructive lung disease might be more sensitive. The results of our study employing a 0.5 ppm NO, exposure for 2 hr found this not to be the case. The authors also noted that short-term toxicity of NO2 at approximately 1 ppm appears to be substantially less et al. (1978) found no significant
402
KERR ET AL. TABLE MEAN
VALUES
OF TESTS
DERIVED
FROM
5
MEASUREMENTS
OF TRANSPULMONARY
Normal subjects (n = IO) Mean Subject groups
Day I (Control)
Day 2 (Exposure)
PRESSURE
Subjects with asthma (n = 13) Standard error of difference in means
Mean Day I (Control)
Day 2 (Exposure)
Standard error of difference in means
R, 2-hr
2.00
1.94
346
0.10
4.41
4.43
0.19
18
269
253
10
C I. da” I6
2-hr
196
197
12
160
159
6
CL ds” 32 2-hr
190
189
18
137
131
7
C L.d>” 4” 2-hr
194
194
21
121
123
7
Subjects with chronic bronchitis (n = 7) Mean Subject groups
R,.
2-hr
CL !,,a, 2-hr CL dY” Iti
2-hr
CL (1sn 32
Day 1 (Control) 3.23
Day 2 (Exposure) 3.17
Standard error of difference in means 0.11
Subjects with asthma and chronic bronchitis (n = 20) Mean Day 1 (Control) 4.00
Day 2 (Exposure) 3.99
Standard error of difference in means 0.13
366
334
18
303
282**
9
210
207
9
178
176
5
170
8
133
140
6
2-hr
187
CL dY” 48 2-hr
155
*P < 0.025. **p
< 0.05.
than that of ozone in healthy people, but adverse NO2 effects in diseased people or in long-term exposures cannot be ruled out. Nitrogen dioxide is an oxidant gas similar to ozone in its oxidative properties and health effects, but at similar concentrations in animal studies NO2 is less toxic than ozone (Mueller and Hitchcock, 1969; National Research Council, 1977). Of interest is a previously reported 6 hr ozone exposure study with normal human
HUMAN
PULMONARY
FUNCTION
WITH
NO2 EXPOSURE
403
subjects, also conducted in our environmental chamber, using the same 0.5 ppm concentration. Significant decrements in pulmonary function occurred with exposure for the 20 subject group as a whole in SGaw, RL, FVC and FEV1, and Ct+,, with the nonsmoking group of 10 subjects (Kerr et al., 1975). However, the changes in SGaw and in FVC with FEV, reached significance after the first 2 hr of ozone exposure, i.e., at 4 and 6 hr, respectively, of exposure. Subjects, who experienced symptoms, in general, were those who developed objective evidence of decreased pulmonary function. Noting the trends seen with our NO% study, a 0.5 ppm NO, exposure of normal subjects for 6 hr also might produce a significant decrement in pulmonary function. From this study we are reasonably confident that exposure of subjects with asthma and chronic bronchitis to 0.5 ppm NO1 for 2 hr does not produce a significant decrement in their pulmonary function. Exposure of either normal, healthy subjects or subjects with asthma or chronic bronchitis to 0.5 ppm NOz for 6 hr could result in a significant decrement with possible correlation with symptoms. Further studies using increased exposure time appear appropriate. ACKNOWLEDGMENT The authors wish to thank Richard L. Riley, M.D. for guidance in this investigation.
REFERENCES Abe, M. (1967). Effects of mixed NOz-SO, gas on human pulmonary functions. BUN. Tok.ro Med. Dent. Univ. 14, 415-433. American Conference of Government Industrial Hygienists (1977). “Threshold Limit Values for Chemical Substances in Workroom Air: Adopted by ACGIH for 1977,” Cincinnati, Ohio. Anthonisen. N. (1972). “Report of Informal Session on ‘Closing Volume’ Determination.” Fedrration Meetings, Atlantic City, New Jersey. DuBois, A. B., Botelho, S. Y., and Comroe, J. H., Jr. (1956). A new method for measuring airway resistance in man using a body plethysmograph: Values in normal subjects and in patients with respiratory diseases. J. C/in. Invest. 35, 327-335. Hackney, J. D., Thiede, F. C., Linn, W. S., Pedersen, E. E., Spier, C. E., Law, D. C., and Fischer, D. A. (1978). Experimental studies on human health effects of air pollutants. IV. Short-term physiological and clinical effects of nitrogen dioxide exposure. Arch. Environ. Hdth 33, 176- 181. Horvath, S. M., and Folinsbee, L. J. (1977). The effect of NO, on lung function in normal subjects. Report under contract with University of California, EPA No. 68-02-1757. Kerr, H. D. (1973). Diurnal variation of respiratory function independent of air quality: Experience with an environmentally controlled exposure chamber for human subjects. Arch. Environ. Health 26, 144-152. Kerr, H. D., Kulle, T. J., McIlhany, M. L.. and Swidersky, P. (1975). Effects of ozone on pulmonary function in normal subjects-An environmental chamber study. Am~r. Rev. Respir. DI’s. 111, 763-773. Mead, J., and Whittenberger, J. L. (1953). Physical properties of human lungs measured during spontaneous respiration. J. Appl. Physiol. 5, 779-196. Mueller, P. K., and Hitchcock, M. (1969). Air quality criteria-Toxicological appraisal for oxidants. nitrogen oxides, and hydrocarbons. J. Air Pollut. Control Assoc. 19, 670-676. National Air Pollution Control Administration. (1971). “Air Quality Criteria for Nitrogen Oxides.” Publication NO. AP-84, Washington, D.C. National Research Council: Committee on Medical and Bio]ogica] Effects of Environmental Pollutants (1977). “Ozone and Other Photochemical Oxidants,” p. 323. National Academy of Sciences, Washington. Nieding, G. V., Krekeler, H., Fuchs, R., Wagner, M., and Koppenhagen, K. (1973). Studies of the
404
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acute effects of NO, on lung function: Influence on diffusion, perfusion and ventilation in the lungs. Int. Arch. Arbeitsmed. 31, 61-72. Pearlman, M. E., Finklea, J. F., Creason, J. P., Shy, C. M., Young, M. M., and Horton, R. V. M. (1971). Nitrogen dioxide and lower respiratory illness. Pediatrics 47, 391-398. Rokaw, S. N. ef al. (1968). Human exposures to single pollutants-NO2 in controlled environment facility (Pre-Print of Presentation at the Ninth AMA Air Pollution Medical Research Conference, Denver). Shy, C. M., Creason, J. P., Pearlman, M. E., McClain, K. E., Benson, F. B., and Young, M. M. (1970a). The Chattanooga school study: Effects of community exposure to nitrogen dioxide, methods, description of pollutant exposure and results of ventilatory function testing. J. Air Pollut. Control Assoc. 20, 539-545. Shy, C. M., Creason, J. P., Pearlman, M. E., McClain, K. E., Benson, F. B., and Young, M. M. (1970b). The Chattanooga school children study: Effects of community exposure to nitrogen dioxide. Incidence of acute respiratory illness. J. Air Pollut. Control Assoc. 20, 582-588. Suzuki, T., and Ishikawa, K. (1965). Research on effect of smog on human body. Research and Report on Air Pollution Prevention No. 2, 199-221 (in Japanese).