EPA-600/1-78-025
April 1978
Environmental Health Effects Research Series
EFFECTS OF NITROGEN DIOXIDE
ON PULMONARY FUNCTION IN HUMAN SUBJECTS
Health Effects Research Laboratory
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina 27711
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RESEARCH REPORTING SERIES
Research reports of the Office of Research and Development, U.S. Environmental
Protection Agency, have been grouped into nine series. These nine broad cate-
gories were established to facilitate further development and application of en-
vironmental technology. Elimination of traditional grouping was consciously
planned to foster technology transfer and a maximum interface in related fields.
The nine series are:
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3. Ecological Research
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5. Socioeconomic Environmental Studies
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9. Miscellaneous Reports
This report has been assigned to the ENVIRONMENTAL HEALTH EFFECTS RE-
SEARCH series. This series describes projects and studies relating to the toler-
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This document is available to the public through the National Technical Informa-
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EPA-600/1-78-025
April 1978
EFFECTS OF NITROGEN DIOXIDE ON PULMONARY FUNCTION
IN HUMAN SUBJECTS
AN ENVIRONMENTAL CHAMBER STUDY
By
H. David Kerr, M. D.
Thomas J. Kulle, Ph. D.
Mary Lou McUhany, M. D.
Paul Swidersky
University of Maryland School of Medicine
Department 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 Wolfe Street
Baltimore, Maryland 21205
Contract No. 68-02-1745
Project Officer
Dr. Brock T. Ketcham
Health Effects Research Laboratory
Environmental Protection Agency
Research Triangle Park, North Carolina 27711
U.S. Environmental Protection Agency
Office of Research and Development
Health Effects Research Laboratory
Research Triangle Park, North Carolina 27711
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DISCLAIMER
This report has been reviewed by the Health Effects
Research Laboratory, U.S. Environmental Protection Agency,
and approved for publication. Approval does not signify
that the contents necessarily reflect the views and policies
of the U.S. Environmental Protection Agency, nor does
mention of trade names or commercial products constitute
endorsement or recommendation for use.
11
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FOREWORD
The many benefits of our modern, developing, industrial society are
accompanied by certain hazards. Careful assessment of the relative risk of
existing and new man-made environmental hazards is necessary for the estab-
lishment of sound regulatory policy. These regulations serve to enhance
the quality of our environment in order to promote the public health and
welfare and the productive capacity of our Nation's population.
The Health Effects Research Laboratory, Research Triangle Park,
conducts a coordinated environmental health research program in toxicology,
epidemiology, and clinical studies using human volunteer subjects. These
studies address problems in air pollution, non-ionizing radiation, environ-
mental carcinogenesis and the toxicology of pesticides as well as other
chemical pollutants. The Laboratory develops and revises air quality
criteria documents on pollutants for which national ambient air quality
standards exist or are proposed, provides the data for registration of new
pesticides or proposed suspension of those already in use, conducts research
on hazardous and toxic materials, and is preparing the health basis for
non-ionizing radiation standards. Direct support to the regulatory function
of the Agency is provided in the form of expert testimony and preparation
of affidavits as well as expert advice to the Administrator to assure the
adequacy of health care and surveillance of persons having suffered imminent
and substantial endangerment of their health.
This study was designed to look at the adverse effects, if any, of
inhalation of Nİ2 by human subjects with known diagnosis of asthma or
chronic bronchitis. N02, at the levels studied, often is present in "smog"
type atmospheres as are individuals with respiratory illness. This study
gives some insight into the effect of a specific pollutant (NO2) at a known
concentration (.5 ppm) and time (2 hours) on an already compromised human
respiratory system. Results from this investigation will provide data on
the spectrum of pulmonary responses in two large classes of the population
at risk. The data will aid HERL in further defining short-term adverse
effects of this specific pollutant.
John H. Knelson, M.D.
Director,
Health Effects Research Laboratory
111
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ABSTRACT
Twenty human subjects with asthma and chronic bronchitis and ten normal,
healthy adults were exposed to 0. 5 ppm of nitrogen dioxide (NO2) for two
hours in an environmental chamber. They engaged in one 15-minute,
light to medium-exercise stint on a bicycle ergometer during this period.
The subjects with asthma experienced the greatest symptoms with exposure
to NO2ğ i. e., seven of. thirteen noting slight burning of the eyes, slight
headache, and chest tightness or labored breathing with exercise. One
each of the subjects with chronic bronchitis and the healthy, normal
group experienced slight nasal discharge. Significant changes from
control values for the group as a whole with exposure to NO2 were observed
for the following pulmonary function tests: quasi-state compliance for
the twenty subjects with asthma and chronic bronchitis as well as for
the ten normal subjects, and functional residual capacity for the twenty
subjects with asthma and chronic bronchitis. Subjects with asthma
and chronic bronchitis as separate groups (n = 13 and 7 respectively) did
not show any significant changes in pulmonary function with the NO2
exposure, even though the group of thirteen subjects with asthma experienced
the greatest symptoms.
IV
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CONTENTS
Page
Abstract iv
List of Tables vi
Acknowledgments V11
Sections
I Conclusions 1
II Recommendations 2
III Introduction 3
IV Materials and Methods 4
t
V Experimental Phase (Results) 9
VI Discussion 16
VII References 17
Glossary 20
v
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TABLES
No. Page
1 Anthropometric Data, Smoking History, and
Symptoms During Exposure to Nitrogen Dioxide
of 30 Human Subjects Classified According to
Diagnosis 11
2 Mean Values of Ventilatory Function Derived
from Spirometry 12
3 Mean Values of Tests Derived from
Plethysmographic Measurements 13
4 Mean Values of Tests Derived from Single-
Breath N2 Elimination Rate 14
5 Mean Values of Tests Derived from
Measurements of Transpulmonary Pressure 15
VI
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ACKNOWLEDGMENTS
The authors wish to thank Richard L. Riley, M. D. for guidance in
this investigation.
vii
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SECTION I
CONCLUSIONS
The symptoms reported were minimal, did not correlate with functional
changes, and are of doubtful significance.
The results of this investigation are in general negative, which is in
itself useful. It appears that no significant alteration in pulmonary
function is likely to result from a two-hour exposure to 0. 5 ppm NO2
alone in normal subjects or patients with chronic obstructive pulmonary
disease. The few significant changes reported here may be due to
chance alone.
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SECTION II
RECOMMENDATIONS
It is of interest to compare this NO2 study with a previously reported 6-hour
ozone exposure study with normal human subjects, also conducted in our
environmental chamber, using the same 0. 5 ppm concentration. With ozone
(0. 5 ppm for 6 hours), significant decrements in pulmonary function occurred
with exposure for the 20 subject group as a whole in specific airway
conductance, pulmonary resistance, forced vital capacity, and 3-second
forced expiratory volume. However, no significant changes in specific
airway conductance and forced vital capacity occurred following the first
two-hours of ozone exposure; the changes reached significance only after
four and six hours, respectively, of exposure. Subjects, who experienced
symptoms, in general, were those who developed objective evidence of
decreased pulmonary function.
With this study we are reasonably confident that exposure of patients with
asthma and chronic bronchitis to 0. 5 ppm NO2 for two hours does not
produce a significant decrement in pulmonary function. Exposure of 0.5
ppm NO2 for longer than two hours could result in a significant decrement
and possible correlation with the symptoms experienced with exposure.
Concern could be expressed for patients with COPD exposed to 0.5 ppm
NO2 for longer than two hours, i. e., six hours. Further studies using
increased exposure time appear appropriate.
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SECTION HI
INTRODUCTION
Nitrogen dioxide (NO2) 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 (1). 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 (2). Limited studies
of the toxic effects of NO2 in man generally have considered high exposure
levels (0. 5 to 5. 0 ppm) for periods of time from ten minutes to three hours.
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 (3,4, 5). Epidemiologic and pulmonary function studies of
children and their families living in neighborhoods with elevated NO2 levels
(proximity to large TNT plant) have demonstrated diminished pulmonary
function (FEV ) and/or an excess of lower respiratory illnesses
U. i D
(6, 7, 8). Horvath, et. al., exposed normal human subjects to 0. 5 ppm NO2
for two hours, observing no significant decrement in pulmonary function (9).
Few controlled studies employing specific NO2 exposures have been
performed on subjects with chronic pulmonary disease. The purpose of this
investigation was to determine if measurable pulmonary function effects
occur breathing 0. 5 ppm (940 fig/m ) nitrogen dioxide for two hours in
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patients with asthma and chronic bronchitis and in normal subjects.
SECTION IV
MATERIALS AND METHODS
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 (10).
o
Temperature was maintained at 75 ħ1 F with relative humidity 45 ħ5%.
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 minutes. Air entering the 2. 1 x 4. 3 x 2. 4
meter (7x14x8 foot) exposure room was passed through high-efficiency
particulate absolute filters and activated carbon filters approaching class
100 cleanliness (<100 particles >0. 5;um/foot ) or (<3534 particles >0.5yum/m ).
Nitrogen dioxide, in compressed gas cylinders of 6000 ppm
concentration, was accurately mete red into the exposure room of the
chamber via the room air input diffuser. For the safety of the human
subjects, the NO2 concentration was monitored, recorded, and controlled
continuously by two NO2 analyzers, one employing the colorimetric method,
the other the coulometric method. The colorimetric analyzer has good
accuracy but a long response time (90% of full scale indication) of nine
-------
minutes; whereas, the coulometric analyzer used had a response time
within one-half a minute, but with somewhat less accuracy, thus being
able to rapidly indicate changes in NO2 concentration in the exposure room
when they occurred. Prior to and following the NO2 study, the two
analyzers were checked for standardization with an accurate NO2 source
at the National Bureau of Standards (NBS), Gaithersburg, Maryland, using
the Federal Register Method described in Code of Federal Regulations
40 CFR, Part 50.
In order to assure accurate setting of the NO2 concentration for each
exposure study, the colorimetric analyzer was calibrated in the laboratory
prior to and on the day of the NO2 exposure of each subject. An NBS
calibrated NO2 permeation tube in a temperature-controlled portable
permeator was used as the calibrator for setting the span controls on the
analyzer. In addition, the coulometric analyzer was also checked for
standardization at NBS midway between the two-year study.
Prior to initiating the subject exposure studies, an NO2 concentration
profile was taken of the chamber exposure room at four- and six-foot levels
above the chamber room, representing sitting and standing levels of the
subject's mouth and nose. The range of concentrations varied between
".47 and 0. 52 ppm NO2.
Nitrogen dioxide mon tor strip chart recordings wer. made during
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each subject exposure. Means and standard deviations were determined
from three minute data points over the two-hour 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.
Thirteen subjects with asthma, seven with chronic bronchitis, and
ten normal, healthy subjects, were studied. Informed consent was
obtained from each subject after the nature of the procedure had been
fully explained. Smokers were asked to abstain for 24 hours prior to,
and during the two days of the research. Twenty-three subjects were
male and seven female. Each subject served as his own control. The
order of subject study in pairs and the sequence of physiological tests
was not varied.
A two-day study procedure was employed; on the first or control day
the subjects remained in the exposure room for two hours breathing
filtered clean air. On the second day, they breathed 0. 50 ppm nitrogen
dioxide for two hours 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 two hour chamber confinement on both day 1 and day 2. The remaining
two physiological tests (pu'.r.ionary resistance and compliance) were done
following the above tests .* y at the end of the two hour confinement on
day 1 and day 2. Bicycle erne-meter exercise at a light-to-moderate
-------
work load of 60-100 watts, depending upon the subject's physical
characteristics and tolerance, at 60 RPM for 15 minutes was performed
during the first hour on both day 1 and day 2. All pulmonary function
tests were performed in a seated position to insure 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 (L.) 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. (H) with certain technical modifications (10). Each of
ten panting breaths for Raw and Vtg at functional residual capacity (FRC)
were determined by computer analysis of analog tape recordings of
pressures, flow, and volume. Airway resistance measurements
determined at 1 L/sec. airflow (0. 5 L/sec. inspiratory to 0.5 L/sec.
expiratory) were converted to specific airway conductance (SGaw =
1/Raw/Vtg), using the V% at which each Raw was measured, and
expressed as the mean of the t^n panting breaths. Practice sessions
7
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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 I/cm H2O x sec. 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 L/sec.
Phase III was expressed as change in percent alveolar nitrogen con-
centration 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 Ill-
Phase IV junction (12). One reader performed all of the line-fitting
procedures.
Pulmonary resistance (R ) and compliance (C ) were determined by
L L
the electronic subtracter method of Mead and Whittenberger (13). In order
to stabilize volume history, each subject fully inflated his lungs to TLC
prior to performing tb^ quasi-static and dynamic compliance maneuvers.
Dynamic compliance -,vas performed at frequencies of 16 breaths per
minute (C dyn. 16), 32/min. and 48/min. in rhythm with an audio
L
8
-------
metronome while maintaining a tidal volume of one liter for 8 to 10
breaths at each breathing frequency. To determine O dyn., a portion
L
of the trans pulmonary 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
J_ğ
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 airflow, volume
change, and transpulmonary pressure. This procedure enabled re-
reading 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 H2O/L/sec. and was not
corrected for the Vtg at which it was measured. All compliance data
were expressed as ml/cm H2O.
SECTION V
EXPERIMENTAL PHASE (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 minutes of exposure. None of the subjects considered
the odor to be unpleasant. Subjects were asked to keep note of symptoms
they might experience; following vhe 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 chronic
bronchitis patient and one normal subject experienced the very mild
symptom of slight rhinorrhea (Table 1), while more than half (seven of
thirteen) asthma patients reported some degree of chest tightness,
burning of the eyes, headache or dyspnea with exercise and exposure to
NO2. There did not appear to be any relationship between history and
symptoms.
Although asthma patients experienced the most symptoms, no
significant changes were observed in any of the parameters of pulmonary
function (Tables 2 to 5). Normal subjects disclosed variance in the pre-
exposure (0-Hour) Phase IV nitrogen elimination rate; but, there was
no significant difference between the control and exposure (2-Hour)
values (Table 4). After NO2 exposure, a significant decrement in
static compliance was noted in normal subjects but not observed in either
patient group; while there were no significant changes in dynamic
compliance for any subject group (Table 5). Chronic bronchitis
patients demonstrate variance in the pre-exposure (0-Hour) Phase III
nitrogen elimination >-ate, although no significant difference was shown
between the control si c. exposure (2-Hour) values (Table 4). No other
significant differer '-served in any of the pulmonary function
tests. When the data :"? - ^'.? t\venty patients are considered together,
10
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TABLE 1
ANTHROPOMETRIC DATA, SMDKING HISTORY, AND SYMPTOMS DURING EXPOSURE TO
NITROGEN DIOXIDE OF 30 HUMAN SUBJECTS CLASSIFIED ACCORDING TO DIAGNOSIS
Subject
NO.
1
2
3
4
5
6
7
10
11
12
Mean
S.D.
Sex
M
M
M
M
M
M
M
M
M
M
Age
(years)
44
29
42
63
39
26
28
29
22
23
34.5
12.7
Height
(cm)
188
175
183
174
173
183
190
183
179
190
181.8
6.4
Weight
(kg)
Normal
73
66
77
64
70
70
92
83
79
83
75.7
3.7
Smoking
History *
(n = 10)
+
+
0
0
0
0
0
f (pipe)
0
0
3/10
Symptoms
During Exposure f
0
0
0
+ (nasal discharge)
0
0
0
0
0
0
1/10
Chronic Bronchitis (n = 7)
13
17
20
21
26
29
30
Mean
S.D.
8
9
14
15
16
18
19
22
23
24
25
.27
28
Mean
"S.D.
* 0,
to,
M
M
M
M
F
F
F
M
M
M
M
M
F
F
M
F
M
M
M
F
53
25
30
24
32
24
24
30.3
10.5
41
23
30
22
24
19
21
21
38
50
20
20
19
26.8
10.0
nonsmoker; +,
no symptoms;
171
165
188
175
168
168
161
170.8
8.7
161
178
165
164
185
159
166
173
160
175
175
185
171
170.5
8.9
smoker
+, symptom
86
99
92
75
75
61
76
80.6
12.7
Asthma
68
75
64
65
64
62
62
68
49
80
72
69
73
67.0
7.6
o
4- (pipe)
4-
--
-r
O
-
3/7
(n = 13)
0
0 (former smoker)
-i- 'occasional)
7
-
0
r
;"
0 former smoker)
r
light)
-. ,- :
0
0
0
0
+ (nasal discharge)
0
0
1/7
0
0
+ (chest tightness)
+ (slight headache)
0
+ (slight burning of
0
0
+ (chest tightness)
+ (chest tightness)
+ (slight burning of
eyes)
eyes)
+ (dysonea with exercise)
0
7/13
experienced.
11
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MEAN VALUES OF VENTILATORY FUNCTION DERIVED FROM SPIRQMETRY
Subject
Groups
Normal Subjects
(n = 10)
Mean
Day 1 Day 2
(Control) (Ex;xji.:,nre)
FVC
0-f'
'. 30
4.05
4.14
4.91
4.98
9.79
10.00
3.70
3.94
1.84
1.82
..29
'.27
4.06
4.10
4.98
4.94
9.04
9.55
3.69
3.74
1.81
1.67
Standard
Error of
Difference
in Means
0.05
0.03
0.05
0.04
0.05
0.03
0.54
0.42
0.10
0.13
0.10
0.08
Patients with Asthma
(n = 13)
Mean
Standard
Error of
Day 1 Day 2 Difference
(Control) (Exposure) in Means
4.51
4.42
3.15
3.12
4.15
4.09
5.76
5.93
2.51
2.65
1.37
1.25
4.49
4.38
3.25
3.14
4.18
4.07
5.85
5.86
2.83
2.70
1.23
1.24
0.07
0.05
0.07
0.05
0.06
0.05
0.27
0.30
0.18
0.13
0.08
0.04
Patients with Chronic Bronchitis
(h = 7)
Mean
Standard
Error of
Day 1 Day 2 Difference
(Control) (Exposure) in Means
4.88
4.81
3.66
3.50
4.47
4.38
8.14
7.20
3.15
2.71
1.63
1.55
4.93
4.82
3.64
3.51
4.51
4.38
8.07
7.51
3.02
2.81
1.63
1.53
0.04
0.06
0.04
0.08
0.03
0.06
0.61
0.47
0.12
0.23
0.08
0.07
12
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TABLE 3
MEAN VALUES OF TESTS DERIVED FROM PLETHYSMOGRAPHIC MEASUREMENTS
Subject
Groups
SGaw
0-Hour
2-Hour
Day 1
(Control
.218
.246
Normal Subjects
(n = 10)
Mean
Patients with Asthma
(n - 13)
Standard
Error of
Day 2 Difference
) (Exposure) In Means
.219
.238
.014
.014
Mean
Day 1
(Control)
.137
.137
Day 2
(Exposure)
.136
.142
Standard
Error of
01 f ference
1n Means
.007
.012
Patients with Chronic
(n= 7)
Mean
Day 1 Day 2
(Control) (Exposure)
.196 .185
.198 .180
Bronchitis
Standard
Error of
01 f ference
In Means
.016
.014
All Patients
(n = 20)
Mean
Day 1
(Control)
.158
.159
Day 2
(Exposure)
.153
.156
Standard
Error of
Difference
in Means
0.007
0.009
TLC
0-Hour
2-Hour
7.24
7.38
7.37
7.44
0.13
0.17
6.47
6.32
6.65
6.49
0.11
0.11
6.67
6.63
6.87
6.86
0.11
0.13
6.54
6.44
6.741"
6.63*
0.08
0.08
FRC
0-Hour
2-Hour
3.83
3.91
3.90
3.83
0.10
0.13
3.37
3.19
3.40
3.38
0.09
0.13
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-Hour
2-Hour
*p < . 05
tp<.025
1.99
2.08
2.08
2.16
0.12
0.18
1.96
1.90
2.16
2.11
0.09
0.12
1.79
1.82
1.94
2.04
0.08
0.11
1.90
1.87
2. oaf
2.09t
0.07
0.09
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TABLE 4
MEAN VALUES OF TESTS DERIVED FROM SINGLE-BREATH N., ELIMINATION RATE
Subject
Groups
Phase III
0-Hour
2-Hour
Phase IV
0-Hour
2-Hour
Phase IV
+ RV
0-Hour
2-Hour
*p < . 05
tp<.01
Normal Subjects
(n = 10)
Mean
Day 1
(Control)
1.15
1.13
0.62
0.54
2.61
2. 62'
Day 2
(Exposure)
1.26
1.08
0.47*
0.65
2.55
2.81
Standard
Error of
Difference
1n Means
0.13
0.13
0.06
0.07
0.14
0.20
Patients with Asthma
(n * 13)
Mean
Day 1
(Control)
1.42
1.30
0.44
0.36
2.44
2.30
Day 2
(Exposure)
1.58
1.41
0.35
0.39
2.54
2.54
Standard
Error of
Difference
in Means
0.18
0.11
0.06
0.06
0.09
0.13
Patients with Chronic
(n = 7)
Mean
Day 1
(Control)
1.14
1.15
0.41
0.48
2.20
2.30
Day 2
(Exposure)
0.85?
0.92
0.53
0.39
2.47
2.43
Bronchitis
Standard
Error of
Di f f erence
1n Means
0.07
0.10
0.13
0.18
0.15
0.18
All Patients
(n = 20)
Mean
Day 1
(Control)
1.32
1.28
0.43
0.41
2.35
2.30
Day 2
(Exposure)
1.33
1.22
0.41
0.39
2.51
2.50
Standard
Error of
Difference
in Means
0.13
0.07
0.06
0.07
0.08
0.10
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TABLE 5
MEAN VALUES OF TESTS DERIVED FROM MEASUREMENTS OF TRANSPULMONARY PRESSURE
Subject Normal Subjects Patients with Asthma Patients with Chronic Bronchitis All Patients
Groups (n ' 10) (n " 13) (n = 7) (n = 20)
Standard Standard Standard Standard
Mean Error of Mean Error of Mean Error of Mean Error of
Day""! Day 2Difference Day! Day 2 Difference Day 1 Day 2 Difference Day 1 Day 2 Difference
_, (Control) (Exposure) in Means (Control^ (Exposure) in Means (Control) (Exposure) in Means (Control) (Exposure) in Means
tn
RL
2-Hour 2.00 1.94 0.10 4.41 4.43 0.19 3.23 3.17 0.11 4.00 3.99 0.13
CL Stat
2-Hour 346 286* 18 269 253 10 366 334 18 303 282f 9
CL dyn 16
2-Hour 196 197 12 160 159 6 210 207 9 178 176 5
CL dyn 32
2-Hour 190 189 18 137 131 7 187 193 14 153 150 7
CL dyn 48
2-Hour 194 194 21 121 123 7 155 170 8 133 140 6
*p<.025
tp<.05
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significant increases were noted in TLC, FRC, RV, and static compliance
on the exposure day (Tables 3 and 5).
SECTION VI
DISCUSSION
A double-blind study would have been desirable for this research.
However, the odor of NO2 is detectable at 0.5 ppm, thus making a double-
blind study impractical. The symptoms reported in this study were in
general mild and more frequently reported by the subjects with asthma.
Although these patients experienced the most symptoms no significant
changes in pulmonary function were observed.
Considering the 13 patients with asthma and the seven patients with
chronic bronchitis, significant changes in some pulmonary function para-
meters only occurred when they were grouped together as 20 subjects.
These changes in compliance, distribution of ventilation and static lung
volumes (TLC, FRC, RV) suggest some degree of change in elastic
properties. However, no meaningful change in function can be implied as
significant differences also were generally observed prior to exposure.
There were no significant changes in any of the flow resistance parameters
by spirometry, plethysmography, or esophageal balloon techniques.
16
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SECTION VII
REFERENCES
1. Air Quality Criteria for Nitrogen Oxides, National Air Pollution
Control Administration, Washington, D. C. , Publication No.
AP-84, 1971.
2. American Conference of Government Industrial HygieniBts: Threshold
Limit Values for Substance in Workroom Air. Adopted by ACGIH,
1976.
3. Abe, M. 1967. Effects of Mixed NO2 - SO2 Gas on Human Pulmonary
Functions. Bulletin Tokyo Med. Dent. Univ., 14; 415-433.
4. Suzuki, T. and K. Ishikawa 1965. Research on Effect of Smog on
Human Body, Research and Report on Air Pollution Prevention
No. 2; 199-221, (In Japanese).
5. Rokaw, S. N., et. al. 1968. Human Exposures to Single Pollutants -
NO2 in a Controlled Environment Facility (Pre-Print of Presentation
at the Ninth AMA Air Pollution Medical Research Conference),
Denver.
6. Shy, C. M., Creason, J. ?. , Pearlman, M. E., McClain, K. E. ,
Benson, F. B. , anc ^'oung. V. M. 1970. The Chattanooga School
Study. Effects of Corn.rrv,.r.ity Exposure to Nitrogen Dioxide, Methods,
Description of Pollutant F.v^oiure and Results of Ventilatory Function
Testing. J. Air Pollut. Contr. Assn., 20 (8); 539-545.
17
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7. Shy, C.M., Creason, J. P., Pearlman, M. E., McClain, K. E.,
'Benson, F. B. , and Young, M. M. 1970. The Chattanooga School
Children Study: Effects of Community Exposure to Nitrogen
Dioxide. Incidence of Acute Respiratory Illness, J. Air Pollut.
Contr. Assn., 20 (9): 582-588.
8. 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 (2); 391-398.
9. Horvath, S. M., and L. J. Folinsbee. 1977. Effects of NO2 on
Lung Function in Normal Subjects. Report Under Contract with
University of California EPA No. 68-02-1757.
10. Kerr, H. D. 1973. Diurnal Variation of Respiratory Function
Independent of Air Quality: Experience with an Environmentally
Controlled Exposure Chamber for Human Subjects, Archives of
Environmental Health, 26; 144.
11. DuBois, A. B., Botelho, A. F., 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, Journal of Clinical Investigation, 35: 327.
18
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12. Anthonisen, N. 1972. Report of Informal Session on "Closing
Volume" Determinations, Federation Meetings, Atlantic City,
New Jersey.
13. Mead, J., and Whittenberger, J. L. 1953. Physical Properties
of Human Lungs Measured During Spontaneous Respiration,
Journal of Applied Physiology, _5: 779.
14. Kerr, H.D., Kulle, T. J., Mcllhany, M. L. and Swidersky, P.
1975. Effects of Ozone on Pulmonary Function in Normal Subjects -
An Environmental Chamber Study, American Review of Respiratory
Disease, 111: 763-773.
19
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SECTION VIII
GLOSSARY
Plethy smog r aphy - Body box method for determining airway resistance
and static lung volumes.
Single Breath Nitrogen Elimination Rate - Percentage rise in nitrogen
fraction per unit of volume expired.
Pulmonary Resistance (Rj^) - The sum of airway resistance and viscous
tissue resistance.
Static Compliance (C^ stat^ ~ Measure °f elastic recoil with no or
insignificant airflow.
Dynamic Compliance (Cy dvnJ ~ Volume change per unit of trans -
pulmonary pressure minus the pressure of pulmonary resistance
during airflow.
20
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TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing)
REPORT NO.
EPA-600/1-78-025
2.
3. RECIPIENT'S ACCESSION NO.
TITLE AND SUBTITLE
Effects of Nitrogen Dioxide on Pulmonary Function
in Human Subjects
5. REPORT DATE
April 1978
6. PERFORMING ORGANIZATION CODE
AUTHOR(S)
H. David Kerr, Thomas J. Kulle, Mary Lou Mcllhany
and Paul Swidersky
8. PERFORMING ORGANIZATION REPORT NO.
PERFORMING ORGANIZATION NAME AND ADDRESS
University of Maryland School of Medicine
Baltimore, Md 21201, and
The Johns Hopkins University
Baltimore, Md 21205
10. PROGRAM ELEMENT NO.
1AA601
11. CONTRACT/GRANT NO.
68-02-1745
12. SPONSORING AGENCY NAME AND ADDRESS
Health Effects Research Laboratory
'Office of Research and Development
U.S. Environmental Protection Agency
Research Trianale Park, N.C. 27711
13. TYPE OF REPORT AND PERIOD COVERED
RTP,NC
<. SPONSORING AG-ENCY CODE '"'
EPA 600/11
15. SUPPLEMENTARY NOTES
16. ABSTRACT
Twenty human subjects with asthma and chronic bronchitis and ten normal, healthy
adults were esposed to 0.5 ppm of nitrogen dioxide (N02) for two hours in an environ-
mental chamber. They engaged in one 15-minute, light to medium-exercise stint on
a bicycle ergometer during this period. The subjects with asthma experienced the
greatest symptoms with exposure to NC>2ğ i.e., seven of thirteen noting slight
burning of the eyes, slight headache, and chest tightness or labored breathing with
exercise. One each of the subjects with chronic bronchitis and the healthy, normal
group experienced slight nasal discharge. Significant changes from control.values
for the group as a whole with exposure to NC>2 were observed for the following
pulmonary function tests: quasi-state compliance for the twenty subjects with asthma
and chronic bronchitis as well as for the ten normal subjects, and functional residua
capacity for the twenty subjects with asthma and chronic bronchitis. Subjects with
asthma and chronic bronchitis as separate groups (n = 13 and 7 respectively) did not
show any significant changes in pulmonary function with the NO2 exposure, even though
the group of thirteen subjects with asthma experienced the greatest symptoms.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b. IDENTIFIERS/OPEN ENDED TERMS C. COS AT I Field/Group
respiratory system
nitrogen dioxide
air pollution
exercise (physiology)
respiratory diseases
06 F, P, T
13. DISTRIBUTION STATEMENT
RELEASE TO PUBLIC
19. SECURITY CLASS (This Report]
UNCLASSIFIED
20. SECURITY CLASS (This page)
UNCLASSIFIED
21. NO. OF PAGES
_2S_
22. PRICE
EPA Form 2220*1 (9-73)
21
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