&EPA
United States
Environmental Protection
Agency
Environmental Criteria and
Assessment Office
Research Triangle Park, NC 27711
EPA/600/8-84/020eF
August 1986
Research and Development
Air Quality
Criteria for
Ozone and Other
Photochemical
Oxidants
Volume V of V
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EPA/600/8-84/020eF
August 1986
Air Quality Criteria
for Ozone and Other
Photochemical Oxidants
Volume V of V
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, N.C. 27711
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DISCLAIMER
This document has been reviewed in accordance with U.S. Environmental
Protection Agency policy and approved for publication. Mention of trade
names or commercial products does not constitute endorsement or recommendation
for use.
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ABSTRACT
Scientific information is presented and evaluated relative to the health
and welfare effects associated with exposure to ozone and other photochemical
oxidants. Although it is not intended as a complete and detailed literature
review, the document covers pertinent literature through early 1986.
Data on health and welfare effects are emphasized, but additional infor-
mation is provided for understanding the nature of the oxidant pollution pro-
blem and for evaluating the reliability of effects data as well as their
relevance to potential exposures to ozone and other oxidants at concentrations
occurring in ambient air. Information is provided on the following exposure-
related topics: nature, source, measurement, and concentrations of precursors
to ozone and other photochemical oxidants; the formation of ozone and other
photochemical oxidants and their transport once formed; the properties, chem-
istry, and measurement of ozone and other photochemical oxidants; and the
concentrations of ozone and other photochemical oxidants that are typically
found in ambient air.
The specific areas addressed by chapters on health and welfare effects
are the toxicological appraisal of effects of ozone and other oxidants; effects
observed in controlled human exposures; effects observed in field and epidemi-
ological studies; effects on vegetation seen in field and controlled exposures;
effects on natural and agroecosystems; and effects on nonbiological materials
observed in field and chamber studies.
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AIR QUALITY CRITERIA FOR OZONE
AND OTHER PHOTOCHEMICAL OXIDANTS
VOLUME I
Chapter 1. Summary and Conclusions 1-1
VOLUME II
Chapter 2. Introduction 2-1
Chapter 3. Properties, Chemistry, and Transport of Ozone-and
Other Photochemical Oxidants and Their Precursors .... 3-1
Chapter 4. Sampling and Measurement of Ozone and Other :
Photochemical Oxidants and Their Precursors .•; 4-1
Chapter 5. Concentrations of Ozone and Other Photochemical
Oxidants in Ambient Air •:. 5-1
VOLUME III
Chapter 6. Effects of Ozone and Other Photochemical Oxidants
on Vegetation 6-1
Chapter 7. Effects of Ozone on Natural Ecosystems and Their
Components 7-1
Chapter 8. Effects of Ozone and Other Photochemical Oxidants
on Nonbiological Materials v 8-1
VOLUME IV
Chapter 9. Toxicological Effects of Ozone .and Other
Photochemical Oxidants ......; 9-1
VOLUME V
Chapter 10. Controlled Human Studies of the Effects of Ozone
and Other Photochemical Oxidants 10-1
Chapter 11. Field and Epidemiological Studies of the Effects
of Ozone and Other Photochemical Oxidants 11-1
Chapter 12. Evaluation of Health Effects Data for Ozone and
Other Photochemical Oxidants 12-1
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TABLE OF CONTENTS
LIST OF TABLES
LIST OF FIGURES
LIST OF ABBREVIATIONS
AUTHORS, CONTRIBUTORS, AND REVIEWERS
10.
11.
CONTROLLED HUMAN STUDIES OF THE EFFECTS OF OZONE AND
OTHER PHOTOCHEMICAL OXIDANTS .
INTRODUCTION
ACUTE PULMONARY EFFECTS OF OZONE
10.1
10.2
10.
10.
10.
10.
10.
10.
10.
10.
10.
vm
x
xii
xvii
10-1
10-1
10-6
10-6
10-7
10-7
Introduction
At-Rest Exposures ..
Exposures with Exercise
Intersubject Variability and Reproducibility of
Responses 10-22
Prediction of Acute Pulmonary Effects ..... 10-25
Bronchial Reactivity , 10-28
Mechanisms of Acute Pulmonary Effects 10-30
Preexi sti ng Di sease :... 10-32
Other Factors Affecting Pulmonary Responses to
Ozone 10-38
10.2.9.1 Cigarette Smoking . 10-38
10.2.9.2 Age and Sex Differences 10-41
10.2.9.3 Environmental Conditions ..., 10^44
10.2.9.4 Vitamin E Supplementation 10-45
10.3 PULMONARY EFFECTS FOLLOWING REPEATED EXPOSURE TO OZONE 10-47
10.4 EFFECTS OF OZONE ON VIGILANCE AND EXERCISE PERFORMANCE 10-60
10.5 INTERACTIONS BETWEEN OZONE AND OTHER POLLUTANTS 10-65
10.5.1 Ozone Plus Sulfates or Sulfuric Acid 10-65
10.5.2 Ozone and Carbon Monoxide , 10-74
10.5.3 Ozone and Nitrogen Dioxide 10-74
10.5.4 Ozone and Other Mixed Pollutants 10-76
10.6 EXTRAPULMONARY EFFECTS OF OZONE 10-77
10.7 PEROXYACETYL NITRATE 10-84
10.8 SUMMARY 10-87
10. 9 REFERENCES 10-97
FIELD AND EPIDEMIOLOGICAL STUDIES OF THE EFFECTS OF OZONE
AND OTHER PHOTOCHECMICAL OXIDANTS
11.1
11.2
11-1
11-1
11.3
INTRODUCTION
FIELD STUDIES OF EFFECTS OF ACUTE EXPOSURE TO OZONE
AND OTHER PHOTOCHEMICAL OXIDANTS 11-2
11.2.1 Symptoms and Pulmonary Function in Field
Studies of Ambient Air Exposures 11-3
11.2.2 Symptoms and Pulmonary Function in Field or
Simulated High-Altitude Studies 11-12
EPIDEMIOLOGICAL STUDIES OF EFFECTS OF ACUTE EXPOSURE 11-13
11.3.1 Acute Exposure Morbidity Effects 11-13
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TABLE OF CONTENTS (continued)
11.4
11.5
11.6
11.3.1.1 Symptom Aggravation in Healthy
Populations ,
11.3.1.2 Altered Performance ,
11.3.1.3 Acute Effects on Pulmonary Function ....
11.3.1.4 Aggravation of Existing Respiratory
D!seases
11.3.1.5 Incidence of Acute Respiratory Illness
11.3.1.6 Physician, Emergency Room, and Hospital
Visits ,
11.3.1.7 Occupational Studies
11.3.2 Trends in Mortality ,
EPIDEMIOLOGICAL STUDIES OF EFFECTS OF CHRONIC EXPOSURE ..,
11.4.1 Pulmonary Function and Chronic Lung Disease
11.4.2 Chromosomal Effects -.
11.4.3 Chronic Disease Mortality
SUMMARY AND CONCLUSIONS ,
REFERENCES
12. EVALUATION OF HEALTH EFFECTS DATA FOR OZONE AND OTHER
PHOTOCHEMICAL OXIDANTS
12.1 INTRODUCTION
12.2 EXPOSURE ASPECTS
12.2.1 Potential Exposures to Ozone
12.2.2 Potential Exposures to Other Photochemical
Oxidants
12.2.2.1 Concentrations
12.2.2.2 Patterns
12.2.3 Potential Combined Exposures and Relationship of
Ozone and Other Photochemical Oxidants
12.3 HEALTH EFFECTS IN THE GENERAL HUMAN POPULATION
12.3.1 Clinical Symptoms
12.3.2 Pulmonary Function at Rest and with Exercise and
Other Stresses
12.3.2.1 At-Rest Exposures
12.3.2.2 Exposures with Exercise
12.3.2.3 Environmental Stresses
12.3.3 Other Factors Affecting Pulmonary Response to
Ozone
Age ..
Sex
Smoking Status
Nutritional Status
Red Blood Cell Enzyme Deficiencies
12.3.4 Effects of Repeated Exposure to Ozone
12.3.4.1 Introduction
12.3.4.2 Development of Altered Responsiveness to
Ozone
12.3.3.1
12.3.3.2
12.3
12.3
12.3
3.3
3.4
.3.5
Page
11-13
11-14
11-14
11-24
11-34
11-34
11-40
11-40
11-40
11-44
11-48
11-49
11-49
11-55
12-1
12-1
12-5
12-5
12-11
12-11
12-14
12-14
12-17
12-17
12-19
12-19
12-21
12-35
12-35
12-35
12-36
12-37
12-37
12-39
12-40
12-40
12-40
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TABLE OF CONTENTS (continued)
12.3.4.3 Conclusions Relative to Attenuation with
Repeated Exposures 12-41
12.3.5 Mechanisms of Responsiveness to Ozone 12-42
12.3.6 Relationship Between Acute and Chronic Ozone
Effects 12-45
12.3.7 Resistance to Infection 12-49
12.3.8; Extrapulmonary Effects of Ozone 12-50
12.4 HEALTH:EFFECTS IN INDIVIDUALS WITH PREEXISTING DISEASE 12-53
12.4.1 Patients with Chronic Obstructive Lung Disease
(COLD) 12-53
12.4.2 Asthmatics 12-54
12.4.3 Subjects with Allergy, Atopy, and Ozone-Induced
Hyperreactivity 12-56
12.5 EXTRAPOLATION OF EFFECTS OBSERVED IN ANIMALS TO HUMAN
POPULATIONS 12-57
12.5.1 Species Comparisons 12-57
12.5.2 Dosimetry Modeling 12-63
12.6 HEALTH EFFECTS OF OTHER PHOTOCHEMICAL OXIDANTS AND POLLUTANT
MIXTURES 12-65
12.6.1 Effects of Peroxyacetyl Nitrate 12-65
12.6.2 Effects of Hydrogen Peroxide 12-66
12.6.3 Interactions with Other Pollutants 12-67
12.7 IDENTIFICATION OF POTENTIALLY AT-RISK GROUPS 12-69
12.7.1 Introduction 12-69
12.7.2 Potentially At-Risk Individuals 12-69
12.7.3 Potentially At-Risk Groups 12-72
12.7.4 Demographic Distribution of the General
Popul ati on 12-75
12.7.5 Demographic Distribution of Individuals with Chronic
Respiratory Conditions 12-76
12.8 SUMMARY AND CONCLUSIONS 12-78
12.8.1 Health Effects in the General Human Population ... 12-78
12.8.2 Health Effects in Individuals with Preexisting
Di sease 12-86
12.8.3 Extrapolation of Effects Observed in Animals to
Human Populations ..... 12-86
12.8.4 Health Effects of Other Photochemical Oxidants and
Pol 1utant Mixtures 12-87
12.8.5 Identification of Potentially At-Risk Groups 12-88
12.9 REFERENCES 12-90
APPENDIX A A-l
vn
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LIST OF TABLES
Table Page
10-1 Human experimental exposure to ozone up to 1978 10-2
10-2 Studies on acute pulmonary effects of ozone since 1978 10-8
10-3 Estimated values of oxygen consumption and minute
ventilation associated with representative types of
exercise -.f 10-14
10-4 Ozone exposure in subjects with pulmonary disease 10-33
10-5 Changes in lung function after repeated daily exposure
to ambient ozone .- 10-48
10-6 Effects of ozone on exercise performance 10-64
10-7 Interactions between ozone and other pollutants 10-66
10-8 Human extrapulmonary effects of ozone exposure 10-78
10-9 Acute human exposure to peroxyacetyl nitrate 10-85
10-10 Summary table: controlled human exposure to ozone 10-88
11-1 Subject characteristics and experimental conditions in
the mobile laboratory studies 11-4
11-2 Symptom aggravation in health populations exposed to
photochemical oxidant pol 1 ution 11-15
11-3 Altered performance associated with exposure to photochemical
oxidant pollution 11-17
11-4 Acute effects of photochemical oxidant pollution on pulmonary
function of children and adults 11-18
11-5 Aggravation of existing respiratory diseases by photochemical
oxidant pollution 11-25
11-6 Incidence of acute respiratory illness associated with
photochemical oxidant pollution 11-35
11-7 Hospital admissions in relation to photochemical
oxidant pol 1 ution 11-36
11-8 Acute effects from occupational exposure to photochemical
oxidants 11-41
11-9 Daily mortality associated with exposure to photochemical
oxidant pollution 11-43
11-10 Pulmonary function effects associated with chronic
photochemical oxidant exposure 11-45
11-11 Summary table: acute effects of ozone and other photo-
chemical oxidants in field studies with a mobile laboratory .. 11-51
12-1 Number of times the daily maximum 1-hr ozone concentration
was >O.Q6, >0.12, >0.18, and >0.24 ppm for specified
consecutive days in Pasadena, Dallas, and Washington,
April through September, 1979 through 1981 12-9
12-2 Relationship of ozone and peroxyacetyl nitrate at urban
and suburban sites in the United States in reports
published 1978 or later 12-16
12-3 Effects of intermittent exercise and ozone concentration on
1-sec forced expiratory volume during 2-hr exposures 12-29
12-4 Comparison of the acute effects of ozone on breathing
patterns i n animal s and man 12-60
viii
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LIST OF TABLES (continued)
Table Page
12-5 Comparison of the acute effects of ozone on airway
reactivity in animals and man 12-61
12-6 Geographical distribution of the resident population of
the United States, 1980 ....... 12-77
12-7 Total population of the United States by age, sex, and
race, 1980 12-78
12-8 Prevalence of chronic respiratory conditions by sex and
age for 1979 12-79
IX
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LIST OF FIGURES
Figure Page
10-1 Change in forced vital capacity (FVC), forced expiratory
volume in 1-sec (FEVi-o), and maximal mid-expiratory flow
(FEF25_75^) during exposure to filtered air or ozone
(0.5 ppm) for 2 hr. Exercise at 45% maximal aerobic
capacity (max $Q2) was performed for 30 min by Group A
after 60 min of ozone exposure and by Group B after
30 min of ozone exposure .-. 10-16
10-2 Frequency distributions of response (percent change from
baseline) in specific airway resistance (SR ) and forced
expiratory volume in 1-sec (FEV^.o) for individuals exposed
to six levels of ozone. One individual with 260% increase
in SR exposed to 0.4 ppm ozone is not graphed * 10-23
10-3 Forcea expiratory volume in 1-sec (FEVi-o) in two groups
of subjects exposed to (A) 0.35 ppm ozone, and (B)
0.50 ppm ozone, for 3 successive days. Numbers on the
abscissa represent successive half-hour periods of
exposure 10-52
10-4 Percent change (pre-post) in 1-sec forced expiratory
volume (FEVi-o), as the result of a 2-hr exposure to
0.42 ppm ozone. Subjects were exposed to filtered air,
to ozone for five consecutive days, and exposed to
ozone again: (A) 1 week later; (B) 2 weeks later; and
(C) 3 weeks 1 ater 10-54
11-1 Changes in mean symptom score with exposure for all
subjects, for normal and allergic subjects, and for
asthmati c subjects 11-7
11-2 Changes in group mean responses, including FEVt-o, symptoms,
and exercise performance in 50 competitive cyclists exercising
continuously for 1 hr while exposed to ozone 11-10
12-1 Distributions of the three highest 1-hr ozone concentrations
at valid sites (906 station-years) aggregated for 3 years
(1979, 1980, and 1981) and the highest ozone concentrations
at NAPBN sites aggregated for those years (24 station-years) 12-7
12-2 The effects of ozone concentration on 1-sec forced expiratory
volume during 2-hr exposures with light intermittent
exercise. Quadratic fit of group mean data, weighted by
sample size, was used to plot a concentration-response
curve with 95 percent confidence limits 12-25
12-3 The effects of ozone concentration on 1-sec forced expiratory
volume during 2-hr exposures with moderate intermittent
exercise. Quadratic fit of group mean data, weighted by
sample size, was used to plot a concentration-response
curve with 95 percent confidence limits ., 12-26
x
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LIST OF FIGURES (continued)
Figure
12-4 The effects of ozone concentration on 1-sec forced expiratory
volume during 2-hr exposures with heavy intermittent exercise.
Quadratic fit of group mean data, weighted by sample size,
was used to plot a concentration-response curve with
95 percent confidence limits 12-27
12-5 The effects of ozone concentration on 1-sec forced expiratory
volume during 2-hr exposures with very heavy intermittent
exercise. ^Quadratic fit of group mean data, weighted by
sample siz,e, was used to plot a concentration-response
curve with 95 percent confidence 1 imits 12-28
12-6 Group mean decrements in 1-sec forced expiratory volume
during 2-hr ozone exposures with different levels of
intermittent exercise: light (VF < 23 L/min); moderate
(V> = 24-43 L/min); heavy (VV = 14-63 L/min); and very
helvy (V£ > 64 L/min) 12-81
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LIST OF ABBREVIATIONS
ACh
AM
ANOVA
ADD
ATPS
BTPS
CC
Cdyn
CE
CHEM
CHESS
CL
CLst
CNS
CO
COHb
COLD
COPD
co2
CV
DL
DLCO
E
ECG, EKG
EEG
EPA
ERV
FEF.
max
FEF
Acetylcholine
Alveolar macrophage
Analysis of variance
Airway obstructive disease
ATPS condition (ambient temperature and pressure, saturated
with water vapor)
BTPS conditions (body temperature, barometric pressure,
and saturated with water vapor)
Closing capacity
Dynamic lung compliance
Continuous exercise
Gas-phase chemiluminescence
Community Health Environmental Surveillance System
Lung compliance
Static lung compliance
Central nervous system
Carbon monoxide
Carboxyhemogl obi n
Chronic obstructive lung disease
Chronic obstructive pulmonary disease
Carbon dioxide
Closing volume
Diffusing capacity of the lungs
Carbon monoxide diffusing, capacity of the lungs
Elastance
Electrocardiogram
Electroencephalogram
U.S. Environmental Protection Agency
Expiratory reserve volume
Maximal forced expiratory flow achieved
during an FVC test
Forced expiratory flow
XI1
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LIST OF ABBREVIATIONS (continued)
FEFooo-1200 Mean forced expiratory flow between 200 ml and 1200 ml of
the FVC [formerly called the maximum expiratory flow rate
(MEFR)]
Mean forced expiratory flow during the middle half of the
FVC [formerly called the maximum mid-expiratory flow rate
(MMFR)]
Instantaneous forced expiratory flow after 75% of the FVC
has been exhaled
FEV Forced expiratory volume
FEV-. Forced expiratory volume in 1 sec
FEV./FVC A ratio of timed forced expiratory volume (FEV.) to
forced vital capacity (FVC)
FIVC Forced inspiratory vital capacity
fn Respiratory frequency
FRC Functional residual capacity
FVC Forced vital capacity
G Conductance
G-6-PD Glucose-6-phosphate dehydrogenase
Gaw Airway conductance
GS-CHEM Gas-solid chemiluminescence
GSH Glutathione
Hb Hemoglobin
Hct Hematocrit
H0« Hydroxy radical
tiOy' Hydroperoxy radical
1C Inspiratory capacity
IE Intermittent exercise
IRV Inspiratory reserve volume
IVC Inspiratory vital capacity
LDH Lactate deyhydrogenase
LD50 Lethal dose (50 percent)
LM Light microscopy
MAST Kl-coulometric (Mast meter)
xm
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LIST OF ABBREVIATIONS (continued)
f
max Vc Maximum ventilation
max VOp Maximal aerobic capacity
MBC Maximum breathing capacity
MEFR Maximum expiratory flow rate
MetHb Methemoglobin
MMAD Mass median aerodynamic diameter
MMFR or MMEF Maximum mid-expiratory flow rate
MVV Maximum voluntary ventilation
NBKI Neutral buffered potassium iodide
(NhL^SO, Ammonium sulfate
NOp Nitrogen dioxide
ANp, dNp Nitrogen washout
02 Oxygen
Op" Oxygen radical
03 Ozone
P(A-a)02 Alveolar-arterial oxygen pressure difference
PABA para-aminobenzoic acid
P/\COp Alveolar partial pressure of carbon dioxide
PaCOp Arterial partial pressure of carbon dioxide
PAN Peroxyacetyl nitrate
P.Op Alveolar partial pressure of oxygen
PaOp Arterial partial pressure of oxygen
PBzN Peroxybenzoyl nitrate
PEF Peak expiratory flow
PEFV Partial expiratory flow-volume curve
PG Prostag!andin
pH Arterial pH
O.
P, Transpulmonary pressure
PMN Polymorphonuclear leukocyte
P , Static transpulmonary pressure
PUFA Polyunsaturated fatty acid
R Resistance to flow
xiv
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LIST OF ABBREVIATIONS (continued)
Raw Airway resistance
RBC Red blood cell
R I-, Collateral resistance
rh Relative humidity
R, Total pulmonary resistance
RQ, R Respiratory quotient
R, Respiratory resistance
R. . Tissue resistance
RV Residual volume
SaQy Arterial oxygen saturation
SBNT Single-breath nitrogen test
SBP Systolic blood pressure
SCE Sister chromatid exchange
Se Selenium
SEM Scanning electron microscopy
SGaw Specific airway conductance
SH Sulfhydryls
SOD Superoxide dismutase
SQy Sulfur dioxide
SO^ Sulfate
SPF Specific pathogen-free
SRaw Specific airway resistance
STPD STPD conditions (standard temperature and
pressure, dry)
TEM Transmission electron microscopy
TGV Thoracic gas volume
THC Total hydrocarbons
TLC Total lung capacity
TV Tidal volume
UV Ultraviolet photometry
V. Alveolar ventilation
V./Q Ventilation/perfusion ratio
VC Vital capacity
xv
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LIST OF ABBREVIATIONS (continued)
VCO,
D anat
>E
max
> QO,
Carbon dioxide production
Physiological dead space
Dead-space ventilation
Anatomical dead space
Minute ventilation; expired volume per minute
Inspired volume per minute
Lung volume
Maximum expiratory flow
Oxygen uptake
Oxygen consumption
MEASUREMENT ABBREVIATIONS
9
hr/day
kg
kg-m/min
L/min
L/s
ppw
mg/kg
mg/m
min
ml
mm
pg/m
pm
|JM
sec
gram
hours per day
ki 1ogram
ki1ogram-meter/mi n
liters/min
liters/sec
parts per million
milligrams per kilogram
milligrams per cubic meter
minute
mill Hiter
millimeter
micrograms per cubic meter
mi crometer
micromole
second
xvi
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
Chapter 10: Controlled Human Studies of the Effects of Ozone
and Other Photochemical Oxidants
Principal Authors .
Dr. Donald H. Horstman
Health Effects Research Laboratory
MD-58
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Steven M. Horvath
Institute of Environmental Stress
University of California
Santa Barbara, CA 93106
Mr. James A. Raub
Environmental Criteria and
Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Authors also reviewed individual sections of the chapter. The following addi-
tional persons reviewed Chapter 10 at the request of the U.S. Environmental
Protection Agency. The evaluations and conclusions contained herein, however,
are not necessarily those of the reviewers.
Dr. Karim Ahmed
Natural Resources Defense Council
122 East 42nd Street
New York, NY 10168
Dr. David V. Bates
Department of Medicine
St. Paul's Hospital
University of British Columbia
Vancouver, British Columbia
Canada V6Z1Y6
Dr. Philip A, Bromberg
Department of Medicine
School of Medicine
University of North Carolina
Chapel Hill, NC 27514
Dr. George L. Carlo
Dow Chemical, U.S.A.
1803 Building, U.S. Medical
Midland, MI 48640
xvi i
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Dr. Lawrence J, Folinsbee
Combustion Engineering
800 Eastowne Rd., Suite 200
Chapel Hill, NC 27514
Dr. Robert Frank
Department of Environmental
Health Sciences
Johns Hopkins School of Hygiene
and Public Health
615 N. Wolfe Street
Baltimore, MD 21205
Dr. Judith A. Graham
Health Effects Research Laboratory
MD-51
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Jack D. Hackney
Rancho Los Amigos Hospital
7601 East Imperial Highway
Downey, CA 90242
Dr. Milan J. Hazucha
School of Medicine
Center for Environmental Health
and Medical Sciences
University of North Carolina
Chapel Hill, NC 27514
Dr. Thomas J. Kulle
Department of Medicine
School of Medicine
University of Maryland
Baltimore, MD 21201
Dr. Michael D. Lebowitz
Department of Internal Medicine
College of Medicine
University of Arizona
Tucson, AZ 85724
Dr. Susan M. Loscutoff
16768 154th Ave., S.E.
Renton, WA 98055
Dr. William F. McDonnell
Health Effects Research Laboratory
MD-58
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
xvm
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Dr. Harold A. Menkes
Department of Environmental
Health Sciences
Johns Hopkins School of Hygiene
and Public Health
615 N. Wolfe Street
Baltimore, MD 21205
Dr. Walter S. Tyler
Department of Anatomy
School of Veterinary Medicine
University of California
Davis, CA 95616
Chapter 11; Field and Epidemiological Studies of the Effects of Ozone
and Other Photochemical Oxidants
Contributing Authors
Dr. David V. Bates
Department of Medicine
St. Paul's Hospital
University of British Columbia
Vancouver, British Columbia
Canada V621Y6
Dr. Robert S. Chapman
Health Effects Research Laboratory
MD-58
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Benjamin G. Ferris
School of Public Health
Harvard University
Boston, MA 02115
Dr. Lester D. Grant
Environmental Criteria and
Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. James R. Kawecki
TRC Environmental Consultants, Inc.
2001 Wisconsin Avenue, N.W.
Suite 261
Washington, DC 20007
xix
-------
Dr. Michael D. Lebowitz
Department of Internal Medicine
College of Medicine
University of Arizona
Tucson, AZ 85724
Mr. James A. Raub
Environmental Criteria and
Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Ms. Beverly E. Tilton
Environmental Criteria and
Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Authors also reviewed individual sections of the chapter. The following addi-
tional persons reviewed Chapter 11 at the request of the U.S. Environmental
Protection Agency. The evaluations and conclusions contained herein, however,
are not necessarily those of the reviewers.
Dr. Karim Ahmed
Natural Resources Defense Council ,
122 East 42nd Street
New York, NY 10168
Dr. Patricia A. Buffler
School of Public Health
University of Texas
P.O. Box
Houston, TX 77025
Dr. George L. Carlo
Dow Chemical, U.S.A.
1803 Building, U.S. Medical
Midland, MI 48640
Dr. Robert Frank
Department of Environmental
Health Sciences
Johns Hopkins School of Hygiene
and Public Health
615 N. Wolfe Street
Baltimore, MD 21205
xx
-------
Dr. Judith A. Graham
Health Effects Research Laboratory
MD-51
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Jack D. Hackney
Rancho Los Amigos Hospital
7601 East Imperial Highway
Downey, CA 90242
Dr. Victor Hasselblad
Center for Health Policy
Duke University
Box GM Duke Station
Durham, NC 27706
Dr. Milan J. H,azucha
School of Medicine
Center for Environmental Health
and Medical Sciences
University of North Carolina
Chapel Hill, NC 27514 \
Dr. Dennis J. Kbtchmar
Environmental Criteria and
Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Thomas J. Kulle
Department of Medicine
School of Medicine
University of Maryland
Baltimore, MD 21201
Dr. Lewis H. Kuller
Department of Epidemiology
Graduate School of Public Health
University of Pittsburgh
Pittsburgh, PA 15261
Dr. Harold A. Menkes
Department of Environmental
Health Sciences
Johns Hopkins School of Hygiene
and Public Health
615 N. Wolfe Street
Baltimore, MD '21205
Dr. Jonathan M. Samet
Department of Medicine
University of New Mexico Hospital
Albuquerque, NM 87131
xxi
-------
Dr. Jan A. J. Stolwijk
Department of Epidemiology and
Public Health
School of Medicine
Yale University
New Haven, CT 06510
Dr. Harry M. Walker
H. M. Walker and Associates, Inc.
Dickinson, TX 77539
Chapter 12: Evaluation of Integrated Health Effects Data
for Ozone and Other Photochemical Oxidants
Contributing Authors
Dr. Robert Frank
Department of Environmental
Health Sciences
Johns Hopkins School of Hygiene
and Public Health
615 N. Wolfe Street
Baltimore, MO 21205
Dr. Donald E. Gardner
Northrop Services, Inc.
Environmental Sciences
P.O. Box 12313
Research Triangle Park, NC 27709
Dr. Judith A. Graham
Health Effects Research Laboratory
MO-51
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Milan J. Hazucha
School of Medicine
Center for Environmental Health
and Medical Sciences
University of North Carolina
Chapel Hill, NC 27514
Dr. Donald H. Horstman
Health Effects Research Laboratory
MD-58
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
xxn
-------
Dr. Michael D. Lebowitz
Department of Internal Medicine
College of Medicine"
University of Arizona
Tucson, AZ 85724
Dr. Daniel B. Menzel
Laboratory of Environmental Toxicology
and Pharmacology
Duke University Medical Center
P.O. Box 3813
Durham, NC 27710
Dr. Frederick J. Miller
Health Effects Research Laboratory
MD-82
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. James A. Raub
Environmental Criteria and
Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Ms. Beverly E. Tilton
Environmental Criteria and
Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Walter S. Tyler
Department of Anatomy
School of Veterinary Medicine
University of California,
Davis, CA 95616
Authors also reviewed individual sections of the chapter,. The following addi-
tional persons reviewed parts of Chapter 12 at the request of the U.S. Environ-
mental Protection Agency. The evaluations and conclusions contained herein,
however, are not necessarily those of the reviewers.
Dr. Steven M. Horvath
Institute of Environmental Stress
University of California
Santa Barbara, CA 93106
Dr. Thomas J. Kulle
Department of Medicine
School of Medicine
University of Maryland
Baltimore, MD 21201
xx i i i
-------
SCIENCE ADVISORY BOARD
CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE
The substance of this document was reviewed by the Clean Air Scientific
Advisory Committee of the Science Advisory Board in public sessions.
SUBCOMMITTEE ON OZONE
Chai rman
Dr. Morton Lippmann
Professor
Department of Environmental Medicine
New York University Medical Center
Tuxedo, New York 10987
Members
Dr. Mary 0. Amdur
Senior Research Scientist
Energy Laboratory
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
Dr. Eileen G. Brennan
Professor
Department of Plant Pathology
Martin Hall, Room 213, Lipman Drive
Cook College-NJAES
Rutgers University
New Brunswick, New Jersey 08903
Dr. Edward D. Crandall
Professor of Medicine
School of Medicine
Cornell University '
New York, New York 10021
Dr. James D. Crapo
Associate Professor of Medicine
Chief, Division of Allergy, Critical
Care and Respiratory Medicine
Duke University Medical Center
Durham, North Carolina 27710
Dr. Robert Frank
Professor of Environmental Health
Sciences
Johns Hopkins School of Hygiene
and Public Health
615 N. Wolfe Street
Baltimore, Maryland 21205
Professor A. Myrick Freeman II
Department of Economics
Bowdoin College
Brunswick, Maine 04011
Dr. Ronald J. Hall
Senior Research Scientist and Leader
Aquatic and Terrestrial Ecosystems
Section
Ontario Ministry of the Environment
Dorset Research Center
Dorset, Ontario
Canada POA1EO
Dr. Jay S. Jacobson
Plant Physiologist
Boyce Thompson Institute
Tower Road
Ithaca, New York 14853
XXIV
-------
Dr. Warren B, Johnson
Director, Atmospheric Science Center
SRI International
333 Ravenswood Avenue
Menlo Park, California 94025
Dr. Jane Q. Koem'g
Research Associate Professor
Department of Environmental Health
University of Washington
Seattle, Washington 98195
Dr. Paul Kotin
Adjunct Professor of Pathology
University of Colorado Medical School
4505 S. Yosemite, #339
Denver, Colorado 80237
Dr. Timothy Larson
Associate Professor
Environmental Engineering and
Science Program
Department of Civil Engineering
University of Washington
Seattle, Washington 98195
Professor M. Granger Morgan
Head, Department of Engineering
and Public Policy
Carnegie-Mellon University
Pittsburgh, Pennsylvania 15253
Dr. D. Warner North
Principal
Decision Focus Inc., Los Altos
Office Center, Suite 200
4984 El Camino Real
Los Altos, California 94022
Dr. Robert D. Rowe
Vice President, Environmental and
Resource Economics
Energy and Resources Consultants, Inc.
207 Canyon Boulevard
Boulder, Colorado 80302
Dr. George Taylor
Environmental Sciences Division
P.O. Box X
Oak Ridge National Laboratory
Oak Ridge, Tennessee 37831
Dr. Michael Treshow
Professor
Department of Biology
University of Utah
Salt Lake City, Utah 84112
Dr. Mark J. Utell
Co-Director, Pulmonary Disease Unit
Associate Professor of Medicine and
Toxicology in Radiation Biology
and Biophysics
University of Rochester Medical
Center
Rochester, New York 14642
Dr. James H. Ware
Associate Professor
Harvard School of Public Health
Department of Biostatisties
677 Huntington Avenue
Boston, Massachusetts 02115
Dr. Jerry Wesolowski
Air and Industrial Hygiene Laboratory
California Department of Health
2151 Berkeley Way
Berkeley, California 94704
Dr. James L. Whittenberger
Director, University of California
Southern Occupational Health .Center
Professor and Chair, Department of
Community and Environmental Medicine
California College of Medicine
University of California - Irvine
19772 MacArthur Boulevard
Irvine, California 92717
Dr. George T. Wolff
Senior Staff Research Scientist
General Motors Research Labs
Environmental Science Department
Warren, Michigan 48090
xxv
-------
PROJECT TEAM FOR DEVELOPMENT
OF
Air Quality Criteria for Ozone and Other Photochemical Oxidants
Ms. Beverly E. Til ton, Project Manager
and Coordinator for Chapters 1 through 5, Volumes I and II
Environmental Criteria and Assessment Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. Norman E. Chi Ids
Environmental Criteria and Assessment Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. J.H.B. Garner
Coordinator for Chapters 7 and 8, Volume III
Environmental Criteria and Assessment Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. Thomas B. McMullen
Environmental Criteria and Assessment Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. James A. Raub
Coordinator for Chapters 9 through 12, Volumes IV and V
Environmental Criteria and Assessment Office (MD-52)
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. David T. Tingey
Coordinator for Chapter 6, Volume III
Environmental Research Laboratory
U.S. Environmental Protection Agency
200 S.W. 35th Street
Con/all is, OR 97330
XXVI
-------
10. CONTROLLED HUMAN STUDIES OF THE EFFECTS OF
OZONE AND OTHER PHOTOCHEMICAL OXIDANTS
10.1 INTRODUCTION
Four major summaries on the effects of controlled human exposure to ozone
(Og) have been published (National Research Council, 1977; U.S. Environmental
Protection Agency, 1978; World Health Organization, 1978; and Hughes, 1979).
In addition, two other reports (National Air Pollution Control Administration,
1970; F.R. April 30, 1971) have reviewed earlier studies.
In 1977 the National Research Council report on ozone and other photochem-
ical oxidants stated a need for comprehensive human experimental studies that
were carefully controlled and documented to ensure reproducibility. This
statement was understandable, considering that the major portion of the report's
section on controlled human studies was devoted to reviews of test methods,
protocol designs, review of a scant amount of published data, and recommenda-
tions for future studies. The available data on controlled studies through
1975 were limited to some 20 publications. Nonetheless, this data base repre-
sented a substantial increase above the information available prior to 1970,
and it became evident that exposure to 0~ at low ambient concentrations resul-
ted in some degree of pulmonary dysfunction. Additional research was conduc-
ted in the intervening years, and by 1978 data were available from studies
conducted on over 200 individuals (Table 10-1). By this time the first reports
were available indicating that under the same exposure conditions, greater
functional deficits were measured during exercise than at rest. In addition,
five studies in which several pollutants (nitrogen dioxide, sulfur dioxide,
and carbon monoxide plus oxidants) were present during exposure became avail-
able for review. Two reports on repeated daily exposure to 0- ("adaptation")
had appeared, as well as one experimental study in which asthmatics were
evaluated. This research was just the beginning of interest in 03 as an
ambient pollutant affecting pulmonary functions of exposed man. Although the
data base was still smaller than desirable, a general conception of this
particular air pollutant's influence was beginning to form.
The early reports summarized in Table 10-1 were described in detail in
the previous 0, criteria document (U.S. Environmental Protection Agency,
1978). In this chapter, emphasis has been placed on the more recent litera-
ture; however, some of the older studies have been reviewed again. Tables
10-1
-------
TABLE 10-1. HUMAN EXPERIMENTAL EXPOSURE TO OZONE UP TO 1978
Ozone
concentration Measurement "
M9/i»J
196
196
784
1176
1960
l_i
T 294
W 588
392
980
451
490
725
980
ppm Method
0.10 CHEM,
NBKI
0.1 I
0.4
0.6
1.0
0.15 UV,
0.30 NBKI
0.2 I
0,5
0.23 CHEM,
NBKI
0.25 CHEM,
0.37 ... -IT NBKI
0.50
b Exposure
duration and
activity6
2 hr
IE (2xR) •
g 15-nin intervals
1 hr
R
1 hr (mouth-
piece} R (11)
& CE (29, 43,
66)
3 hr/day
6 days/week
x 12 weeks
2 hr
IE (2xR)
@ 15-min intervals
2-4 hr
R & I£.(2xR)
@ 15-min intervals
d No. and sex
Observed effect(s) of subjects Reference
P(A-a)02 and R increased; Pa02 decreased. 12 male von Nieding et al., 1977
Results questionable.
Airway resistance: mean increases of 3.3% 4 male Goldsmith and Nadel, 1969
(0.1 ppm), 3.5% (0.4 ppm), 5.8% (0.6 ppm),
and 19. 3% (1.0 ppm) at 0 hr after exposure;
mean increases of 12.5% (0.4 ppn), 5% (0.6
and 1.0 ppi) at 1 hr after exposure; one
subject had history of asthma and experi-
enced hemoptysis 2 days after 1 ppra. No
symptoms at 0.1 ppm; odor detected at 0.4
and 0.6 ppm; throat irritation and cough
at 1.0 ppra.
RV, FEVj.o, HMFR, and VT decreased and fR 6 male DeLucia and Adams, 1977
increased at 0.30 ppia during IE (66); saill
but nonsignificant changes at 0.15 ppw.
Congestion, wheezing, and headache reported.
Slight (nonsignificant) decrease in VC and 6 male Bennett, 1962
significant decrease in FEVj.Q at 0.5 ppm
toward end of 12 weeks; returned to normal
withfn 6 weeks after exposure; 0.66 (0.2 ppm),
0.80 (0.5 ppm) upper respiratory infections/
person in 12 weeks compared to 0;95 for the
controls. No irritating symptoms, but
could detect ozone- by smell at 0.5 ppm.
No changes in spirontetry, closing volume, and 20 male (asthma) Linn et al., 1978
HZ washout; small blood biochemical changes; 2 female (asthma)
increased frequency of symptoms reported.
• Medication~maintained during exposure. •--•.-
No effect in normal reactors. Changes 16 normal and Hackney et al., 1975a,b,c
(2-12%) observed in spirometry, lung reactive subjects
mechanics, and small airway function
in non-reactors (IE) and hyperreactors
(R) at 0.5 ppm. -
-------
TABLE 10-1 (continued). HUMAN EXPERIMENTAL EXPOSURE TO OZONE UP TO 197a
H
O
.1-'
U)
Ozone
concentration
ug/»3 pi»
725
725
725
1470
725
980
1470
725
980
1470
784
784
980
0.37
0.37
0.37
0.75
0.37
0.50
0.75
0.37
0.50
0.75
0.4
0.4
0.5
Measurement '
method
CHEW,
NBKI
CHEM,
NBKI
MAST,
NBKI
MAST,
NBKI
MAST,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
. Exposure
duration and
activity
2 hr
IE (2xR)
S 15-nin intervals
2 hr
IE (2xR)
@ 15-01 n intervals
2 hr
IE (2xR)
i 15-nin intervals
2 hr
R (11) & IE (29)
i 15-nin intervals
2 hr
R (11) & IE (29)
® 15-nin intervals
1-4 hr
IE (4xR) for two
15-min periods
2.25 hr
IE (2xR)
§ 15-nin intervals
4 days
2.5 hr/day
IE (2xR)
@ 15-min intervals
Observed effect(s)
No changes in spiroraetry or small airway
function in the combine* group; sensitive
subjects had decreased FEVj.o (4.7%).
No changes in group mean pulmonary function;
individual subjective symptoms and spiro-
metric decrements were more severe
In Toronto than L.A. subjects. Blood
enzyme activity increased in both
groups, but RBC fragility increased
in Toronto subjects only.
At 0.37 ppm, less than 20% decrements in
spirometry. Smokers less responsive than
nonsmokers. At 0.75 ppn, severe decrements
in spirometric variables (2QX-558.). Smokers
more responsive, with RV and CC increased.
0.75 ppm: at rest, less than 21% decrements
in spiroraetry, while during IE nearly 33%
decrements in spirometry and dN2. Relatively
smaller effects at lower concentrations.
Reasonably good correlation between dose
(cone, x min. vent.) and changes in spiro-
metric variables.
fo increased and V-,- decreased with exercise;
TO2 not affected by exposure. Variables
correlated to total dose of ozone.
FVC and HMEF decreased and R increased at
2 hr and 4 hr; FEVj.0, Vso, aRd V2S decreased
at 4 hr only.
FVC, FEVj-o, and MMF decreased in new arrivals,
which were more responsive than L.A. residents.
Inconsistent changes in blood biochemistry.
Very small changes in pulmonary function; tem-
poral pattern of these changes is suggestive of
"adaptation."
No. and sex
of- subjects Reference
4 normal (L.A.) Bell et al..' 1977
4 sensitive (L.A.)
2 male (Toronto) Hackney et al., 1977b
2 female (Toronto)
3 male (L.A.)
1 fenale (L.A.)
12 male Bates and Hazucha, 1973
Hazucha et al., 1973
Hazucha, 1973
20 male Silver-man et al. , 1976
8 female (divided into
6 exposure groups)
20 male Folinsbee et al. , 1975
8 female (divided into
6 exposure groups)
22 male Knelson et al., 1976
6 female (L.A.) Hackney et al. , 1976
7 female (new arrival)
2 male (new arrival)
6 male (atopic) Hackney et al., 1977a
-------
TABLE 10-1 (continued). HUMAN EXPERIMENTAL EXPOSURE TO OZONE UP TO 1978
Ozone k
concentration Measurement '
[ig/ina ppra method
980 0.5 CHEM,
NBKI
980 0.5 MAST,
NBKI
1176 0.6 CHEM,
NBKI
0 H76 0.6 CHEH,
J-, NBKI
11/6 0.6 MAST
1568 0.8
1470 0.75 MAST,
NBKI
14 ;o 0.75 HAST,
NBKI
Exposure
duration and
activity0
2 hr
R (9) & IE (37)
for 30 min
6 hr
IE (44) for two
15-nin periods
2 hr (noseclips)
R
2 hr
IE for two
15-min periods
2 hr
R(9)
2 hr
IE (20-^25)
f 15-nin intervals
2 hr
R & IE (2XR)
IS Ib-min intervals
Observed effect(s)
Changes in pulmonary function (FVC, FEV^o,
FEF2s_7s) wre greatest immediately following
exercise. Heat stress potentiated the re-
sponse while relative humidity had insignifi-
cant effects.
FVC, FEV3<0, and SG decreased and R. in-
creased. "Nonsmokers were more susceptible.
Inconsistent changes in lung mechanics and
small airway function.
Bronchoreactivity to 'histanrine increased
following exposure; persisted for up to
3 weeks; blocked by atropine..
Significant decrements in spirometric
variables (19%-35%). Cough and pain on
deep inspiration most frequently reported;
no symptoms persisted beyond 48 hr.
DLrn: mean decrease of 25% (11/11 subjects).
VCr mean decrease of 10% (10/10 subjects).
FEVo-75 x 40; mean decrease of 10%.
FEF2S_7S: mean decrease of 15%, which was
not significant.. Mixing efficiency: no
change (2/2 subjects). Airway resistance:
slight increase, but within normal limits.
Dynamic compliance: no change (2/2 subjects).
Sub'sternal soreness and trachea! irritation
6 to 12 hr after exposure.
HR , Vr, Vp V02 , and maximum workload
an Hecreasefl. At maximum workload only,
fD increased (45%) and V, decreased (29%).
o 1
FEF5o and PcyTLC decreased, R, increased;
returned to control levels within 24 hr.
IE increased changes in R. , C . , maxPj* ' ,
and spirometry. Cough ana sufreternal sore-
ness reported.
No. and sex
of subjects
14 male
(divided into 2
exposure groups)
19 male
1 female
(equally divided by
smoking history)
3 male
5 female
20 male
10 male
1 female
..13 male
13 male:
10(R) & 3(IE)
Reference
Folinsbee et al., 1977b
Kerr et al . , 1975
Golden et al., 1978
Ketcham et al., 1977
Young et al. , 1964
Folinsbee et al., 1977a
Bates et al., 1972
-------
TABLE 10-1 (continued). HUMAN EXPERIMENTAL EXPOSURE TO OZONE UP TO 1978
Ozone . Exposure
concentration Measurement ' duration and
K
o
U1
ug/md
1764
2940
3920
1960
5880
9800
19600
ppm method activity^
0.9 MAST, 5 min
NBKI CE
1.5- I 2 hr
2.0 R
1- MAST 10-30 min
3 R "
5- I Not available
10
. No. and sex
Observed effect(s) of subjects
SG decreased during and 5 min following 4 male
exposure. Recovery complete within 30 min
post-exposure.
VC: decreased 13% immediately after exposure; 1 male
returned to normal in 22 hr. FEV3.0: decreased
16.8% after 22 hr. Maximum breathing capacity
decreased very slightly. CNS depression, lack
of coordination, chest pain, tiredness for
2 weeks.
VC: mean decrease of 16.5% (4/8 subjects 11 subjects
showed decrease > 10%). FEVi.0: mean
decrease of 20% (5/8 subjects showed
decrease > 10%. FEF25_75: mean decrease
of 10.5% (5/6 subjects showed a decrease).
MBC: decrease of 12% (5/8 subjects showed
decrease). DLrn: decrease of 20 to 50% in
7/11 subjects; Increase of 10 to 50% in 4/11
subjects; only 5/11 subjects tolerated
1 to 3 ppm for full 30 min. Wide varia-
tions in DL-Q. Headache, shortness of
breath, lasting more than 1 hr.
Drowsiness and headache reported. 3 male
Reference
Kagawa and Toyama, 1975
Griswold et al. , 1957
Hallett, 1965
Jordan and Carlson, 1913
Measurement methods: MAST = Kl-coulometric (Mast meter); I = iodometric; CHEM = gas-phase chemiluminescence; UV = ultraviolet photometry.
Calibration methods: NBKI = neutral buffered potassium iodide.
Activity level: R = rest; CE = continuous exercise; IE = intermittent exercise; minute ventilation (vV) given in L/min or in multiples of resting
ventilation. .
See Glossary for the definition of symbols.
Source: U.S. Environmental Protection Agency (1978).
-------
have been provided to give the reader an overview of the studies discussed in
the text and provide some additional information about measurement techniques
and exposure protocols. Unless otherwise stated, the 0- concentrations pre-
sented in the text and tables are the levels cited in the original manuscript.
No attempt has been made to convert the concentrations to a common standard,
although suggestions for conversion along with a discussion of 0, measurement
can be found in Chapter 4.
10.2 ACUTE PULMONARY EFFECTS OF OZONE
10.2.1 Introduction
The most prevalent and prominent pulmonary responses to 0- exposure are
cough, substernal pain upon deep inspiration, and decreased lung volumes
(forced vital capacity, FVC; forced expiratory volume in Is, FEV1>0; tidal
volume, VT). Less substantial increases in airway resistance (R_.,) also
I 3W
occur. In most of the studies reported, greatest attention has been accorded
decrements in FEV1<0, as this variable represents a summation of changes in
both volume and resistance. While this is true, it must be pointed out that.
for exposure concentrations critical to the standard-setting process (i.e.,
<0.3 ppm 03), the observed decrements in FEV1<0 primarily reflect FVC decre-
ments of similar magnitude, with little or no contribution from changes in
resistance. As examples, for,subjects exposed to 0.3 ppm 0, and performing
exercise with associated minute ventilations (VV) of 31, 50, or 67 L/min,
decrements in FEVn.o and FVC were 0.23 and 0.11, 0.31 and 0.29, 0.38 and 0.40
liters, respectively (Folinsbee et al., 1978). For subjects performing heavy
exercise (V£ = 65 L/min) and exposed to 0.12, 0.18, 0.24, or 0.30 ppm 03,
decrements in FEV1<0 and FVC were 0.21 and 0.17, 0.29 and 0.23, 0.59 and 0.53,
0.74 and 0.66 liters, respectively (McDonnell et al., 1983). In another study
of subjects performing heavy exercise (VE = 57 L/min and exposed to polluted
ambient air (mean 03 concentration =0.15 ppm), 0.16 or 0.24 ppm 0,, decrements
in FEVi.o and FVC were 0.20 and 0.18, 0.24 and 0.24, 0.74 and 0.73 liters,
respectively (Avol et al., 1984). Thus, it is highly probable that most of
the decrements in FEV1>0 reported to result from 0, exposure are indicative of
restrictive changes and that little or no change in FEVi.o/FVC occurs which
would indicate resistive changes.
10-6
-------
10.2.2 At-Rest Exposures
Results from studies reported prior to 1978 (Table 10-1) indicate that
impairment of pulmonary function and pulmonary symptoms occur when normal
o
subjects are exposed for 2 hr at rest to 1176-1568 ng/m (0.6-0.8 ppm) of 0.,
(Young et al., 1964), and to 1479 ug/m3 (0.75 ppm) of QS (Bates et al., 1972;
Silverman et al., 1976). In addition to decrements in the usual indicators of
pulmonary function, Young et al. (1964) also found decreases in diffusion
capacity of the lung (D.CO).
Results from studies of at-rest exposures published since 1978 (Table 10-2)
have generally confirmed these earlier findings. Folinsbee et al. (1978)
observed decrements in FVC, FEV-, n, and other spirometric variables when
3
10 normal subjects rested for 2 hr while exposed to 980 yg/m (0.5 ppm) of 0~;
R was not affected. No changes in pulmonary function resulted from expo-
Q.W ^
sures to 588 or 196 ug/m (0.3 or 0.1 ppm) of Og. Horvath et al. (1979)
reported that decreases in FVC and FEV-, Q resulted from 2-hr at-rest exposures
of 15 subjects (8 males, 7 females) to 980 and 1470 ug/m3 (0.50 and 0.75 ppm)
of Ooj the decreases at 0.75 ppm were greater than those at 0.50 ppm of O^.
No changes in pulmonary function were observed at 490 ug/m (0.25 ppm) of 63.
Kagawa and Tsuru (1979a) observed small decreases in specific airway
conductance (SG ) when three subjects rested for 2 hr while exposed to 588
and 980 (jg/m (0.3 and 0.5 ppm) of.Oo. In contrast to other studies, this is
the only report of changes in airway resistance resulting from at rest expo-
sures to Oo.
Kb'nig et al. (1980) exposed 14 healthy nonsmokers (13 men, 1 woman) for 2
hr at rest to 0, 196, 627, and 1960 (jg/m3 (0.0, 0.10, 0.32, and 1.0 ppm) of
03. Specific airway conductance was measured and samples of arterialized ear
lobe capillary blood were taken for determinations of oxygen tension (PO^)
before and after the exposures. No changes in P09 or SG_W were observed.
C- QW
Subjective symptoms (substernal burning) were reported by two individuals at
196 ug/m3 (0.1 ppm), by three at 627 ug/m3 (0.32 ppm), and by eight at 1960
o
[jg/m (1.0 ppm) of O^.
10.2.3 Exposures With Exercise
The majority of controlled human studies since 1978 have been concerned
with the effects of combined rest and exercise exposures to various concentra-
tions of 03 for variable periods of time (Table 10-2). Exercise during these
10-7
-------
TABLE 10-2. STUDIES ON ACUTE PULMONARY EFFECTS OF OZONE SINCE 1978
Ozone
concentration
(jg/«d
157
314
470
627
196
196
294
392
490
H-
O
00 196
588
980
196
627
1960
235
353
470
588
784
235
353
470
588
784
ppm
0.08
0.16
0.24
0.32
0.1
0.10
• 0.15
0.20
0.25
0.1
0.3
0.5
0.1
0.32
1.0
0.12
0.18
0.24
0.30
0.40
0.12
0.18
0.24
0.30
0.40
Measurement3 '
method
UV,
UV
CHEH,
NBKI
UV,
UV
CHEH,
NBKI
HAST,
NBKI
CHEH,
UV
CHEM,
UV i
, Exposure
duration and
act1vityc
1 hr
CE (57)
2 hr
IE (2xR)
@ 15-nrin intervals
2 hr
IE (68)
(4) 14-min periods
2 hr
R (10), IE (31,
50, 67)
@ 15-min intervals
2 hr
R
2.5 hr
IE (65)
@ 15-min intervals
2.5 hr
IE (65)
@15-min intervals
Observed effect(s)
Small decreases in FVC and FEVli0 at 0.16 ppm
with larger decreases at XJ.24 ppm; lower-re-
spiratory symptoms increased at MJ.16 ppm.
Incomplete recovery of function and symptoms
1 hr postexposure.
No effect on Pa02 or R taking into account
intra-individual variation.
Concentration-response curves produced; exponen-
tial decreases in FVC, FEVi.o. FEF2s_7s«, SG ,
1C, and TLC with increasing 03 concentration? at
any given 03 concentration, linear decreases
in FVC and FEVi>0 with time of exposure. Sig-
nificant individual variation in response.
Cough, nose and throat irritation, and chest
discomfort or tightness also showed signifi-
cant concentration-response relationships.
Changes in pulmonary function found at 0.5 ppm
during R and 0.3 and 0.5 ppm with IE. The
magnitude of spirometric changes was gener-
ally related to ozone concentration and
minute ventilation, but concentration showed
stronger association. Effective dose-
functional response curves developed.
No changes in SR or P02 following exposure;
SR increased wfth ACh challenge at 60.32 ppm;
SRaw increased in 2/3 COLD patients at 0.1 ppm.
Small decreases in FVC, FEVj.o, and
FEF25_75y at 0.12 and 0.18 ppm with larger
decrease! at 60.24 ppm; f and SRgw in-
creased and VT decreased at 60.24 ppm;
regression curves produced; coughing
reported at all concentrations, pain and
shortness of breath at 60.24 ppm.
Individual responses to 03 (FVC, FEV1-0) were
highly reproducible for periods as long as 10
months and at 03 concentrations >_ 0.18 ppm;
large intersubject variability in response
due to intrinsic responsiveness to 03.
No. and sex
of subjects
42 male
8 female
(competitive
bicyclists)
11 male
20 male
40 male
(divided into 4
exposure groups)
13 male
1 female
(3 COLD)
(1 asthma)
135 male
(divided into six
exposure groups)
32 male
Reference
Avol et al . , 1984
von Nieding et al., 1979
Kulle et al., 1985
Folinsbee et al. , 1978
Konig et al., 1980
HcDonnel 1 et al . , 1983
McDonnell et al. , 1985a
-------
TABLE 10-2 (continued). STUDIES OF ACUTE PULMONARY EFFECTS OF OZONE SINCE 1978
Ozone
concentration
Mg/V
235
235
297
594
O
294
588
392
392
588
784
392
686
ppn
0.12
0.12
0.15
0.30
0.15
0.3
0.2
0.2
0.3
0.4
0.20
0.35
Measurement *
method
CHEM,
UV
UV
UV,
UV
CHEM,
NBKI
UV,
NBKI
UV,
UV
UV,
UV
. Exposure
duration and
activity
2.5 hr
IE (39)
@ 15-min intervals
1 hr (mouthpiece)
R
1 hr (mouthpiece)
CE (55)
+ heat
2 hr
IE
8 15-nin intervals
2 hr
IE (2xR)
@ IS-min intervals
30-80 rain
(mouthpiece)
CE (34.9, 61.8)
1 hr (mouthpiece)
IE (77.5) § vari-
able competitive
intervals
CE (77.5)
Observed effect(s)
Small decrease in FEVli0; decrement persists
for 24 hr. No change in frequency or severity
of cough.
No significant changes in pulmonary function
or subjective symptoms.
Increased fB, decreased VT and V, at 0.3 ppni;
FVC, FEV1>0, FEF2s.7sx, and TLC decreased at
0.3 ppm. "Most subjects reported pain on inspira-
tion and coughing at 0.3 ppm. FVC decreased with
increased temperature; interaction of 03 with
increased temperature for f« and V,
Small decreases in SS and FVC after exposure
to 0.15 and 0.30 ppm 9|. Increased &N2 at 0,15
ppm 03. Questionable statistics.
No meaningful changes in PA02; Pa02, and
P(A-a)Oj. Inconsistent changes in spirometric,
plethysrnographic, and ventilatory distribution
variables.
Progressive impairment of lung function with
increasing effective dose; questionable sig-
nificance during CE (61.8).
FVC, FEVi.0, and FEF2S_75 decreased, subjective
symptoms increased with 03 concentration; fp
increased and V-, decreased during CE; no effect
on VOZ, HR, Vr, or V.. No exposure mode effect.
No. and sex
of subjects Reference
23 male McDonnell etal.,
(children aged 1985b,c
8-11 yr)
4 male Koenig et al., 1985
6 female
(adolescents aged
13-18 yr)
10 female Gibbons and Adams, 1984
15 male Kagawa, 1983a, 1984
13 male Linn et al., 1979
5 female
8 male Adams et al., 1981
10 male Adams and Schelegle,
(distance runners) 1983
-------
TABLE 10-2 (continued). STUDIES OF ACUTE PULMONARY EFFECTS OF OZOHE SINCE 1978
.H
o
H
O
Ozone
concentration
ug/M3
392
823
980
392
784
412
490
490
980
1470
pp»
0.2
0.42
0.50
0.2
0.4
0.21
0.25
0.25
0.50
0.75
Measurement8'
itethod
uv,
uv
uv,
NBKI
uv,
UV
UV, UV
CHEH,
NBKI
Exposure
duration and
activity0
2 hr
IE (30 for
male, 18 for
female subjects)
@ 15-nrin intervals
2 hr
IE (2xR)
§ 15-nrin intervals
1 hr
CE (81)
1 hr
CE (63)
2 hr
R (8)
Observed effect{s)
Pre-exposure to 0.2 ppa did not alter response
to higher concentrations; FEVji.0 decreased
in sensitive subjects (n = 9) at 0.2 ppn;
no significant sex differences.
SR increased with histanine challenge
in 1 subjects at 0.4 ppm. "Adaptation" shown
with repeated exposures.
Decreases in FVC (6.9%), FEV,.0 (14.8*),
reF2S.7SX (18%), 1C (113!) , and MVV (17%).
Symptoms reported: laryngeal and tracheal
irritation, soreness, and chest tightness
on inspiration.
FVC, FEV1( FEF2S_7Sv, FEF7S.8S%> HW, and 1C
decreased; decrements in FEVj, were 6% and
15% larger with reexposure 12 and 24 hr
later, respectively. Increased responsiveness
to Og persisted in some subjects for 48 hr but
was lost within 72 hr. Symptoms paralleled
the changes in lung function.
Spironietry: FVC, FEVt.0, and fWFR decreased
immediately following 0.75 ppm; FVC and FEV^o
decreased immediately following 0.5 ppm. Meta-
No. and sex
of subjects Reference
8 male Gliner et a!., 1983
13 female
12 nale Dineo et al., 1981
7 female
(divided into three
exposure groups)
6 «ale Folinsbee et al., 1984
1 female
(distance cyclists)
19 male Folinsbee and Horvath,
7 female 1986
(divided into four
exposure groups)
8 male Horvath et al., 1979
7 female
holism: respiratory exchange ratio and venti-
latory equivalent increased (0.75 ppm); oxygen
uptake decreased at all 03 concentrations. In-
creased Vp during exposure facilitates decrement
in lung function but does not facilitate return
to normal following exposure. No effect on max
V02 following exposure.
588 0.3
UV, 1 hr (mouthpiece)
NBKI CE 850% VO,
+Vit E
U2max
RV increased while VC and FEV1>0 decreased with
03. Expired pentane (lipid pefoxldation) in-
creased with exercise but not Oa exposure; atten-
uated by vitamin E supplementation.
5 male
5 female
Dillard et al., 1978
-------
TABLE 10-2 (continued). STUDIES Of ACUTE PULMONARY EFFECTS OF OZONE SINCE 1978
H
O
H
H
Ozone
concentration
pg/m3
588
588
980
725
1470
980
1470
784
ppm
0.3
0.3
0.5
0.37
0.75
0.50
0.75
0.4
"»
Measurement '
method
MAST,
BAKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBK!
u Exposure
duration and
activity
1 hr (mouthpiece)
CE (34.7 for
female and 51
for male subjects)
2 hr
R
2 hr
R
2 hr
IE (2.5xR)
@ 15-min intervals
3 hr
IE (4-5xR)
for 15 min
.
A
Observed effect(s)
FVC, FEVj.o and FEF25.75% decreased; fg
increased and V,. decreased with exercise;
nonsmokers and females may be more sensi-
tive; increase in subjective complaints
noted.
SG decreased at 0.3 and 0.5 ppm.
Tendency toward increased bronchial
reactivity to ACh challenge. Smoking
effects were similar to those of ozone.
FEVj o decreased at 0.37 ppm; FVC and % ,-n~
decreased at 0.75 ppm. maxou*
FVC, FEVi.o, V SM> V K% decreased. No
interaction betslsn ciglrltli smoking and 03
but smokers may have decreased responsiveness
to 03. - . .
FVC and FEVj 0 decreased and bronchial reactivity
to methacholine increased following exposure.
Responses attenuated with repeated exposure.
No. and sex
of subjects
12 male
12 female
(equally divided
by smoking history)
i male
(equally divided
by smoking history)
26 male
6 female
(habitual
smokers)
13 male
11 female
(divided into 2
phases)
Reference
De Lucia et al., 1983
Kagawa and Tsuru, 1979a
Shephard et al. , 1983
Kulle et al.,
Kulle, 1983
784 0.4
CHEM, UV 2.5 hr
IE (71)
@ 15-min intervals
SR increased and FVC, FEVt, FEF2S_7S~,
ana TLC decreased with Os; f., increasea
and Vj decreased with exercise; no change
in FRC or RV. Atropine pretreatment
prevented the increased R with Og,
partially blocked the decreases in forced
expiratory flow, but did not prevent the
Oa-induced decreases in FVC and TLC, change
in exercise ventilation, or reported symptoms
of cough and pain on deep inspiration.
8 male
Beckett et al., 1985
-------
TABLE 10-2 (continued), STUDIES OF ACUTE PULMONARY EFFECTS OF OZOHE SINCE 1978
Ozone
concentration
(jg/m3 ppn
882 0.45
980 0.5
1176 0.6
L Exposure
Measurement ' duration and
method activity
UV, UV 2 hr
IE (27)
6 20-min intervals
CHEM, 2 hr
NBKI IE (2xR)
@ 15-ain intervals
+ Vit E
UV, 2 hr (noseclip)
NBKI IE (2xR)
@ 15-min intervals
Observed effect(s)
FVC, FEVt, FEV3, and FEF2S.75« decreased;
decrements were -7X larger with reexposure
48 hr later. RV increased and TLC decreased
after exposure; there were no significant
changes in FRC or ERV.
FEVUO decreased in both placebo and vitamin E -
supplemented subgroups; FVC decreased only in
the placebo group. No significant effect of
vitamin E.
No change in symptoms; FVC, FEV1>0, FEF2Sy,
FEFsov, ANz, and TLC decreased in both placebo
and vitamin E-supplemented subgroups. No
significant effect of vitamin E.
SR increased in nonatopic subjects (n = 7)
witn histamine and methacholine and in a topic
subjects (n = 9) with histamine following
exposure, returning to control values by the
following day; response prevented by pre-
treatnent with atropine aerosol.
No. and sex
of subjects Reference
1 male Bedi et al., 1985
5 female
9 male - Hackney et al., 1981
25 female
22 male
11 male Holtzman et al., 1979
5 female (divided
by history of atopy)
Measurement method: MAST = Kl-coulometric (Mast meter); CHEM = gas phase chemiluminescence; UV = ultraviolet photometry.
Calibration method: NBKI = neutral buffered potassium iodide; BAKI = boric acid potassium iodide; UV ~ ultraviolet photometry.
Activity level: R = rest; CE = continuous exercise; IE = intermittent exercise; minute ventilation ($F) given in L/min or as a multiple of resting
ventilation.
See Glossary for the definition of symbols.
-------
exposures has been at different intensities and at different times during the
exposures. The level of minute ventilation (V^), which varies with exercise
intensity, is a primary determinant of the magnitude of pulmonary effects
resulting from exposure to a given level of 0~. Therefore, results from
studies using different regimens of exercise, even with exposure to the same
0- concentration, may be difficult to compare. Most studies used alternating
15-min periods of rest and exercise. Pulmonary function and/or subjective
symptoms were usually measured pre- and post-exposure. In a few studies, such
measurements were also made during the rest periods after each exercise period.
Exposures in these studies were usually performed only on one day, and were
therefore likely to induce smaller functional decrements than would have been
observed if subjects had been exposed on two sequential days, as noted in
Section 10.3 entitled "Pulmonary Effects Following Repeated Exposure to Ozone."
Other factors that may influence the results obtained by different inves-
tigators and account for some of the inconsistencies observed among the find-
ings from various studies are discussed in this chapter. Such factors include
experimental design (more specifically: number of subjects, exposure time,
recurrent exposures, length of and sequencing of exercise periods, and time of
measurements), and specific measurement techniques used to determine 0- concen-
tration (see Chapter 4) and to characterize pulmonary responses. The variabil-
ity of intrinsic responsiveness of individual subjects to 0-,, effects of 0- on
subjects with pulmonary disease, and other factors affecting the responsiveness
of subjects to 0~, such as smoking history, sex, and environmental conditions,
are discussed in this section. Studies on the interaction between 03 and other
pollutants are presented in Section 10.5.
As previously stated, increased VV accompanying exercise is one of the
most important contributors to pulmonary decrements during 0- exposure. While
the more recent reports include actual measurements of VV obtained during
exposure, earlier publications often included only a description of the exercise
regimen. Table 10-3 may aid the reader in estimating the VV associated with a
given exercise regimen.
The values for 02 consumption and VV in Table 10-3 are approximate esti-
mates for average physically fit males exercising on a bicycle ergometer at 50
to 60 rpm (if rpms are higher or lower, values may be different). Note that
individual variability is great and that the level of physical fitness, age,
level of training, and other physiological factors may modify the estimated
values. The only precise method of obtaining these data is to actually measure
10-13
-------
TABLE 10-3. ESTIMATED VALUES OF OXYGEN CONSUMPTION AND MINUTE VENTILATION ASSOCIATED WITH REPRESENTATIVE TYPES OF EXERCISE
Level of work
Light
Light
Moderate
l_i - Moderate
o
rf». Moderate
Heavy
Heavy
Very Heavy
Very heavy
Very heavy
Severe
Work Performed b
watts kg-m/min
25
50
75
100
125
150
175
200
225
250
300
150
300
450
600
750
900
1050
1200
1350
1500
1800
02 consumption,
L/min
0.65
0.96
1.25
1.54
1.83
2.12
2.47
2.83
3.19
3.55
4.27
Minute
ventilation,
L/min
12-16
17-23
23-30
29-38
35-46
42-55
52-67
62-79
73-93
89-110
107-132
Representative activities0
Level walking at 2 raph; washing clothes
Level walking at 3 mph; bowling; scrubbing floors
Dancing; pushing wheelbarrow with 15-kg load;
simple construction; stacking firewood
Easy cycling; pushing wheelbarrow with 75-kg load;
using sledgehammer
Climbing stairs; playing tennis; digging with spade
Cycling at 13 mph; walking on snow; digging trenches
Cross-country skiing; rock climbing; stair climbing
with load; playing squash and handball; chopping
with axe
Level running at 10 mph; competitive cycling
Competitive long distance running; cross-country
skiing
See text for discussion.
kg-m/niin = work performed each minute to move a mass of 1 kg through a vertical distance of 1 n against the force of gravity.
cAdapted from Astrand and Rodahl (1977).
-------
the VV and Oy consumption. If exercise is conducted on a treadmill, adequate
relative standards for 02 consumption and VE can not be estimated. Thus, with
such activity, there is an absolute need to measure these variables.
Bates et al. (1972) and Bates and Hazucha (1973), as described in the
previous 0- criteria document (U.S. Environmental Protection Agency, 1978),
were the first to consider the role of increased ventilation due to exercising
in an 0™ environment. These observations emphasized an important aspect of
ambient exposure; namely, that individuals who are engaged in some type of ac-
tivity during ambient exposure to polluted air experience greater pulmonary
function decrement than resting individuals.
Hazucha et al. (1973) reported data obtained on 12 subjects exposed for
2 hr to either 725 (n=6) or 1470 (n=6) ug/m3 (0.37 or 0.75 ppm) of 0.,. These
subjects performed light exercise (VV reported to be double resting ventilation)
alternately every 15 minutes. Three subjects also had total lung capacity
(TLC), residual volume (RV), and closing capacity (CC) measured before and
3
after 2-hr exposure to 1470 |jg/m (0.75 ppm) of Q~. Significant decreases in
lung function derived from the measurements of forced expiratory spirometry
were observed at both 0.37 ppm (P <0.05) and 0.75 ppm (P <0.001) of 03; the
decrease was greater at the higher level of 03. After exposures, all subjects
complained to varying degrees of substernal soreness, chest tightness, and
cough. While the number of subjects was small and the results therefore incon-
clusive, the mean RV and CC increased and TLC was unchanged after exposure to
0.75 ppm of 03.
Kerr et al. (1975) reported small, but significant, decreases in FVC,
3
FEV, n> R. , and SG when 20 subjects were exposed to 980 ug/m (0.5 ppm) of
o.U l_ 9 w
0- for 6 hr with two 15-min periods of medium exercise (100 W), The symptoms
of dry cough and chest discomfort were also experienced after exposure. No
changes in TLC, FRC, C ., dN-, or D.CO were observed.
Folinsbee et al. (1977b) demonstrated that the heightened pulmonary
effect of 0~ associated with intermittent exercise during exposure occurred
- 7 •
principally, if not entirely, during the exercise period. In this study,
involving subjects who had exercised for a single 30-min period during a 2-hr
3
980-ug/m (0.50-ppm) 0., exposure, the maximum impairment of forced expiratory
spirometry appeared immediately (2 to 4 min) after exercise (Figure 10-1).
Despite continued exposure to 03, but at rest, pulmonary function either
improved or showed no
while TLC was reduced.
improved or showed no further impairment. No change in RV or R was observed,
10-15
-------
W
Q.
fc
S2
£
&
2
2
I
LL.
CO
Q.
IS
U
8
GROUP A
GROUP B
30 60 90 120 0 30 60 90 120
EXERCISE EXERCISE
EXPOSURE, minutes
Figure 10-1. Change in forced vital capacity (FVC), forced
expiratory volume in 1 -sec (FEV , 0)r and maximal mid-
expiratory flow (FEF2B 75%) during exposure to filtered air
(O) or ozone (A) (0.5 ppm) for 2 hr. Exercise at 45%
maximal aerobic capacity (max VO2) was performed for 30
min by Group A after 60 min of ozone exposure and by
Group B after 30 min of ozone exposure.
Source: Folinsbee et al. (1977b).
10-16
-------
Folinsbee et al. (1978) reported results from 40 subjects in studies
designed to evaluate the effects of various concentrations of 03 at several
different levels of activity from rest through heavy exercise. Half of the
subjects had previously resided in an area having high 03 concentrations; 14
reported symptoms associated with irritation or breathing difficulty on high-
pollution days. Five subjects who had not resided in such areas reported
similar symptoms upon visiting a high-oxidant-pollution region. Nine subjects
had a history of allergy, 11 were former smokers, and one had had asthma as a
child. Ten subjects in each of four groups were exposed four times, in random
order, to filtered air or 196, 588, or 980 ug/m (0, 0.10, 0.30, or 0.50 ppm)
of 03. One group rested throughout the exposure. The other three groups
exercised at four intervals throughout the exposure; each 15-min exercise
period was followed by a 15-min rest period. Each subject in the three exer-
cise groups walked on a treadmill at a level of activity to produce minute
ventilations of approximately 30, 50, or 70 L/min, respectively. The integra-
ted minute ventilatory volumes for the total 2 hr of exposure were 10, 20.35,
29.8, and 38.65 L, respectively. No pulmonary changes were observed with
3
exposure to filtered air or 196 ug/m (0.10 ppm) of 0- at any workload. At
3
rest (10. L/min), pulmonary function changes were confined to 980 ug/m (0.50
ppm) 0, exposures. Some changes were apparent at the lowest work load (30 L/
3 3
min) and 588 ug/m (0.30 ppm) of 03, and effects were more marked at 980 ug/m
(0.50 ppm) of 0,,. At the two highest work loads (49 and 67 L/min), pulmonary
3
function changes occurred at both 588 and 980 ug/m (0.30 and 0.50 ppm), with
3
the changes at 980 ug/m (0.50 ppm) of 0- usually significantly greater than
3
those at 588 ug/m (0.30 ppm) of 0,,. During exercise, respiratory frequency
was greater and tidal volume lower with 03 exposure than with sham exposure.
The change in respiratory pattern was progressive and was most striking at the
two heaviest work loads and at the highest 03 concentrations. Reductions in
TLC and inspiratory capacity (1C), but not RV or functional residual capacity
(FRC), were also noted.
3
Von Nieding et al. (1977) exposed normal subjects to 196 ug/m (0.1 ppm)
03 for 2 hr with light intermittent exercise and found no changes in either
forced expiratory functions or symptoms. However, they found significant
increases (~7 mm Hg) in both alveolar-arterial PO,, difference and airway
resistance (~0.5 cm H00/L/s) and a significant decrease in P 00 (~7 mm Hg).
c. a. £.
These data were later reanalyzed (von Nieding et al., 1979) using more stringent
statistical criteria and the changes in both airway resistance and PaO£ were
10-17
-------
found to be nonsignificant. In both analyses, the nonparametric Wileoxen
procedure which ranks paired differences was used. In the 1977 analysis, PaO?
and airway resistance changes <5 mm Hg and 0.5 cm HpO/L/s, respectively, were
considered as zero but used in the analysis. In the 1979 analysis, Pa02 and
airway resistance changes <5 mm Hg and 0.5 cm H^O/L/s, respectively, and
within the range of normal variation for each individual subject were not
included in the analysis. Thus, data from about half the subjects analyzed in
1977 were included in the 1979 analysis.
In a study similar to that of von Nieding et al. (1977; 1979), Linn et
al. (1979) exposed normal subjects to 392 \jg/m3 (0.2 ppm) of Og. The 18
subjects exercised at twice resting ventilation for 15 min of every half hour.
Blood and alveolar gas samples were taken shortly after 1 and 2 hr of their
2.5 hr of exposure. Blood samples were taken both from an arterialized ear
lobe and a brachial artery. No significant differences between air and Og
exposures were observed for changes in P^Op* ^a^2 or ^CA-a) ^2*
Adams et al. (1981) required eight subjects (22 to 46 years of age) to
exercise continuously (i.e., no rest periods) while orally inhaling 0.0, 392,
588, and 784 jjg/m3 (0.0, 0.2, 0.3, and 0.4 ppm) of Og. The duration of the
exercise periods varied from 30 to 80 min, and the two exercise loads were
sufficient to induce minute ventilations of 34.9 and 61.8 L/min, respectively.
Pulmonary functions were measured before and within 15 min after exercise. At
both minute ventilations, decrements in forced expiratory spirometry were ob-
3
served for exposures to 588 and 784 jjg/m (0.30 and 0.40 ppm) of 03 with the
magnitude of decrement greater at the higher minute ventilation. The magnitude
of decrement also increased with increasing exposure time. No pulmonary
3
effects were observed for exposures to clean air or 392 ug/m (0.2 ppm) of 0~.
The authors suggested that the detectable level for 0- functional effects in
healthy subjects during sustained exercise at a moderately heavy work load (VV
3
of ~62 L/min) occurred between 0~ concentrations of 392 and 588 ug/m (0.2 and
0.3 ppm). The responses to continuous exercise were similar to those observed
in studies using intermittent but equivalent exercise.
Kagawa (1983a; 1984) presented data on 15 subjects exercising intermit-
3
tently (15 min exercise, 15 min rest) during a 2-hr exposure to 294 or 588 ug/m
(0.15 or 0.30 ppm) of 0,. These subjects reported the typical symptoms at the
higher 0« concentrations. Paired t-tests were used to compare responses to
filtered air and 0~. SQ decreased 6.4 percent (P <0.05) following the
"2 *>$.
294-ug/m (0.15-ppm) exposure and 16.7 percent (P <0.01) following the 588-ug/m
10-18
-------
(0.30-ppm) exposure. In the latter environment, only FVC showed a significant
(P <0.05) decrement; FEV-, was unaffected. These subjects had resided in a
low-oxidant-pollutant environment.
McDonnell et al. (1983) provided further information related to high
levels of ventilation during exercise in 135 healthy subjects exposed to 0~.
Subjects were excluded from the study if they had smoked within 3 yr or had a
history of asthma, allergy, rhinitis, cardiac disease, chronic respiratory
disease, recent acute respiratory illness, or extensive exposure to pollutants.
They divided their subjects into six groups, each group exposed to a different
concentration of 03; viz. 0.0 (n=20), 0.12 (n=22), 0.18 (n=20), 0.24 (n=21),
0.30 (n=21), and 0.40 (n=29) ppm, equivalent to 0.0, 235, 353, 470, 588, and
3
784 ug/m of O^, The subjects were exposed for 2.5 hr, with exposure consist-
ing of alternating 15-min periods of rest and exercise (vV/BSA of ="35 L/m or
VV = 64 to 68 L/min) during the first 120 min. Forced expiratory spirometry
and pulmonary symptoms were measured between 5 and 10 min after the final
exercise (i.e., at 125 min of exposure), while plethysmography was performed
between 25 and 30 min after the final exercise (i.e., at 145 min of exposure).
The pulmonary symptom, cough, showed the greatest sensitivity to 0- (it occurred
3
at the lowest concentration, 235 ug/m or 0.12 ppm of 03). Small changes in
forced expiratory spirometric measures (FVC, FEV, , maximal mid-expiratory flow
3
[FEF~r_-7ccg]) were suggested at 235 ug/m (0.12 ppm) of 0., and were definitely
present at 353 ug/m (0.18 ppm) of 0,. Greater changes were found at and
3
above 470 ug/m (0.24 ppm) of 03. Significant decreases in tidal volume (Vy)
and increases in respiratory frequency (fR) during exercise (similar changes
had been reported by other investigators) and specific airway resistance
(SR ), pain on deep inspiration, and shortness of breath occurred at 0,
olW <*} O
levels of >470 ug/m (0.24 ppm). The sigmoid-shaped dose-response curves
indicated a relatively large decrease in FVC, FEV-,, and FEFoe-^ew between 353
and 470 ug/m (0.18 and 0.24 ppm) On. However, in contrast to the results of
other investigations, a plateau in response was suggested at the higher levels
3
(>470 ug/m ; 0.24 ppm) of Q~. Regarding SR , a significant increase was
J *3 51W
observed beginning at 470 ug/m (0.24 ppm) of Oo and the magnitude of this
change was greater with increasing 0~ levels. These findings are in agreement
with the results of other investigators. The two different patterns in
response plus the observation that individual changes in SR . and FVC were
c*W
poorly correlated prompted these investigators to suggest that more than a
single mechanism might have to be implicated to define the effects of 0- on
10-19
-------
pulmonary functions. Findings from this study are particularly relevant in
that a large subject population was studied and pulmonary effects were suggested
o
at an 0- concentration (235 |jg/m ; 0.12 ppm) lower than that for which they
had previously been observed.
More recent studies on well-trained subjects have become available. Six
well-trained men and one well-trained woman (all of the subjects except one
male being a competitive distance cyclist) exercised continuously on a bicycle
ergometer for 1 hr while breathing filtered air or 412 pg/m (0.21 ppm) of 0-
(Folinsbee et al., 1984). They worked at 75 percent maximal aerobic capacity
(max VQ^) with mean minute ventilations of 89 L/min. Pulmonary function
measurements were made pre- and post-exposure. Decreases occurred in FVC
(6.9 percent), FEV-j^ Q (14.8 percent), FEF25-75% (18 percent), 1C (11 percent),
and maximum voluntary ventilation (MVV) (17 percent). The magnitude of these
changes were of the same order as those observed in subjects performing moderate
intermittent exercise for 2 hr in a 686-|jg/m (0.35-ppm) 03 environment.
Symptoms included laryngeal and/or tracheal irritation and soreness as well as
chest tightness upon taking a deep breath.
Adams and Schelegle (1983) exposed 10 well-trained distance runners to
0.0, 392, and 686 ng/m3 (0-0, 0.20, and 0.35 ppm) of 03 while the runners
exercised on a bicycle ergometer at work loads simulating either a 1-hr steady-
state training bout or a 30-min warmup followed immediately by a 30-min competi-
tive bout. These exercise levels were of sufficient magnitude (68 percent of
their max VQ2) to increase mean VE to 77.5 L/min. In the last 30 min of the
competitive exercise bout, minute ventilations were approximately 105 L/min.
Subjective symptoms, including shortness of breath, cough, and raspy throat
increased as a function of 03 concentration for both continuous and competitive
levels. The high ventilation volumes (77.5 L/min) resulted in marked pulmonary
function impairment and altered ventilatory patterns (increased fD and decreased
3
VT) when exercise was performed in 392 |jg/m (0.20 ppm) of 03. Two-way analysis
of variance (ANOVA) procedures performed on the pulmonary function data indi-
cated significant decrements (P <0.0002) for FVC, FEV-^, and FEF25-75%- Tne
investigators noted that the decrements in FEV-, Q were similar to those observed
by Folinsbee et al. (1978) when the two studies were compared on the basis of
effective dose. The concept of effective dose will be treated in a later
section.
Avol et al. (1984; 1985) randomly exposed trained cyclists (n = 50) to 0,
157, 314, 470, and 627 M9/m3 (0.0, 0.08, 0.16, 0.24, and 0.32) ppm Og. Each
10-20
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exposure consisted of 10 min warm-up, 60 min of exercise at 50% max V0? (Vp =
57 L/min), 5 min cool down (all performed on a bicycle ergometer), and 5 min
post-exercise pulmonary function testing. Most subjects resided in the Los
Angeles area and therefore were subject to prior exposure to ambient 0^. Two
subjects had histories of asthma; all others were free of chronic respiratory
disease. Three subjects were current smokers, while six others had previously
smoked. Forced expiratory spirometry and respiratory symptoms were evaluated
before exposure, immediately after exercise, and 1 hr after exposure. When
compared to exposure at 0.0 ppm, significant decreases in FVC and FEV1<0 and
an increase in lower respiratory symptom score combined (cough, sputum, dyspnea,
wheeze, substernal irritation, chest tightness) were observed following exposure
3
at and above 314 pg/m (0.16 ppm) 0,; no significant changes occurred with
3
exposure to 157 ug/m (0.08 ppm) 0,. An increasing number of subjects could
3
not complete the 1 hr of exercise at 0, concentrations of 470 and 627 ug/m
(0.24 and 0.32 ppm) without reducing their workloads. The magnitudes of
change in FVC, FEV,, and symptom score were concentration-dependent and remark-
ably consistent with those previously reported by McDonnell et al. (1983) (see
Section 10.2.1). While they did not return to levels observed prior to expo-
sure, substantial recovery of both function and symptoms was observed 1 hr
following exposure. Significant changes in FVC, FEV;,, and lower respiratory
symptom score also resulted from exposure to polluted ambient air with a mean
2
DO concentration of 294 ug/m (0.15 ppm) (see Section 11.2.1). Although the
pulmonary changes in response to polluted ambient air appeared to be of lesser
3
magnitude than those in reponses to the nearest generated Qg level (314 ug/m ;
0.16 ppm), the difference between the two exposures was not statistically
significant.
Kulle et al. (1985) randomly exposed male nonsmokers (n = 20), with no
history of chronic respiratory or cardiovascular disease, to 0, 196, 294, 392,
and 490 ug/m3 (0.0, 0.10, 0.15, 0.20, and 0.25 ppm) 03 for 2 hr. Each exposure
consisted of four cycles of 14 min treadmill exercise (VV = 68 L/min) alternated
with 16 min of rest. Forced expiratory spirometry was performed before exposure
and 9 min after each exercise. Measurements of R and V. (FRC) were made
3W T*S
prior to and after each exposure; respiratory symptoms were evaluated after
each exposure. Significant concentration-dependent decreases in FVC, FEVl>0,
FEF25_75, SG , 1C, and TLC and increases in respiratory symptoms (cough,
nose/throat irritation, chest discomfort) were observed; RV and FRC did not
10-21
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change with exposure to any concentration. Significant responses were best
modeled as an exponential function of 03 concentration. Additionally, FVC and
FEV1>0 decreased as a linear function of time of exposure. While these results
are discussed by the authors as though significant changes resulted from expo-
o
sure to 294 ug/m (0.15 ppm) 03, the magnitude of change at this concentration
was quite small (<1 percent) when compared to preexposure levels. Moreover,
while the statistical procedures (ANOVA) used by these investigators did indi-
cate a significant 03 effect when data from exposures to all 03 concentrations
were analyzed, no statistical comparisons of responses at individual 03 concen-
trations were performed. Thus, the legitimacy of ascribing 03 effects at any
individual 03 concentration is questionable and discussion of data should be
confined to the overall concentration-response relationship.
10.2.4 Intersubject Variability and Reproducibility of Responses
In the majority of the above studies, assessment of the significance of
results was typically based on the mean ± variance of changes in lung function
resulting from exposure to 03 as compared to exposure to clean air. Although
consideration of mean changes is useful for making statistical inferences
about homogeneous populations, it may not be adequate to describe the differ-
ences in responsiveness to 03 among individuals. While the significant mean
changes observed demonstrate that the differences in response between 03 and
clean air exposures were not due to chance, the variance of responses was
quite large in most studies. While characterization of reports of individual
responses to 03 is useful since it permits an assessment of the proportion of
the population that may actually be affected during 03 exposure, statistical
treatment of these data is still rudimentary and their validity is open to
question.
Results from a small number of studies (Horvath et al.} 1981; Gliner et
a!., 1983; McDonnell et al., 1983; Kulle et al., 1985) that have reported
individual responses indicate that a considerable amount of intersubject
variability does exist in the magnitude of response to 03. Figure 10-2 illu-
strates the variability of responses in FEVn n and SR obtained from subjects
JL • U clw
exposed to different 03 concentrations.
Decreases in FEV, Q ranging from 2 to 48 percent (mean = 18 percent) were
reported by Horvath et al. (1981) for 24 subjects exposed for 2 hours to 823
o
ug/m (0.42 ppm) of 0~ while performing moderate intermittent exercise. When
10-22
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10
5
0
10
5
0
tn 10
JMBER OF SUBJECT!
o o en
2 5
0
10
5
0
10
5
0
_
i
M M I M
0.40 ppm
—
•ffLiF
M M M
0.30 ppm
*
—
—
I
—
I I M M
0.24 ppm
—
ri
n.nj
l-l I I i hn
n
M M M
0.18 ppm
~h n , , ,
I
H
M I M M M
0.12 ppm
"T-i I M I
n
_
—
M I M M
0.00 ppm
—
-1 1 I I M I
I
—
n
rl
\
rl
1
M M I 1
0.40 ppm
—
n n —
n
_
1 M 1 1 1
0.30 ppm
_
nrfTTr-nn i
n
— •
(Mill
0.24 ppm
—
"rThfL , , r
_
M M M
0.18 ppm
TTfln ,,,r
i
BMM
1
—
mam
M M M
0.12 ppm
-r-i-i 1 ! 1
1 1 i 1 i I
0.00 ppm
' —
lihii ii M
-10 0 10 20 30 40
20 0 20 40 60 80
AFEVi.Q(DECREASE), percent ASRaw(INCREASE), percent
Figure 10-2. Frequency distributions of response (percent
change from baseline) in specific airway resistance (SRaw)
and forced expiratory volume in 1-sec (FEV1 0) for
individuals exposed to six levels of ozone. One individual
with 260% increase in SRaw exposed to 0.4 ppm of ozone
is not graphed.
Source: McDonnell et al. (1983).
10-23
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these same subjects were exposed to clean air under the same conditions, the
response of FEV-, Q ranged from an 8-percent increase to an 11-percent decrease
(mean = 0 percent).
diner et al. (1983) exposed subjects (13 females, 8 males) performing
o
intermittent light exercise for 2 hr to clean air and 392 ug/m (0.20 ppm) of
Og. Changes in FEV-, Q resulting from clean-air exposure ranged between
+7.8 percent and -7.5 percent (mean = 0 percent), while the range of changes
in FEV^ 0 was +6.0 to -16.6 percent (mean = -3 percent) with exposure to 392
ug/m3 (0.20 ppm) of 03.
For subjects performing 2 hr of intermittent heavy exercise while exposed
to DO, McDonnell et al. (1983) observed changes in FEV-. Q ranging from -1 to
-45 percent (mean = -18 percent) at 784 ug/m (0.40 ppm), -1 to -42 percent
o
(mean = -17 percent) at 588 ug/m (0.30 ppm), -1 to -36 percent (mean =
o
-15 percent) at 470 ug/m (0.24 ppm), 0 to -23 percent (mean = -6 percent) at
353 ug/m (0.18 ppm), +7 to -16 percent (mean = -4 percent) at 235 ug/m3 (0.12
ppm), and +2 to -6 percent (mean = -1 percent) in clean air. Large intersub-
ject variability was also reported for changes in SR_ during these exposures
(Figure 10-2).
Kulle et al. (1985) exposed each of their 20 subjects to four 0- concentra-
tions for 2 hr with heavy intermittent exercise. For these subjects, changes
in FEV1>0 ranged from +5 to -2 (mean = +1 percent) in clean air, +10 to -4
3
percent (mean = +1 percent) at 196 ug/m (0.10 ppm), +3 to -9 percent (mean = -1
3
percent) at 294 ug/m (0.15 ppm), +3 to -16 percent (mean = -3 percent) at 392
3 o
ug/m (0.20 ppm), and +1 to -36 percent (mean = -6 percent) at 490 ug/m (0.25
ppm). Concentration-response curves were also constructed for individual
subjects and individual 03 responsiveness assessed. Three subjects exhibited
a slight increase in FEVi following exposures to all four of the 0- concentra-
tions. Most of the remaining subjects demonstrated progressive decreases in
FEV1>0 with increasing 03 concentrations. Five subjects exhibited FEV1<0
decreases of <5 percent, seven subjects were between 5 and 10 percent, three
subjects were between 10 and 15 percent, and two subjects exhibited FEV±4o
decrease of >15 percent. The reported symptom of cough correlated with the
observed decrements in FVC and FEV.. (r = 0.52) and nose and throat irritation
correlated with FEV-. changes (r = 0.49).
The degree to which a subject's response to a given 0- concentration can
be reproduced is an indication of how precisely the measured response estimates
10-24
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that subject's intrinsic responsiveness. In a 1983 study, Gliner et al.
q
exposed subjects performing intermittent light exercise for 2. hr to 392 (jg/m
(0.20 ppm) of 0~ on three consecutive days, followed the next day by an expo-
sure to either 823 or 980 |jg/m3 (0.42 or 0.50 ppm) of 0,. Each subject had
3
also been exposed prior to or was exposed after the study to 823 or 980 ug/m
(0.42 or 0.50 ppm) 0.,. For individual responses of FEV-, n, a moderate corre-
lation (r = 0.58) between changes resulting from the first exposure to 392
ug/m (0.20 ppm) of 03 and the second exposure to 823 or 980 ng/m (0.42 or
0.50 ppm) of Oo was observed. When responses in FEV-, Q from the first and
second exposures to 0.42 or 0.50 ppm Q3 were compared, the correlation between
the two exposures was quite high (r = 0.92). Although these comparisons were
confounded by possible effects of prior 0, exposure, they do suggest that indi-
vidual changes in FEV-. ,, resulting from 0, exposure are reasonably reproducible.
Moreover, a given individual's response to a single, 03 exposure is probably a
reliable estimate of that individual's intrinsic responsiveness to 03«
McDonnell et al. (1985a) exposed each of 32 subjects for 2 hr to one of
five different 03 concentrations (235, 353, 470, 588, and 784 [jg/m ; 0.12,
0.18, 0.24, 0.30, and 0.40 ppm) with intermittent heavy exercise. Each subject
was exposed at least twice to the same 03 concentration at 3 to 75-week
intervals. The correlation coefficients between the two exposures closest in
time (mean ± S.D. = 9 ± 4 weeks) for individual changes in FVC, FEVli0, and
were 0-89, 0.91, and 0.83, respectively. Correlation coefficients
were moderate for changes in SR (r = 0.63) and the pulmonary symptoms of
cough (r = 0.75), shortness of breath (r = 0.65), and pain upon deep respiration
(r = 0.48). With a longer time between exposures (mean ± S.D. = 33 ± 20
weeks), changes in FVC (r = 0.72), FEV1>0 (r = 0.80), and FEF25-75% ^ = °'76^
were nearly as reproducible. This high degree of reproducibility indicates
that the magnitude of response to a single exposure is a reliable estimate of
that subject's intrinsic responsiveness to 03. Moreover, intersubject variabi-
lity in magnitude of Og-induced effects is probably the result of large differ-
ences in intrinsic responsiveness to 0,.' . .
10.2.5 Prediction of Acute Pulmonary Effects ,
Nomograms for predicting changes in lung function resulting from the
performance of light intermittent exercise while exposed to different 03
concentrations were included in one of the earliest reports of the effects of
10-25
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Og on normal subjects (Bates and Hazucha, 1973). Then in 1976, Silverman
et al. reported that pulmonary function decrements were related as linear and
second-order polynomial functions of the effective dose of 03, defined as the
product of concentration, exposure duration, and VV. Equations were derived
from lung function measurements at 1 and 2 hr of exposure to 725, 980, and
2
1470 ug/m (0.37, 0.50, and 0.75 ppm) of 03 under conditions of both rest and
intermittent exercise sufficient to increase VV by a factor of 2.5. Although
the fit of their data to linear and second-order curves was good, the authors
also commented that for a given effective dose, exposure to a high concentra-
tion of 0, for a short period of time induced greater functional decrements
than a longer exposure to a lower concentration. This phenomenon implies that
Og concentration is a more important contributor to response than is exposure
duration. Moreover, they also observed extensive individual variability in
pulmonary function changes, suggesting that use of effective dose is not
satisfactory for predicting individual responses to 0- exposure.
Since the inception of the concept of an effective dose, additional
studies have used, and in some cases refined it for prediction of pulmonary
responses to 03 exposure. However, these prediction models must be interpreted
with extreme caution since the data base is limited and the great intersubjeet
variability in responsiveness to 0- makes truly refined modeling of effective
dose highly improbable. Extension of the effective-dose concept was accom-
plished in the studies of Folinsbee et al. (1978) on subjects at rest and
performing intermittent exercise during 2-hr exposures to 0, 196, 588, and
o
980 ug/m (0.0, 0.10, 0.30, and 0.50 ppm) of Og. The exercise loads required
$P of some three, five, and seven times greater than resting ventilations.
Again, the effective dose was calculated as the product of 0~ concentration x
^P (L/min) during exposure (includes, both exercise and rest minute ventilation)
x duration of exposure. Polynomial regression analyses were performed first
on mean data at each level of V>, and second on all subject groups together
after computing the effective dose. Predictions of pulmonary function changes
in FEV-, based on effective doses up to 1.5 ml 0~ agreed with data collected by
other investigators. Prediction equations using the effective dose for all
measured pulmonary functions were constructed. All equations were significant
at the 0.01 level. These investigators also used a multiple regression approach
to refine further the prediction of changes in pulmonary function resulting
from O exposure. Duration of exposure was not analyzed as a contributing
10-26
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factor since all exposures were of equal time. Their analyses indicate that
essentially all of the variance of pulmonary responses could be explained by
Og concentration and VV. For example, these two predictors accounted for
approximately 80 percent (multiple r = 0.89) of the variance in FEV-, Q.
Moreover, Q~ concentration accounted for more of variance than did VV, and for
a given effective dose, exposure to a high concentration with a low VV induced
greater functional decrements than exposure to a lower concentration with
elevated VV. Equations (with appropriately weighted 03 concentration and VV)
for predicting the magnitude of pulmonary decrements were also provided.
Adams et al. (1981) further extended the effective-dose concept in studies
using a multiple regression approach and arrived at essentially the same con-
clusions reached by Folinsbee et al. (1978), namely that most of the variance
for pulmonary function variables could be accounted for by 0~ concentration,
followed by Vr, and then by exposure time. Adams et al. emphasized the predomi-
nant importance of 0, concentration and suggested that the detectable level
for 0,, functional effects in healthy subjects during sustained exercise at a
moderately heavy work load (Vc ~ 62 L) occurred between 0- concentrations of
3
392 and 588 [jg/m (0.2 and 0.3 ppm). The responses to continuous exercise
were similar to those observed in studies using intermittent but equivalent
exercise. They also noted, as had others, that the effective-dose concept was
not satisfactory for predicting individual responses.
Colucci (1983) assembled data available from the literature and analyzed
them with the purpose of constructing dose/effects profiles for predicting
pulmonary responses to 0~ based on results combined from many different labora-
tories. Basically, he examined changes in R_w and FEV-, Q as functions of
exposure rate (0- concentration x VV) and total exposure dose (exposure rate x
duration of exposure), which is equivalent to effective dose. The correlation
for changes in R was slightly better than that for changes in FEV-, Q. The
author states that he elected to use linear equations to fit the data rather
than polynomials because he found little difference in the degree of correla-
tion between the two methods. The analysis also found an attenuation in the
rate of increase of SR as VV increased to higher levels; there was no atten-
O.W , t,
uation of the decrease in FEV-, Q as a function of increasing VV. This observa-
tion suggested to Colucci that different mechanisms may be involved in the
effects on R and FEV-, Q. Whether expressed as functions of exposure rate or
total exposure dose, the patterns of pulmonary responses were approximately
10-27
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equivalent. This is not surprising since both Folinsbee et al. (1978) and
Adams et al. (1981) had previously shown that most of the variance in pulmonary
response depended primarily on 03 concentration and VV. The overall finding,
that increases in R and decreases in FEV-, n are reasonably correlated with
o,W JL* U
increases in effective dose of 03, only confirms the results reported by
previous investigators. As proposed by Folinsbee et al. (1978) and Adams
et al. (1981), a better fit of the data may have been obtained had Colucci
used multiple regression and equations that appropriately weighted the relative
contributions of each of the exposure variables to pulmonary decrements.
10.2.6 Bronchial Reactivity
In addition to overt changes in pulmonary function, several studies have
reported increased nonspecific airway sensitivity resulting from CL exposure.
Airway responsiveness to the drugs acetylcholine (ACh), methacholine, or
histamine is most often used to define nonspecific airway sensitivity.
Eight healthy nonsmoking men served as subjects (Golden et al., 1978) for
evaluation of bronchial reactivity due to histamine after a 2-hr exposure to
g
1176 fjg/m (0.6 ppm) of 0-. The resting subjects breathed orally (a nose-clip
was worn). These investigators concluded that CL exposure at this concentra-
tion and dose produced an enhanced response to histamine, which returned to
normal within 1 to 3 weeks after exposure.
Kagawa and Tsuru (1979a) studied both smokers and nonsmokers exposed to
0.0, 588, and 980 M9/m3 (°-0> °-3, and 0.5 ppm) 0-. Their three nonsmoking
subjects were exposed for 2 hr followed by measurements of bronchial reac-
tivity to ACh. They found that these subjects demonstrated an increased
reactivity to ACh. However, because of the small number of subjects and the
large variability of responses, the results may not represent a significant
effect.
The bronchial reactivity of atopic and nonatopic subjects was evaluated
by Holtzman et al. (1979). They studied 16 healthy nonsmoking subjects and
found that nine could be classified as "atopic" based on medical history and
allergen skin testing. All subjects had normal pulmonary functions determined
in preliminary screening tests and were asymptomatic. Both atopic and non-
atopic subjects performed intermittent exercise while wearing nosedips and
3
exposed by mouthpiece to filtered air and 1176 pg/m (0.6 ppm) of 03. Bronchial
10-28
-------
reactivity was determined 1 hr after exposure to each condition (when post-
exposure SR had returned to normal) by measuring the increase in SR produced
by inhalation of histamine or methacholine aerosols. In both atopic and non-
atopic subjects, the bronchial response to histamine and methacholine was
enhanced after 0- exposure when compared to exposure in filtered air. The
increase in SR resulted predominantly from an increase in airway resistance,
with only small changes in trapped gas volume. Symptoms of bronchial irrita-
tion were increased; however, these changes were transient, and were not
detectable by the next day. This result contrasts with previous results
observed by these investigators (Golden et a!., 1978), which indicated that
enhanced bronchial responsiveness persisted for a more prolonged period.
Premedication with atropine sulfate aerosol prevented the increase in SR*
clW
after histamine inhalation. Atopic subjects appeared to respond to a greater
degree than nonatopic subjects, although the pattern of change and the induc-
tion and time course of increased bronchial reactivity after exposure to 0,
were unrelated to the presence of atopy.
Konig et al. (1980) exposed 14 healthy nonsmokers (13 men, 1 woman) for
2 hr to 0, 196, 627, and 1960 jjg/m3 (0.0, 0.10, 0.32, and 1.00 ppm) of Og.
Bronchial reactivity to ACh was determined after exposure. Significant in-
creases in bronchial reactivity were observed with the ACh challenge following
exposure to 627 ug/m3 (0.32 ppm) and 1960 ug/m3 (1.0 ppm) of 03-
Bronchial reactivity of normal adult subjects was assessed by measuring
the increase in SR produced by inhalation of histamine aerosol (Dimeo et al.,
clW
1981). Seven subjects, intermittently exercising (15 min exercise, 15 min
*j
rest) at a load sufficient to double their resting VV, were exposed to 392 ug/m
(0.2 ppm) of 03 over a 2-hr period. Two air exposures preceded the 0^ exposure,
which was followed by another air exposure. Another group (five individuals)
were only repeatedly tested pre- and post-air exposure for their response to
histamine. In these two groups, the bronchial responsiveness to histamine was
not different in the air exposures. The bronchomotor response to inhaled
3
histamine aerosol was not altered following the 392-ug/m (0.2-ppm) 0- exposure.
However, a third group (seven individuals) was also exposed to air for 2 days
and to 784 ug/m (0.4 ppm) of 03 on the following day. The mean bronchial
responsiveness to inhaled histamine was increased following exposure to 784
3
ug/m (0.4 ppm) of 0~. Baseline SR (i.e., before histamine) after the
o dw
0.4-ppm exposure remained unchanged.
10-29
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As part of a study of repeated exposures to 0~ (discussed in detail in
Section 10.3), Kulle et al. (1982b) exposed two separate groups of subjects
(13 males, 11 females) for 3 hr to filtered air and then 1 week later to 784
3
ug/m (0.4 ppm) of Og. One hour before the end of exposure, 15 min of exercise
at 100 W was performed approximating a VV of four to five times resting values.
Bronchial reactivity to methacholine was assessed after each exposure and was
significantly enhanced (P <0.01) in both subject groups following exposure to
Og as compared to filtered-air exposure.
Two hypotheses have been proposed that are consistent with the observations
of increased airway reactivity to histamine and methacholine following 0,
exposure (Holtzman et al., 1979). The first suggests that 0- increases airway
epithelial permeability, resulting in greater access of histamine and metha-
choline to bronchial smooth muscle and vagal sensory receptors. The second
hypothesis suggests that 0^ or a byproduct of Og causes an increase in the
number or the binding affinity of acetylcholine receptors on bronchial smooth
muscle.
10.2.7 Mechanisms of Acute Pulmonary Effects
The primary acute respiratory responses to 03 exposure are decrements in
variables derived from measures of forced expiratory spirometry (volumes and
flows) and respiratory symptoms (notably, cough and substernal pain upon deep
inspiration). Altered ventilatory control during exercise (increased fp and
decreased Vy with VV remaining unchanged) and small increases in airway resis-
tance have also been observed.
3
Decrements in FVC observed at relatively high (1470-ug/m ; 0.75-ppm) 0_
concentrations have been associated with increases in RV" (Hazucha et al.,
1973; Silverman et al., 1976). Since increased RV occurs only at higher 0-
concentrations, it has been postulated by Hazucha et al. (1973) that this
increase results from gas trapping and premature airway closure caused by a
direct effect of 03 on small airway smooth muscle or by interstitial pulmonary
edema.
3
At DO concentrations of 980 ug/m (0.50 ppm) and less, decrements in FVC
are related to decreases in TLC without changes in RV. Decreased TLC results
from reductions in maximal expiratory position as indicated by the observation
that inspiratory capacity also .declines (Hackney eta!,, 1975c; Folinsbee
et al., 1977b; Folinsbee et al., 1978). Moreover, a decrease in inspiratory
10-30
-------
effort, rather than a decrease in lung compliance, most likely causes the
reduced inspiratory capacity resulting from 03 exposure (Bates and Hazucha,
1973; Silverman et al., 1976; Folinsbee et a!., 1978). Ozone is thought to
"sensitize" or stimulate irritant (rapidly adapting) and possibly other airway
receptors (Folinsbee et al., 1978; Golden et al., 1978; Holtzman et al., 1979;
McDonnell et al., 1983). This results in vagally mediated inhibition of
maximal inspiration, either involuntarily or due to discomfort (Bates et al.,
1972; Silverman etal.s 1976; Folinsbee etal., 1978; Adams -et al., 1981).
Stimulation of irritant receptors is also believed to be responsible for the
occurrence of respiratory symptoms (Folinsbee et al., 1977b; McDonnell et al.,
1983) and for alterations in ventilatory control (Folinsbee et al., 1975;
Adams et al., 1981; McDonnell et al., 1983). These hypotheses remain to be
proven.
Unless measured at absolute lung volumes, decrements in forced expiratory
flows (e.g., FEV, ,,, FEFpB-?1^ are difficult to interpret. A small portion
of the decrease in flow may be related to airway narrowing (Folinsbee et al.,
1978; McDonnell et al., 1983). Airway narrowing, as indicated by increased
airway resistance, probably results from either smooth-muscle contraction,
mucosal edema, or secretion of mucus. These can be initiated by vagally
mediated reflexes from irritant receptor stimulation, by the interaction of an
endogenous or exogenous substance with the vagal efferent pathway, or by the
direct action of 03 (or an Q~-induced, locally released substance) on smooth
muscle or mucosa (Folinsbee et al., 1978; Holtzman et al., 1979; McDonnell
et al., 1983). Beckett et al. (1985) effectively blocked Oy-induced increases
in airway resistance by having subjects breathe aerosols of atropine, a
muscarinic cholinergic antagonist, prior to exposure. These findings support
the conclusion that CL~induced increases in airway resistance involve parasym-
pathetic neural release of acetylcholine at the site of muscarinic receptors
on the smooth muscle of large airways and suggest mediation of this response
by vagal efferent reflex pathways.
It is probable that stimulation of airway receptors is an afferent mechan-
ism common to changes in airway resistance as well as changes in volumes and
flows. However, McDonnell et al. (1983) postulated the existence of more than
one mechanism for the normal processing of this sensory input, implying that a
different efferent mechanism is responsible for 0~-induced changes in lung
volume. They based this postulation on their observed lack of correlation
10-31
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between individual changes in lung volumes and airway resistance and on differ-
ences in the concentration-response curves for these variables. Kulle et al.
(1985) also observed a lack of correlation between individual changes in SG
and FVC (r = 0.09) and in SG_lf and FEV, (r = 0.24). Beckett et al. (1985)
clW X
provide strong support for the involvement of more than one mechanism in 03~
induced pulmonary responses. While pretreatment with atropine blocked in-
creased airway resistance in their Q3~exposed subjects, it had no effect on
the Qg-induced decreases in lung volumes (FVC, TLC). Thus, while these findings
indicate increased airway resistance is via a reflex stimulation of airway
smooth muscle, the failure of atropine to block the decrease in lung volumes
suggests a separate mechanism for this response which is not dependent on
functioning muscarinic receptors.
10.2.8 Preexisting Disease
According to the National Health Interview Survey for 1979 (U.S. Depart-
ment of Health and Human Services, 1981), there were an estimated 7,474,000
chronic bronchitics, 6,402,000 asthmatics, and 2,137,000 individuals with
emphysema in the United States. Although there is some overlap of about
1,000,000 in these three categories, it can be reasonably estimated that over
15,000,000 individuals reported chronic respiratory conditions. In clinical
studies that have been published, individuals with asthma or chronic obstructive
lung disease (COLD) do not appear to be more responsive to the effects of 0.,
exposure than are healthy subjects. Table 10-4 presents a summary of data from
Og exposure in humans with pulmonary disease.
Linn et al. (1978) assessed pulmonary and biochemical responses of 22
asthmatics (minimal asthma to moderately severe chronic airway obstruction
3
with limited disability) to 2-hr exposures to clean air, sham 03, and 392 \ig/m
(0.20 ppm) 0- with secondary stressors of heat (31°C, 35 percent rh) and
intermittent light exercise (VV = 2 x resting VV). Subjects continued the use
of appropriate medication throughout the study. Evaluation of responses was
not made in relation to the severity of the disorder present in these patients.
After baseline (zero 0^) studies were completed, subjects were exposed to
filtered air, a sham (i.e., some 0., was initially present in the exposure
chamber), and a 392- to 490-ug/m3 (0.20- to 0.25-ppm) 03 condition (a 3-day
control study was conducted over 3 days [0 ppm 03] on 14 of these individuals).
During each 2-hr exposure condition, subjects exercised for the first 15 min
10-32
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TABLE 10-4. OZONE EXPOSURE IN SUBJECTS WITH PULMONARY DISEASE
Ozone
concentration
pg/ir"
196
627
• 1960
235
235
353
490
-------
of each 30-min period. The exercise load was designed to double ventilatory
volumes, but because of the relative physical condition of the subjects there
was a wide variation in absolute VV so that inhaled 03 volume varied widely.
Standard pulmonary function tests were performed pre- and post-exposure. No
significant changes were noted except for a small change in TLC, which could
have been explained by typical daily variations in this function. A slight
increase in symptoms was also noted during 0- exposures, but this increase was
not statistically different from sham or control conditions. A spectrum of
biochemical parameters was measured in blood obtained only post-exposure. The
significant biochemical changes reported were small, and probably only represent
the normally found individual and group variability seen in these parameters
despite the investigators' suggestion that asthmatics may react biochemically
at lower 03 concentrations than nondiseased individuals.
Clinically documented asthmatics (16 years average duration of asthma) were
q
exposed either to filtered air or 490 jag/m (0.25 ppm) of 03 for 2 hr while
quietly resting (Silverman, 1979). Pulmonary functions were measured in these
17 asthmatics before and after exposure. Additional measurements of expiratory
flow-volume and ventilation were made at half-hour intervals during the 2-hr
exposures. The objective of the study was to study asthmatics irrespective of
the severity of their disease under the best degree of control that could be
achieved, i.e., in their normal conditions of life. Paired t-tests showed no
significant changes in lung-function measures related to 0~. However, some
individual asthmatics did respond to 03 exposure with a decrease in lung
function and an exacerbation of symptoms. One group of six subjects had
demonstrable decreases in function, but information concerning the stage
and/or development of their asthma was inadequately addressed. Such informa-
tion would have been extremely valuable in providing opportunities to study
this more susceptible portion of the asthmatic population further.
Koenig et al. (1985) exposed 10 adolescent asthmatics at rest to clean
3
air and to 235 ytg/m (0.12 ppm) 03. Exposure was via a rubber mouthpiece for
1 hr. The subjects, aged 11 to 18 years old, had a history of atopic (Type I,
IgE mediated) extrinsic asthma, characterized by documented reversible airways
obstruction, elevated serum IgE levels, positive reaction to inhaled dust,
mites, mold and/or pollen antigens, and exercise-induced bronchospasm. Because
of the relative severity of their asthma, subjects maintained their usual
medication therapy during testing. A comparable group of 10 healthy, nonatopic
10-34
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adolescents, aged 13 to 18 years old, was also similarly exposed. No significant
changes in pulmonary function or symptoms resulted from 0- exposure as compared
to exposure to clean air in either the healthy or asthmatic adolescent subjects.
Data from clinical studies have not indicated that asthmatics are more
responsive to 03 than are healthy subjects. However, the relative paucity of
studies and some of the experimental design considerations (subject popula-
tion, control of medication, exposure VF, appropriateness of pulmonary function
measurements) in the three studies that have been published suggest that the
responsiveness of asthmatics to 0~, relative to healthy subjects, may be an
unresolved issue. (This issue is treated in more detail in Chapter 12).
Linn et al. (1982a) studied 25 individuals (46 to 70 years old) with
COLD (emphysema and chronic bronchitis); 12 percent were nonsmokers and the
remainder were moderate to heavy smokers, with 11 individuals not smoking at
this time. All had chronic respiratory symptoms with subnormal forced expira-
tory flow rates; the mean FEV1/FVC ratio was 50 percent. Each subject.under-
3
went a control filtered air and a 235-ug/m (0.12-ppm) 0, exposure (randomized)
for 1 hr. These subjects first exercised for 15 min, then rested for 15 min,
then exercised for 15 min, and finally rested for 15 min. Exercise loads were
designed to elevate VE to 20 L/min (the physiological cost of this exercise to
each of the wide variety of subjects was not identified). Pre- and post-exposure
measurements of various pulmonary functions as well as arterial oxygen saturation
(SaOp) (Hewlett-Packard ear oximeter) were made. No significant differences in
forced expiratory performance or symptoms attributable to 0, were found. From
pre-exposure values at rest (normal saturations) to mid-exposure values during
exercise, mean SaOp increased by 0.65 ± 2.28 percent with purified air, but
decreased by 0.65 ± 2.86 percent with O,. This difference was significant.
However, this small decrement attributable to 0- was near the limit of resolu-
tion of the oximeter and was detected by computer signal averaging; thus, its
physiological and clinical significance is uncertain. Moreover, since many of
the COLD subjects were smokers, interpreting changes in SaOp without knowing
carboxyhemoglobin saturation (%COHb) is difficult. Preliminary reports of these
same data have also been published (Hackney et al., 1983).
Solic et al. (1982) conducted a similar study of 13 COLD patients with
the same age range (40 to 70 years) and with an approximately similar history
as those used by Linn et al. (1982a). Their protocol consisted of two exposure
3
days, one to filtered air (sham 03) and one to 392 ug/m (0.2 ppm) of 03 in a
10-35
-------
randomized fashion. Subjects maintained their usual patterns of activity,
drug use, etc., except for an imposition of no smoking for 1 hr prior to the
baseline studies. During the 2-hr exposures, the subjects exercised for
7,5 min every half-hour at a load sufficient to increase V> to 20 to 30 L/min
and an oxygen uptake of ~1 L/min. SaO? was measured during the last exercise
period. Pulmonary function measurements were made before and after exposure,
with FVC maneuvers also obtained at 1 hr of exposure. There was no statisti-
cally significant difference between the effects of air exposure versus 03
exposure in any of the spirometric measurement values or symptoms. The only
significant alteration resulting from 03 exposure was found in Sa02, where
decrements were reported in 11 of 13 subjects. Arterial saturation was 95.3
percent on filtered-air days and 94.8 percent on 0™ days. Again, knowledge of
%COHb is necessary to interpret these small changes in SaO^ correctly.
Kehrl et al. (1983) presented further information on individuals with
COLD. They restudied eight subjects from the group that Solic et al. (1982)
3
had exposed to 392 ug/m (0.2 ppm) of 0~. In this experiment the subjects
3
were exposed to 588 ug/m (0.3 ppm) of 0™ with a protocol similar to that used
by Solic et al. Data presented consisted of measurements made during the
•3 o
392-ug/m (0.2-ppm) exposure, as well as new data obtained during the 588-ug/m
(0.3-ppm) exposures. The second exposure occurred 6 to 9 months later. No
statistically significant 03~induced changes in respiratory mechanics or
symptoms were found in the COLD patients at either 03 concentration. Statisti-
cally significant changes in pulmonary function or symptoms were also not
o
observed when the number of COLD patients exposed to 588 ug/m (0.3 ppm) was
increased to 13 (Kehrl et al., 1985). Arterial oxygen saturation (ear oximeter)
measured in eight of these subjects during the last exercise interval was 0.95
percent less with 03 exposure ,as opposed to clean air exposure; this difference
nearly attained statistical significance (P = 0.07),
Linn et al. (1983) presented data on 28 COLD patients exposed for 1 hr to
3
0, 353, and 490 ug/m (0.0, 0.18, and 0.25 ppm) of 03> Subjects had chronic
respiratory symptoms; their mean FEVli0/FVC was 58%, indicating a mild degree
of obstruction for the group. Severity of COLD was classified as minimal for
12 subjects, moderate for 14 subjects, and severe for 2 subjects. Two subjects
had never smoked, while eleven were ex-smokers and 15 were current smokers.
Subjects continued use of chronic medication during the study but avoided
inhaled bronchodilators on testing days. Subjects exercised for the first
10-36
-------
and third 15-nrin periods and rested in the second and fourth periods. The
exercise performed varied in intensity as did the corresponding V>. Forced
expiratory function and symptoms measured before and after exposure were not
influenced by the exposures, confirming other reports that these individuals
do not respond to 03 exposures even at levels of 03 exceeding first-stage
alert levels. Arterial oxygen saturation (ear oximeter) was not changed
during the second exercise period and post-exposure. Medication and severity
of disease may explain the divergent results previously obtained. Differences
may also be related to the level of exercise and the resulting ventilation.
As a consequence, these patients may have inhaled comparatively small doses of
°3-
In all these studies on COLD patients, a wide diversity of symptoms and
ventilatory deficits was present. The common findings by Linn and Solic as to
small changes in SaC^ may be of some significance, although they were not
confirmed in subsequent studies at higher 0- concentrations. The exercise
performed in these studies was of very low intensity, and results from 0»
exposures where COLD patients exercised at higher intensities may be of in-
terest.
Konig et al. (1980) performed studies on 18 individuals, three of whom
suffered from COLD and one of whom had extrinsic allergic asthma (bronchial
symptom free,). The bronchial reactivity test used ACh as the test substance.
Specific airway resistance was measured in the patients after a 2-hr exposure
3
to 196 |jg/m (0.1 ppm) of GO as well as on a sham-exposure day. In two of the
three patients with COLD, increases in SR of 37 and 39 percent were recorded
after the 0., exposure. The asthmatic patient was not affected by exposure to
this level of 03. Whether the results presented represent the response to a
bronchial reactivity test immediately post-exposure or to the 0, exposure is
unclear. In addition, the small number of COLD subjects studied makes an
adequate evaluation difficult.
Kulle et al. (1984) exposed 20 chronic bronchitic smokers with some
o
evidence of airway obstruction for 3 hr to filtered air and 804 pg/m (0.41 ppm)
of 0,. Fifteen minutes of bicycle exercise at 100 W was performed during the
second hour of exposure. Forced vital capacity and FEV3 decreased significantly
with exposure to 03 compared to clean-air exposure; the decreases were small
in magnitude (< 3 percent), and respiratory symptoms were mild.
10-37
-------
One study (Superko et al., 1984) has attended the physiological responses
of patients with ischemia coronary heart disease (n = 6) randomly exposed to
o
0, 392, and 588 ng/m (0.0, 0.2, and 0.3 ppm) 0-. The diagnosis of coronary
disease was made by documented previous myocardial infarction, angiography, or
classic angina pectoris with reproducible ECG changes on graded exercise
testing. Each patient had a well defined and reproducible symptomatic angina
pectoris threshold. Three of the patients also exhibited evidence of obstruc-
tive pulmonary disease as indicated by FEVlt0/FVC of less than 70 percent;
smoking history of the subjects was not included. Each exposure was of 40 min
duration and consisted of 10 to 15 min gradually incremented exercise warm-up
followed by 25 to 30 min exercise at an intensity slightly below the subjects'
symptom threshold (mean VV = 42 L/min). Changes in pulmonary function (RV,
FVC, FEV1>0, FEF25-75^ f°ll°win9 exposures were not different among the three
conditions. Considering the magnitude of exercise VE (42 L/min), changes in
pulmonary function might have been expected. This lack of change may be
related to the relatively short exposure duration, small number of subjects,
or past smoking history of subjects. There were also no significant differences
in cardiopulmonary responses (V£, fR, V02, HR, SBP) during exercise, time to
onset of angina, or ischemic cardiovascular changes among the three conditions.
10.2.9 Other Factors Affecting Pulmonary Responses to Ozone
10.2.9.1 Cigarette Smoking. Smokers have been studied as a population group
having potentially altered sensitivity to oxidant exposures. Hazucha et al.
(1973) and Bates and Hazucha (1973) reported the responses of 12 subjects
divided by smoking history (six smokers and six nonsmokers) who were exposed
to 725 and 1470 ng/m3 (0.37 and 0.75 ppm) 0^. These young (23.6 ±0.7 years
old) individuals alternated 15 min of exercise at twice resting ventilation
and 15 min of rest during the 2 hr of the test. Pulmonary-function measure-
ments were made after each exercise period. The characteristic odor of 0, was
initially detectable by all subjects, but they were unaware of it after one-half
hour. Symptoms of typical oxidant exposures were reported by all subjects at
the termination of exposure. Decrements in FVC and FEF05-75% were 9reater f°r
nonsmokers after either 0, exposure, whereas smokers exhibited greater decre-
3
ments in FEV-. n and 50% V . Smokers exposed to 1470 ng/m (0.75 ppm) of 0-
j..u max , o
had a greater decrease in FEFp5-757 than ^^ nonsm°kers. The FEF?5-75% cnan9es
were much larger than the changes in FEV-, Q, regardless of 0, concentration,
10-38
-------
exposure duration, and smoking habit. Smoking history (not given specifically)
appeared to have different effects on the various pulmonary functions measured.
Kerr et al. (1975) exposed their subjects (10 smokers and 10 nonsmokers)
3
to 980 |jg/m (0.5 ppm) of 0, for 6 hr, during which time the subjects exercised
twice for 15 min each (V> = 44 L). For the remainder of the exposure time the
subjects were resting. Follow-up measurements were made 2 and 24 hr later. A
control day on which subjects breathed filtered air preceded the 0--exposure
day. The 24-hr post-exposure study was conducted in filtered air. Variance
analyses were used to interpret the data. In nonsmokers, significant decre-
ments in ventilatory function were observed following 0, exposure, being most
prominent for FVC and FEV^. Similar significant decrements were observed for
FEV-, and maximum mid-expiratory flow. No decrements were observed in mean
spirometry values in smokers as a group; in fact, all tests disclosed some
degree of improvement, with significance at the 5 percent level for MEF. A
significant reduction in SG and increase in R, were observed, for the most
part in nonsmokers experiencing subjective symptoms. (All nonsmokers experi-
enced one or more symptoms, while only 4 of 10 smokers had symptoms. These
four smokers had been smoking for relatively short periods of time.)
Six subjects (three nonsmokers and three smokers of 20 cigarettes/day for
2 to 3 years) were studied by Kagawa and Tsuru (1979a). These subjects were
exposed, no smoking on one day and smoking on another day, in either a flltered-
2
air environment or one containing 588 M9/m (0-3 ppm) of On. Two periods
(10 min in duration) during the 2-hr exposure were devoted to smoking a ciga-
rette. Smokers took one puff each minute (a total of 20 puffs) and nonsmokers
took one puff every 2 min (a total of 10 puffs). Both groups reported a
slight degree of dizziness and nausea after smoking. Measurements of SG
were obtained before and at the end of the first and second hours of exposure.
Bronchial reactivity to an ACh challenge was determined pre- and post-exposure.
The data presented in this report are minimal and sketchy, and statistical
analyses are inadequate. One of the six subjects (a smoker) was a nonresponder
to On. The remaining five responded in variable, fashions, and direction of
change could not be evaluated.
Kagawa (1983a) presented data on 5 smokers and 10 nonsmokers apparently
3
exposed to 294 [jg/m (0.15 ppm) of 03 for 2 hr to his standard intermittent
rest-exercise regime. SG was measured three times: at 1 and 2 hr during
exposure and also at 1 hr post-exposure. Significant decreases were found
10-39
-------
during exposure, i.e., 4 percent at 1 hr and 10 percent at 2 hr in nonsmokers,
No change from baseline occurred in the smokers. These data, which suggest
significant differences in response between smokers and nonsmokers exposed to
3
the low ambient level of 294 ug/m (0.15 ppm) of 0~, were not presented in
enough detail to permit in depth evaluation of the findings. Thus, the statis-
tical significance, if any, of these findings is unclear.
DeLucia et al. (1983) reported that smokers (six men and six women) were
relatively resistant to the oral inhalation of 588 (jg/m (0.3 ppm) of 03> Few
smokers detected the presence of Oq, whereas the majority of nonsmokers (six
men and six women) experienced significant discomfort. Pulmonary function
tests (FVC, FEV, and FEVyS-JS/t) were made pre- and post-exposure (within 15
min). Overall, the decrements in pulmonary functions were significant and the
authors attributed them to 0™. The relative insensitivity of smokers based on
these three measurements was indicated by the decrements of 5.9 to 12.9 percent
in nonsmokers, whereas smokers had 1.2 to 9.0 percent diminutions in these
functions. Additional analyses of their pulmonary function data suggested
3
that women nonsmokers were more sensitive to 588 ug/m (0.3 ppm) of 03 than
women smokers. No apparent differences were noted for the men.
Thirty-two moderate or heavy smoking subjects (26 men and 6 women) were
divided into four groups and exposed randomly to air alone, air plus smoking
(2 cigarettes/hr), 0- alone, and 0,, plus smoking (Shephard et al., 1983),
3 3
Four 03-exposure protocols were employed: 725 ug/m (0.37 ppm) and 1470 ug/m
(0.75 ppm) in subjects at rest; and 980 ug/m3 (0.50 ppm) and 1470 ug/m3 (0.75
ppm) with the subjects exercising during the last 15 min of each half hour
(the first 15 min of each period were at rest) for the 2-hr exposure. Carboxy-
hemoglobin was determined indirectly with the initial value being 1.61 percent.
In nonsmoking days, COHb decreased, while on smoking days COHb increased by as
much as 1.14 percent above the initial value. The increase in COHb was signi-
ficantly lower on those days when smoking was conducted in an 03 environment,
Ozone exposure alone (no smoking during exposure) resulted in the typical and
anticipated decreases in pulmonary functions (FVC, FEV-. ns 25% V__v, and 50%
J.. U maX
^m=«) as reported by others. However, the onset of these pulmonary changes
max
was slower and the response less dramatic compared to data obtained on non-
smokers. The authors offered two explanations to account for the diminished
response: (a) the presence of increased mucus secretion by these chronic
smokers may have offered transient protection against O^'s irritant effect or
10-40
-------
(b) the sensitivity of the airway receptors may have been reduced by chronic
smoking. The chronic effect of smoking induced a delay in the bronchial
irritation response to 0, exposure. There was no significant interaction
between cigarette smoking and responses to Q~.
10.2,9.2 Age and Sex Differences. Although a number of controlled human
exposures to 0~ have used both male and female subjects of varying ages, in
most cases the studies have not been designed to determine age or sex differ-
ences. In fact, normal young males usually provide the subject population,
and where subjects of differing age and sex are combined, the groups studied
are often too small in number to test for potential differences reliably.
Adams et al. (1981) attempted to examine the effects of age on response
to 0, in a small number (n=8) of nonsmoking males varying in age from 22 to 46
years. Comparison of the mean change in pulmonary function between the three
oldest subjects (33 to 46 years old) and the five youngest subjects (22 to 27
years old) revealed only small, inconsistent differences.
McDonnell et al. (1985b) exposed boys (n = 23), aged 8 to 11 yr, once to
3
0.0 and once to 235 pg/m (0.12 ppm) 0, in random order. The exposure protocol
was identical to that previously employed in their study of adult males
(McDonnell et al., 1983). Exposure duration was 150 min, and the subjects
" o
alternated 15-min periods of rest and heavy exercise (Vp = 35 L/min/m BSA)
during the first 120 min of exposure. Forced expiratory spirometry and respira-
tory symptoms were measured before and at 125 min of exposure; airway resistance
was measured before and at 145 min of exposure. Definitive statistical analyses
(paired t-tests) were restricted to testing changes in FEV^o and cough since
these variables demonstrated the most statistically significant changes in
their previous study of adults. Exploratory statistical analyses were performed
for changes in the other measured variables; however, these analyses cannot be
interpreted as tests of hypotheses. When compared with air exposure, a small
(3.4 percent) but significant decrement in FEV1>0 was observed, and exploratory
analyses suggest that decrements in FVC and forced expiratory flow rates may
also have occurred. No significant increase in cough was found due to 0,
exposure, and the other exploratory functions and symptoms did not change.
Results from this study of boys were compared to those of adult males exposed
under identical conditions (McDonnell, 1985c). Actually, exercise VV was less
in the children (39 L/min) than in the adults (65 L/min), however, when normal-
ized for BSA, both children and adults were exercising at similar ventilation
10-41
-------
rates (V"E/BSA of £ 35 L/min/m ). Statistical comparisons of the 03 effects
between children and adults were not performed due to the repeated measures
design in the children's study and the use of independent samples in the adult
3
study. With exposure to 235 |jg/m (0.12 ppm) 03, FEV1<0 decreased 3.4 percent
for the children as compared to a 4.3 percent decrease for the adults. Exposure
to Do caused an increase in cough reported by adults while children experienced
little or no increase in cough after CU exposure. These results indicate that
the effects of 0, exposure on lung spirometry were very similar for both
adults and children. However, adults had an increase in cough as a result of
exposure, while children reported no symptoms. The reason for this difference
is not known and needs further study.
Folinsbee et al. (1975), noting the lack of enough subjects for adequate
subdivision, attempted to make sex comparisons in a group of 20 male and 8
female subjects exposed to 0,. No significant differences could be shown in
either symptomology or physiological measurements between male and female
subjects.
Horvath et al. (1979) studied eight male and seven female subjects exposed
for 2 hr to 0, 490, 980, and 1470 ug/m3 (0, 0.25, 0.50, and 0.75 ppm) of 03-
Forced expiratory function decreased immediately following exposure to 980 and
o
1470 ug/m (0.50 and 0.75 ppm), with greater changes occurring at the highest
Do concentration. The average decrements in FEV-, n were 3.1 and 10.8 percent,
O x. U
respectively, for men, compared to 8.6 and 19.0 percent for women. Although
the data suggested that there may be potential sex differences in the extent
of changes in lung function due to 0, exposure, the results of an analysis of
variance for sex differences were not presented.
Gliner et al. (1983) presented data on 8 male and 13 female subjects
exposed for 2 hr on five consecutive days to 0, 392, 392, 392, and 823 or
980 ug/m (0, 0.20, 0.20, 0.20, and 0.42 or 0.50 ppm) of 03, respectively.
During exposure the subjects alternated 15 min of rest with 15 min of exercise
on a bicycle ergometer at loads sufficient to produce expired ventilations of
approximately 30 L/min for men and 18 L/min for women. Forced expiratory
measurements of FVC, FEV-, Q, and FEF25_75o/ indicated that prior exposure to
392 ug/m (0.20 ppm) of 0., had no effect on functional decrements occurring
3
after subsequent exposure to either 823 or 980 ug/m (0.42 or 0.50 ppm) of 03
on the fourth day (see Section 10.3). Although differences between men and
women were reported for all three measurements, with men having expected
10-42
-------
larger expired volumes and flows, there were no gender by pollutant interactions,
indicating that male and female subjects responded to 0- in a similar fashion.
DeLucia et a~l. (1983) reported on 12 men and 12 women (equally1'divided by
smoking history) exercising for 1 hr at 50 percent of their max V09 while
2
breathing 588 |jg/m (0.3 ppm) of 0- through a mouthpiece. Minute ventilation
for the men averaged 51 L/min and for the women 34.7 L/min. Women nonsmokers
who did not inhale as much 0, as nonsmoking men reported approximately a
fourfold increase in symptoms, while smoking women had less severe symptomatic
responses than smoking men. Although significant decrements in pulmonary
function were found for FVC (6.9 percent), FEV-, Q (7.9 percent), and FEf:25-75%
(12.9 percent), there were no significant differences between the sexes.
These investigators also found increases in f~ and decreases in VT during
exercise. These effects are similar to those reported by other investigators.
Gibbons and Adams (1984) reported the effects of exercising 10 young
women for 1 hr at 66 percent of max V09 while the women breathed 0, 297, or
3
594 ug/m (0, 0.15, or 0.30 ppm) of 0~. Significant decrements in forced
3
expiratory function were reported at 594 ng/m (0.30 ppm) of 03> Comparison
of these effects with the results from male subjects previously studied by the
authors (Adams et a!., 1981) indicated that the women appeared to be more
responsive to 03 even though the men received a greater effective dose than
the women. However, large individual variations in responsiveness were present
in all groups.
The possible enhancement of responses to 0, inhalation in female subjects
was investigated in the same laboratory (Lauritzen and Adams, 1985). Comparisons
between the sexes were made on a equivalent effective dose basis (0, concentra-
tions x Vp x exposure duration). Six young women exercised continuously for
1 hr at three exercise levels (23, 35, and 46 L/min) while being exposed to 0,
392, 588, and 784 (jg/m (0.0, 0.2, 0.3, and 0.4 ppm) 03. Significant, 0^-
dependent decrements were observed for FVC, FEV-,, and FEFpc.yc along with
changes in the exercise ventilatory pattern (i.e., increased fR and decreased
V-J-). A comparison of these effects with the responses reported in an equal
number of young adult males previously studied by the authors (Adams et al.,
1981) at the same total Q3 effective doses revealed significantly greater
effects on FVC, FEVp and fR for the females. Many, but not all, of the
gender differences were lost when responses were normalized for "relative
effective dose." The ratio of VQ,, max or TLC in males compared to females
was 0.68 and 0.69, respectively. Thus, when responses were expressed at the
10-43
-------
same relative exercise intensity or as dose per unit TLC, the gender
differences were diminished. Sample sizes were too small (n=6), however, to
quantitatively identify other specific factors that could account for the
apparent differences between male and female subjects exposed to 0,.
10.2.9.3 Environmental Conditions. Very few controlled human studies have
addressed the potential influence environmental conditions such as heat or
relative humidity (rh) may have on responses to 03. In fact, most exposures
have been performed under standard room temperature and humidity conditions
(20-25°C, 45-50 percent rh). A series of studies by Hackney et al. (1975a,b,c;
1977a) and Linn et al. (1978) were conducted at a higher temperature and lower
humidity (31°C, 35 percent rh) to simulate ambient environmental conditions
during smog episodes in Los Angeles. No comparisons were made to the effects
from 0, exposure at standard environmental conditions in other controlled
studies.
Folinsbee et al. (19775) studied the effects of a 2-hr exposure to
3
980 ug/m (0.5 ppm) of 0- on 14 male subjects under four separate environmental
conditions: (1) 25°C, 45 percent rh; (2) 31°C, 85 percent rh; (3) 35°C,
40 percent rh; and (4) 40°C, 50 percent rh. Wet bulb globe temperature (WBGT)
equivalents were 64.4, 85.2, 80.0, and 92.0°F, respectively. The subjects
exercised for 30 min at 40 percent of their max vX)« (Section 10.2.2 and Figure
10-1). Decreases in vital capacity and maximum expiratory flow during 0.,
exposure were most severe immediately after exercise. There was a trend for a
greater reduction when heat stress and 03 exposure were combined (WBGT=92.0°F),
but this effect was only significant for FVC. In a similar study with eight
3 3
subjects exposed to 980 ug/m (0.5 ppm) of 0- plus 940 |jg/m (0.5 ppm) of
nitrogen dioxide (NOp) (Folinsbee et al., 1981) (Section 10.6.3), the effects
of heat and pollutant exposure on FVC were found to be no greater than additive.
Part of the modification of 0- effects by heat stress was attributed to in-
creased ventilation since ventilatory volume and tidal volume increased signi-
ficantly at the highest thermal condition studied (40°C, 50 percent rh).
More recently, Gibbons and Adams (1984) had 10 trained and heat-acclimated
young women exercise for 1 hr at 66 percent of their maximum oxygen uptake
33 3
while breathing either 0.0 ug/m (0.0 ppm), 297 ug/m (0.15 ppm), or 594 ug/m
(0.30 ppm) of 0-. These studies were conducted at two ambient conditions,
i.e. 24° or 35°C. (Whether these are only dry bulb (db) temperatures or
represent WBGT values is unclear, since humidity was not reported). No signi-
3
ficant changes in any measured function were observed at 0 ug/m (0.00 ppm) or
10-44
-------
297 (jg/m (0.15 ppm) of 0~. Significant reductions in FVC, FEV-, n, TLC, and
o X • U '" Q
(P < 0.004) were reported as a consequence of exercising at 594 |jg/m
(0.30 ppm). Pre-post decrements in FVC, FEV-, Q, and 1^25-757 in the 0.30 ppm,
24°C environment were 13.7, 16.5, and 19.4 percent respectively, compared to
observed decrements of 19.9, 20.8, and 20.8 percent, respectively, in the
0.30-ppm Oo and 35°C condition. Only FVC differed significantly between the
two temperature conditions. Some subjects failed to complete the exercise
period in 35°C and 0.30 ppm Oo, and one subject could not finish the exercise
in 24°C and 0.30 ppm 0~. Subjects reported more subjective discomfort, (cough,
pain on inspiration, throat tickle, dizziness, and nausea) as 0- concentrations
increased. No other effects were reported, although it was observed that 0-
(0.30 ppm) exposure and ambient high temperature induced an interactive effect
on V. and fR.
10.2.9.4 V i tarn i n E S upp 1 erne n t at i o n . The possible protective effects of
vitamin E against short-term responses to 0- exposure have not been as exten-
sively investigated in humans as they have in animals (see Chapter 10). Only
two studies have been published on the pulmonary effects of vitamin E supple-
mentation in healthy subjects exposed to 0~. Both of these have failed to
show any protective effect against 0.,- induced changes in respiratory symptoms
and lung function (Hackney et al., 1981) or against j_n vivo lipid peroxidation
of the lung, as measured by decreased pentane production (Dillard et al . ,
1978). Additional studies demonstrating the lack of significant differences
between the extrapulmonary responses of vitamin-E supplemented and placebo
groups exposed to 0- are discussed in Section 10.6.
Dillard et al . (1978) studied ten vitamin E-sufficient adults breathing
filtered air or 588 \ig/m (0.3 ppm) 03 on a mouthpiece while continuously
exercising for 1 hr at 50 percent V02 . Pulmonary function was measured
before and after each exercise period. Expired air samples were collected
from five subjects at rest, after 5 min of exercise while breathing air, and
after 5, 15, 30, 45, and 60 min of exercise while breathing 0~. Expired
pentane, an index of lipid peroxidation, was measured during the pre- and
postexercise resting periods by gas chromatography. Exposure to 0, caused a
significant increase in RV and significant decreases in VC and FEV1<0- All
subjects reported throat tickle associated with 0- while some subjects experi-
enced symptoms such as chest tightness, cough, pain on deep inspiration,
congestion, wheezing, or headache. Exercise alone resulted in an increased
10-45
-------
production of pentane. However, there was no change in pentane production as
a result of exposure to 03 above that caused by the stress of exercise.
In a separate experiment, Dillard et al. (1978) tested six subjects
exposed to hydrocarbon-scrubbed air during an initial 5-min rest, during
graded exercise (25, 50, and 75 percent V02 ) for 20, 40, and 60 min, and
during a 20-min postexposure rest period. The same exercise protocol was
repeated after supplementation of the subjects with 400 IU dl-ortocopherol
three times a day for 2 weeks, which increased plasma tocopheral levels 240
percent. This treatment significantly reduced expired pentane levels at rest
and during exercise. No significant differences in pulmonary function were
obtained in response to 1 hr of exercise before and after vitamin E supplemen-
tation.
Hackney et al. (1981) studied the effects of a 2-hr exposure to filtered
2
air or 980 ug/m (0.5 ppm) 0, in healthy subjects (9 males and 25 females)
receiving either 800 IU dl-a-tocopherol (n = 16) or a similar appearing placebo
(n = 18) daily for 9 or 10 weeks. Mean serum vitamin E concentration increased
by 70 percent over this period in the supplemented group while the mean concen-
tration in the placebo group did not change significantly. During exposure,
the subjects alternated 15-min periods of rest and exercise at two times
resting ventilation. Pulmonary function and respiratory symptoms were evaluated
at the end of each exposure. No significant effects of vitamin E supplementa-
tion were found; however, a few of the supplemented male subjects showed a
possible beneficial effect. Since the sample size of male subjects was small
(n = 9), a follow-up study was performed. Subjects received either 1600 IU of
dl-a-tocopherol (n = 11) or placebo (n = 11) daily for 11 or 12 weeks. The
mean serum vitamin E concentration increased by 140 percent in the supplemented
group and 30 percent in the placebo group. Exposures took place on three
successive days during the last week of supplementation. The subjects were
exposed to filtered air for 2 hr on the first day, followed by 2-hr exposures
3
to 980 ug/m (0.5 ppm) 03 on the second and third days. The exercise protocol
during exposure was similar to that described above. Pulmonary function and
respiratory symptoms were evaluated at the end of each exposure. Ozone caused
significant decreases in FVC, FEV1<0» FEV25%» FEF50%' AN2' and TLC in both the
vitamin E-supplemented and placebo groups. The mean changes were not signifi-
cantly different between groups. Although symptoms did not significantly
increase with 03 exposure, there were no differences between the vitamin E and
10-46
-------
placebo groups. Results from these studies do not support a protective effect
of vitamin E supplementation against short-term pulmonary responses in human
subjects exposed to 0.
10.3 PULMONARY EFFECTS FOLLOWING REPEATED EXPOSURE TO OZONE
Just as pulmonary function decrements following a single exposure to 03
are well documented, several studies of the effects of repeated daily exposures
to 0, have also been completed (Table 10-5). In general, results from these
studies indicate that with repeated daily exposures to 03, decrements in pul-
monary function are greatest on the second exposure day. Thereafter, on each
succeeding day decrements are less than the day before, and on about the fifth
exposure day small decrements or no changes are observed. Following a sequence
of repeated daily exposures, there is a gradual time-related return of the
susceptibility of pulmonary function to 03 exposure similar to that observed
prior to repeated exposures. Repeated daily exposure to a given low concentra-
tion of Oo does not affect the magnitude of decrement in pulmonary function
resulting from exposure at higher 0, concentration.
All the reported studies of repeated responses to 0- have used the term
"adaptation" to describe the attenuation of decrements in pulmonary function
that occurs. Unfortunately, since the initial report of such attenuation used
adaptation, each succeeding author chose not to alter the continued use of
this selected term. In the strict sense, adaptation implies that changes of a
genetic nature have occurred as a result of natural selection processes, and
as such, use of adaptation in the prior context is a misnomer.
Other terms (acclimation, acclimatization, desensitization, tolerance)
have been recommended to replace adaptation and perhaps are more suitable.
However, the correct use of any of these terms requires knowledge of (1) the
physiological mechanisms involved in the original response, (2) which mecha-
nisms are affected and how they are affected to alter the original response,
and/or (3) whether the alteration of response is beneficial or detrimental to
the organism. The present state of knowledge is such that we do not fully
understand the physiological pathway(s) whereby decrements in pulmonary func-
tion are induced by 0- exposure, and of course, the pathways involved in
attenuating these decrements and how they are affected with repeated 03 exposure
are even less understood. Moreover, while attenuation of 0~-induced pulmonary
10-47
-------
TABLE 10-5. CHANGES IN LUNG FUNCTION AFTER REPEATED DAILY EXPOSURE TO AMBIENT OZONE
Ozone
Concentration
H
O
>£>
CO
Hi/in4
392
392
392
686
784
784
784
784
804
823
921
980
980
ppm
0.2
0.2
0.2
0.35
0.4
0.4
0.4
0.4
0.41
0.42
0.47
0.5
0.5
Measurenent3'
method
CHEM, NBKI
UV, UV
UV, UV
CHEM, NBKI
CHEM, NBKI 4 HAST, NBKI
CHEM, NBKI 4 MAST, NBKI
CHEM, NBKI & MAST, NBKI
UV, NBKI
CHEM, NBKI & UV, UV
UV, UV
UV, UV
CHEM, NBKI
CHEH, NBKI
Exposure duration
and activity
2 hr
2 hr
2 hr
2 hr
3 hr
3 hr
3 hr
2 hr
3 hr
2 hr
2 hr
2 hr
2.5
, IE(30)
, IE(18 4 30)
, IE(18 & 30)
, IE(30)
, IE(4-5 x R)
, IE(4-5 x R)
, IE(4-5 X R)
, IE(2 x R)
, IE(4-5 x R)
, IE(30)
, IE(3 x R)
, IE(30)
hr, IE(2 x R)
Ho. of
subjects
10
21
9d
10
14
13e
7f
20g
24
ll(7)h
8
6
Percent change in FEV^.o on
consecutive exposure days
First
+1.4
-3.0
-8.7
-5.3
-10.2
-9.2
-8.8
ttt
-2.8
-21.1
-11.4
-8.7
-2.7
Second
+2.7
-4.5
-10.1
-5.0
-14.0
-10.8
-12.9
t
-0.9
-26.4
-22.9
-16.5
-4.9
Third
-1.6
-1.1
-3.2
-2.2
-4.7
-5.3
-4.1
0
0
-18.0
-11.9
-3.5
-2.4
Fourth Fifth
...
—
—
-3.2 -2.0
-0.7 -1.0
-3.0 -1.6
-0.6 -1.1
-6.3 -2.3
-4.3
—
-0.7
References
Folinsbee et al., 1980
Gliner et al., 1983
Gliner et al., 1983
Folinsbee et al., 1980
Parrel! et al., 1979
Kulle et al., 1982b
Kulle et al., 1982b
Dimeo et al., 1981
Kulle et al., 1984
Horvath et al . , 1981
Linn et al., 1982b
Folinsbee et al., 1980
Hackney et al., 1977a
Measurement methods: MAST = Kl-couloraetric (Mast meter); CHEM = gas-phase chemiluminescence, UV ;
Calibration methods: NBKI = neutral buffered potassium iodide; UV = UV photometry.
Exposure duration and intermittent exercise (IE) intensity were variable; minute ventilation (VE)
ventilation.
Subjects especially sensitive on prior exposure to 0.42 ppM 0| as evidenced by a decrease in FEV1
These nine subjects are a subset of the total group of 21 individuals used in this study.
eBronchial reactivity to a methacholine challenge was also studied.
Bronchial reactivity to a histamine challenge (no data on FEV^o). SR measured (t). Note that on third
day histamine response was equivalent to that observed in filtered air "see text).
^Subjects were smokers with chronic bronchitis.
Seven subjects completed entire experiment.
1 ultraviolet photometry.
given in L/min or as a multiple of resting
o of more than 2Q&
-------
function decrements appears to reflect protective mechanisms primarily directed
against the acute and subchronic effects of the irritant, Bromberg and Hazucha
(1982) have also speculated that this attenuation may reflect more severe
effects of 0~ exposure, such as cell injury. Therefore, in the following
discussion of specific studies, results will be presented without use of a
specific term to describe observed phenomena generally. The use of response
to imply pulmonary decrements resulting from Q~ exposure and changes in response
or responsiveness of the subject to imply alterations in the magnitude of
these decrements will be retained.
Hackney et al. (1977a) performed the initial experiments that demon-
strated that repeated daily exposures to 0., resulted in augmented pulmonary
function responses on the second exposure day and diminution of responses
after several additional daily exposures. Six subjects who in prior studies
had demonstrated responsiveness to 0, were studied during a season of low smog
to minimize potential effects from prior 0« exposure. All but one subject had
3
a history of allergies. They were exposed for approximately 2.5 hr to 980 pg/m
(0.5 ppm) of Og for four consecutive days after .one sham exposure. Ambient
conditions in the chamber were 31°C db and 35 percent rh. During the first
2 hr, light exercise (of unknown level) was performed for 15 min every 30 min.
The last half hour was used for pulmonary testing. Small decrements occurred
in FVC and FEF-^c and differed among the five test days. Additional statistical
evaluation showed that these differences were related to the larger decrements
in function observed on the second 0~ exposure day. Other pulmonary functions,
i.e., total airway resistances (R.) and nitrogen washout (ANp), also improved
on latter exposure days, but the differences were not statistically significant.
The pattern of change clearly indicated that subjects had lesser degrees of
pulmonary dysfunction by the third day of exposure, and these functions were
nearly similar on day 4 to values found on the pre-exposure day to filtered
air. In this small subject population, considerable variability in responses
was noted (one subject with no history of allergies showed no pulmonary decre-
ments, while another subject had a large reduction in FVC and FEV-, and an
increase in AN« on day 2 with a return of responses to near control levels on
day 4).
Parrel! et al. (1979) investigated the pulmonary responses of 14 healthy
nonsmoking (10 men and 4 women) subjects to five consecutive, daily 3-hr expo-
sures to filtered air or 0,,. In the first week, subjects were studied in a
10-49
-------
2
filtered-air environment, followed in a second week with exposures to 784 [jg/m
(0.4 ppm) of 0,,. Pulmonary function (FVC, FEV, , FEV-, SG,,,, and FRC) was
O J. u aw
determined at the end of the 3-hr exposures. One bout of exercise (VV measured
on one subject = 44 L/min) was performed after 1.5 hr of exposure. Statistical
evaluations used a repeated measures analysis of variance for significant
differences between the control and Q3 exposure weeks, using each day of each
exposure to make the comparisons. The analysis of variance showed that FVC,
FEV.., FEV3, and SG differed significantly between control and Q~ exposure
weeks. No changes in FRC were found. In the 0- exposure, SG_tl decreased
•3 ctw
significantly only on the first 2 days; this response was similar to air
exposure day values on the last 3 days. Significant decreases in FVC occurred
on the first three days only; however, the decrements were significantly
greater on the second day than on the first. Decrements in FEV-, Q and FEV3 „
were substantial on the first day and increased on the second day of exposure.
These decrements diminished to air exposure levels by the third day (FEV- Q)
and fourth day (FEV-, Q) of 03 exposures. The severity of symptoms generally
corresponded to the magnitude of pulmonary function changes. Symptoms were
maximal on the first 2 days, decreasing thereafter with only one subject being
symptomatic on the final day of exposure to 0,. Reporting of symptoms was
maximal on the second 0- day. These investigators noted that five consecutive
o „
days of exposure (10 subjects) to 588 H9/i" (0.3 ppm) of 03 failed to induce
significant changes in FVC or SG , implying that measurable changes are
3W
likely to occur in pulmonary function at 0~ concentrations between 588 and
3
784 ng/m (0.30 and 0.4 ppm) with 2 hr of exposure at these exercise levels.
Folinsbee et al. (1980) exposed healthy adult males for 2 hr in an environ-
mental chamber at 35QC and 45 percent rh to filtered air on day 1, to 03 on
days 2 through 4, and to filtered air on day 5. Three groups of subjects were
used, each exposed to a different concentration of 03: group 1 (n=10), 392
pg/m3 (0.20 ppm) of QS; group 2 (n=10), 686 (jg/m3 (0.35 ppm) of 03; group 3
(n=8), 980 pg/m (0.50 ppm) of 0^. Subjects alternately rested and exercised
at a Vr of 30 L/min for 15-min periods. There were no significant acute or
3
cumulative effects of repeated exposure to 392 jjg/m (0.20 ppm) of 0,. With
3
exposure to 686 jjg/m (0.35 ppm) of 03, decrements in forced expiratory varia-
bles appeared on the first 03 exposure day. Similar decrements occurred on
the second 03 exposure day, although there was no significant difference in
responses observed on the first two exposure days. On the third day of expo-
sure the pulmonary function changes were of lesser magnitude than on the first
10-50
-------
2 days. In group 3, marked decrements in pulmonary function occurred (FEV-, n
o ••-• U
decreased 8.7 percent) after the first exposure to 980 [jg/m (0.50 ppm) of 0.,;
these decrements were even greater (FEV-, Q decreased 16.5 percent) after the
second 03 exposure (Figure 10-3). While not totally abolished, an attenuation
of these decrements (FEV-, Q decreased 3.6 percent) was observed following the
third GO exposure. The subjects claimed the most discomfort for the second 03
exposure. Many noted marked reductions in symptoms on the third consecutive
day of exposure to 0,. Two additional subjects were exposed to 980 [jg/m
(0.50 ppm) of DO for four consecutive days. Although effects of 0, on pulmonary
function were observed on the first two days of exposure, few effects were
seen on the third day, and no effect was observed on the fourth day. The
authors concluded that there were some short-term (2-day) cumulative effects
of exposure to concentrations of 0, that produced acute functional effects.
This response period was followed by a period in which there was a marked
lessening of the effect of 03 on pulmonary function and on the subjective
feelings of discomfort associated with exposure to 03. The subjects for these
studies represented a broad population mix in that some subjects had a prior
history of respiratory difficulties, some essentially had no past respiratory
history, and approximately two-thirds had prior experience with pollutant
exposure.
Horvath et al. (1981) performed studies designed not only to determine
3
further the influence of five consecutive days of exposure to 823 [jg/m (0.42
ppm), but to estimate the persistence of the attenuation of pulmonary responses.
During the 125 min of exposure, 24 male subjects alternately rested and exer-
cised (Vr = 30 L/min) for 15-min periods. Measurements of pulmonary functions
were made daily pre- and post-exposure. A filtered-air exposure was conducted
during the week prior to the 03 exposures. Selected subjects were then randomly
assigned to return after 6 to 7, 10 to 14, and 17 to 21 days for a single
exposure to 03. Ambient 03 levels in the locations where the subjects lived
seldom exceeded 235 (jg/rn (0.12 ppm). The major pulmonary function measurements
made"and subjected to statistical analysis on these subjects were FVC, FEV-,,
and FEF25-75%' Changes with time in all three measurements were similar and
major emphasis was directed toward FEV-, changes. Significant interaction
effects occurred between the two within-subject factors (day of exposure and
pre- and post-exposure change in FEV-^). The interaction resulted primarily
from the post-exposure FEV-, data, which revealed a "U"-shaped pattern across
10-51
-------
A. GROUP 2
CO
m
(A
5.0
O
i" 4.6
ui
WLTEREDI
AIR
DAY1
da) I i i |
OZONE
DAY 2
, ,
OZONE
DAY 3
S i i i i I
| i i i i |
OZONE
DAY 4
•FILTERED'
AIR
DAYS _
1 2 3 4 fc Jg1234£g. 1234&g1234£
o a- o °- o a- Q
D. Q. Q- Q.
. i
1 2 3 4
o
B. GROUP 3
5.2
5.0
4.8
4.6
2
2
-------
days during 0- exposure. A significant decline appeared on day 1 (+1.7 to
-63 percent, mean = -21 percent), and a greater significant decline appeared
on day 2 (-26.4 percent). On day 3 the decrement in FEV., had returned to that
observed on day 1, but it was still significantly greater than during room air
exposure. The decrements in FEV-, from preexposure to postexposure on days 4
and 5 were no longer significant although the absolute value of postexposure
FEVi continued to be significantly less than the initial filtered air exposure.
Subjective symptoms followed a similar pattern, with subjects on the fifth day
indicating that they had not perceived any Og, Two subjects showed little
attenuation of response to 0,, and one subject was not affected by the 03
exposures. Subjects who were more responsive on the first day of exposure
required more consecutive days of daily exposure to attenuate response to 0.,.
All 24 subjects returned for an additional exposure to CU from 6 to 21 days
later; of these, only 16 were considered to be sensitive to GO, and their data
are shown in Figure 10-4. Although the number of subjects in each repeat
exposure was small, it was apparent that attenuation of response did not
persist longer than 11 to 14 days, with some loss occurring within 6 to 7
days. In general, these authors made some interesting observations: (1) the
time required to abolish pulmonary response to 03 was directly related to the
magnitude of the initial response; (2) the time required for attenuation of
pulmonary responses to occur was apparently inversely related to the duration
of attenuation and (3) in one individual, attenuation of pulmonary response to
0~ persisted up to 3 weeks. The mechanism responsible for attenuation of re-
sponse was not elucidated, although two mechanisms were postulated, i.e.,
diminished irritant receptor sensitivity and increased airway mucus production.
Linn et al. (1982b) also studied the persistence of the attenuation of
pulmonary responses that occurs with repeated daily exposures to Q~. Initial-
ly, 11 selected subjects, known to have previously exhibited pulmonary decre-
ments in response to 0., exposure, were exposed for 2 hr daily for four conse-
3
cutive days to 921 |jg/m (0.47 ppm) 0,. Exposure consisted of alternating
15-min periods of moderate exercise (VV = 3 x resting VV) and rest. An expo-
sure to filtered air, under otherwise equivalent conditions, was conducted on
the day prior to the first 03 exposure. The pattern of change in pulmonary
response to 0~ was similar to that previously reported for repeated daily
exposures. For example, while the initial exposure to filtered air produced
essentially no change, on the first 0- exposure day FEV\ decreased 11 percent,
10-53
-------
FILTERED
AIR
PRE-EXPOSURE
a
DAILY 2-hr EXPOSURE
TO 0.42 ppm Os
1 2 3 "4 5
0.42 ppm O3,
3 WKS
POST-EXPOSURE
Figure 10-4. Percent change (pre-post) in 1-
sec forced expiratory volume (FEV: 0), as the
result of a 2-hr^xposure to 0.42 ppm ozone.
Subjects were exposed to filtered air, to
ozone for five consecutive days, and exposed
to ozone again: (A) 1 wk later; (B) 2 wks
later; and (C) 3 wks later.
Source: Horvath et al. (1981).
10-54
-------
with a further decline to 23 percent on the second day, returning to approxi-
mately 11 percent on the third day. By the fourth day, the mean response was
essentially equivalent to that observed with exposure to filtered air. While
most of the subjects demonstrated attenuation of response (complete data sets
on only seven subjects), the response of one subject, who may have had a
persistent low-grade respiratory infection, never diminished. Two others
showed relatively little response to the initial daily exposures, but showed
some severe responses during follow-up exposures. This pattern was not to be
unexpected, based on other studies demonstrating similar atypical responses.
To evaluate persistence of attenuated response, subjects repeated 03 exposures
under the above conditions 4 days after the repeated daily exposures and
thereafter at 7-day intervals for five successive weeks. Four days after the
repeated daily exposures, decrements in pulmonary function in response to 0-
exposure were not significantly different from the first exposure (FEVl40
decreased 11.4 percent on the first day and decreased 8.6 percent four days
after the repeated exposures). The decrement in FEV1<0 on the subsequent
weekly CU exposures averaged 13.5 percent. Subjective symptoms generally
paralleled lung-function studies, but were significantly fewer on the 03
exposure which Occurred four days after the repeated exposures. Since attenua-
tion of pulmonary responses to 0- may fail to develop or may be reversed
quickly in the absence of frequent exposure, these authors questioned the
importance of attenuation of response in the public health sense.
Following the design of an earlier protocol (Parrel! et al., 1979), Kulle
et al. (1982b) exposed 24 subjects (13 men and 11 women) for 3 hr on five con-
secutive days beginning on Monday to filtered air during week 1 and to 784
3
ug/m (0.4 ppm) of 0, during week 2. During week 3, they exposed 11 subjects
3
to filtered air on the first day and to 784 n9/m (°-4 ppm) of 03 on the
second day, while they exposed the remaining 13 subjects for 4 days to filtered
o
air and then to 784 jjg/m (0.4 ppm) of 03 on the fifth day. One hour prior to
the end of each exposure, the subjects performed 15 min of exercise at 100 W
(VV = 4 to 5 times resting VV). Although the magnitude of decrement was
notably less, the patterns of change in responses of FVC and FEV-. were similar
to those observed in previous studies, i.e., attenuation of response occurred
during the 5 days of exposure. Attenuation of response was partially reversed
4 days after and not present 7 days after repeated daily exposures. These
results agree with those of Linn et al. (1982b), but contrast to those of
10-55
-------
Horvath et al. (1981). Since the magnitude of decrements in pulmonary func-
tion (and also effective-exposure dose) was notably less in this study than in
that of Horvath et al. (1981), these authors have suggested that the duration
of attenuation of pulmonary response to 03 may be related to the magnitude of
decrement in response observed with the initial exposure to 0-.
Gliner et al. (1983) performed a study to determine whether daily repeated
3
exposures to a low concentration of 03 (392 ug/m ; 0.20 ppm) would attenuate
pulmonary function decrements resulting from exposure to a higher 03 concentra-
tion (823 or 980 ug/m3; 0.42 or 0.50 ppm). Twenty-one subjects (8 male,
13 female) were exposed for 2 hr on five consecutive days to filtered air
(0.0 ppm 03) on day 1, to 392 ug/m3 (0.20 ppm) of GS on days 2, 3, and 4, and
to 823 or 980 ug/m (0.42 or 0.50 ppm) of 0, on day 5. For comparison, subjects
who were exposed to 0.42 or 0.50 ppm of 03 were exposed to the same 0^ concen-
tration under identical conditions 12 weeks prior to or 6 to 8 weeks following
the daily repeated exposures. During exposure, subjects alternately rested
for 15 min and exercised for 15 min. Minute ventilation was 30 L/min for men
and 18 L/min for women. Forced expiratory spirometry (FVC) was performed
before and 5 min after the last exercise period. Analysis of continued results
from all subjects indicated that three consecutive daily exposures to a low Q~
3
concentration (392 ug/m ; 0.20 ppm) did not alter expected pulmonary function
response to a subsequent exposure to a higher 0~ concentration (823 or 980
3
ug/m ; 0.42 or 0.50 ppm).
Subjects were divided into two groups based on the magnitude of their
response to the acute exposure to 823 or 980 ug/m (0.42 or 0.50 ppm) CL.
Nine subjects were considered to be responsive (FEV-, decrements averaged
34 percent), and nine subjects were considered to be nonresponsive (FEV-,
decrements averaged less than 10 percent). Statistical analysis based on this
grouping indicated that responsive subjects exhibited pulmonary function
decrements after both their first and second, but not their third, exposure to
q
392 ug/m (0.20 ppm); decreases in FVC and FEV-, were about 9 percent. No
3
significant effects of 392-ug/m (0.20-ppm) 03 exposure were found in the
nonresponsive group. In both groups, repeated exposures to 0.20 ppm of 0, had
no influence on the subsequent response to the higher ambient 0, exposure (823
3
or 980 ug/m ; 0.42 or 0.50 ppm). Note that repeated exposures to the low 03
concentration for only three consecutive days may have constituted insufficient
total exposure (some combination of number of exposures, duration of exposures,
10-56
-------
Vr, and 0, concentration) to affect pulmonary function decrements resulting
from exposure to higher 0~ concentrations. Additional studies, with considera-
tion of total exposure and component variables, are needed to clarify this
issue, .
Haak et al. (1984) made a similar observation as Gliner et al. (1983)
that exposure to a low effective dose of CL did not attenuate the response to
a subsequent exposure at a higher effective dose of 0~. The pattern of pulmonary
function decrements was evaluated following repeated daily 4-hr exposures to
•n
784 ug/m (0.40 ppm) of 03 with two 15 min periods of heavy exercise (Vr = 57
L/min). As expected, pulmonary function decrements were greater on the second
of five consecutive days of 0- exposure; thereafter, the response was attenu-
3
ated. Exposure at rest to 784 |jg/m (0.4 ppm) of 0_ for two consecutive days
had no effect on pulmonary function. Ozone exposure on the next two succeeding
days with heavy exercise produced pulmonary function decrements similar to
those observed previously in this study for the first two days of exposure to
ozone.
. Kulle et al.. (1984) studied 20 smokers with chronic bronchitis over a
3-week period. The subjects breathed filtered air for 3 hr/day on Thursday
3
and Friday of week 1 (control days), were exposed to 804 pg/m (0.41 ppm) 0~
for 3 hr/day on Monday through Friday of week 2, and on week 3 breathed fil-
tered air on Monday, then were re-exposed to 0.41 ppm 03 on Tuesday. Bicycle
ergometer exercise was performed at 2 hr of exposure at an intensity of 100 W
for 15 min (Vr ^ 4-5 times resting). Spirometric measurements and recording
of symptoms were made at the completion of all exposures. Small but signifi-
cant decrements in FVC (2.6 percent) and FEV-, (3.0 percent) occurred on the
first day only of the 5-day repeated exposures as well as on re-exposure 4 days
following cessation of the sequential exposures. Symptoms experienced were mild
and did not predominate on any exposure days. These results indicate that in-
dividuals with chronic bronchitis also have attenuated responses with repeated
exposures to 0~ that persist for no longer than 4 days. These results for
smokers with chronic bronchitis contrast to those reported by the same investi-
gators for normal nonsmoking subjects exposed under nearly identical conditions
(Kulle et al., 1982b). Their normal subjects demonstrated larger decrements in
FVC (8 percent) after the first and second exposures; thereafter the response
was attenuated. This attenuation of response persisted beyond 4 days, and only
with re-exposure 7 days after repeated exposures did significant decreases in
10-57
-------
FVC once again appear. These data also support the contention that persistence
of an attenuated pulmonary response to 0™ is related to the magnitude of the
initial response.
Bedi et al. (1985.) performed a study to determine if lung responsiveness
to ozone after an initial exposure would persist for 48 hr. Six healthy, non-
smoking audits (5 females and 1 male) were exposed for 2 hr to filtered air on
3
the first day, to 882 pg/m (0.45 ppm) 0~ on the second day (day 1), and two
days later to a second exposure to 0.45 ppm 03 (day 2). Subjects alternately
rested and exercised at a VV of 27 L/min for 20-min periods. Forced expiratory
spirometry was performed before the exposure started and 5 min after each
exercise period. There were significant pulmonary function decrements on both
03 exposure days. The decrements in FVC (DAY 1 = 9.7 percent; DAY 2 = 15.7
percent), FEVj (DAY 1 = 13.3 percent; DAY 2 = 22.8 percent), and FEfr25-75%
(DAY 1 = 19.6 percent; DAY 2 = 30.4 percent) were 6.0, 9.5, and 10.8 percent
larger, respectively, after the day 2 exposure than after the day 1 exposure.
Increased pulmonary responsiveness to 03 was, therefore, still present when
exposures were separated by 48 hr. It is not known, however, if this pattern
of every-other-day exposures would lead to attenuation of the response, as has
been demonstrated for consecutive days of exposure.
Folinsbee and Horvath (1986) studied the time course of hyperresponsive^-
ness following acute ozone exposure. Four groups of healthy, nonsmoking
3
adults (n=6,6,7,7) were exposed for 1 hr to 490 ug/m (0.25 ppm) 03 and then
reexposed at 12, 24, 48, or 72 hr, respectively. Subjects exercised continuous-
ly at a vV of 63 L/min during exposure. Forced expiratory spirometry and
maximal voluntary ventilation were performed prior to and within 10 min after
exposure. As expected, 0- exposure was associated with a significant decline
in FVC, FEVp FEfr25-75%1 FEf:75-85%5 MVVj and IC' The 9eneral Pattern for
pulmonary function showed an increased responsiveness to 0- on the second
exposure if it occurred within 24 hr. For example, the decrements in FEV-,
were 6 percent larger in the 12-hr group (EXP 1 = 13 percent; EXP 2 = 19
percent) and 14 percent larger in the 24-hr group (EXP 1 = 20 percent; EXP 2 =
34 percent). An increased responsiveness to 03 persisted in some subjects for
48 hr but it appeared to be lost within 72 hr. Symptoms generally paralleled
the changes in lung function. Differences in persistence of responsiveness to
Q3 between the Folinsbee and Horvath (1986) and Bedi et al. (1985) studies are
likely related to the different 03 concentrations used and the magnitude of
the initial 03~induced decrements in lung function.
10-58
-------
To determine if nonspecific bronchial reactivity is a factor involved in
the attenuation of pulmonary responses to Q3, Dimeo et al. (1981) evaluated
the effects of single and sequential Q3 exposures on the bronchomotor response
to histamine. To determine the lowest concentration of Q3 that causes an
increase in bronchial reactivity to histamine and to determine whether adapta-
tion to this effect of Og develops with repeated exposures, they studied 19
healthy, nonsmoking normal adult subjects. Bronchial reactivity was assessed
by measuring the rise in specific airway resistance (ASR ) produced by inhala-
aW
tion of 10 breaths of histamine aerosol (1.6-percent solution). In five
subjects, bronchial reactivity was determined on four consecutive days without
exposure to 0~ (group I). In seven other subjects (group II), bronchial
reactivity was assessed on two consecutive days; subjects were exposed to
3
392 ug/m (0.2 ppm) of 03 on the third succeeding day and bronchial reactivity
was determined after exposure. Seven additional subjects (group III) had
bronchial reactivity assessed for two consecutive days and then again on the
2
next three consecutive days after 2-hr exposures to 784 |jg/m (0.4 ppm) of Q~-
Exposures consisted of alternating 15-min periods of rest and light exercise
(Vp = 2x resting VV). Pre-exposure bronchial reactivity of the groups was the
same, and no change in bronchial reactivity occurred in group I tested repeated-
ly but not exposed to 0«. An increase in ASR ,, provoked by histamine was
•5 -j olw o
noted after the first exposure to 784 ug/m (0.4 ppm) but not to 392 ug/m
(0.2 ppm) of 03. With three repeated 2-hr exposures to 0.4 ppm on consecutive
days, the ASR produced by histamine progressively decreased, returning to
pre-exposure values after the third exposure. Their results indicated that
with intermittent light exercise, the lowest concentration of ozone causing an
increase in bronchial reactivity in healthy human subjects was between 392 and
3
784 ug/m (0.2 and 0.4 ppm), and that attenuation of this effect of 03 developed
with repeated exposures. The lowest concentration of 03 (identified in other
studies using light or moderate exercise) that caused changes in symptoms,
3
lung volumes, or airway resistance was also between 392 and 784 ug/m (0-2 and
0.4 ppm), and the time course for the development of attenuation of these
responses to 03 was similar to that observed in this study. These authors
propose that the appearance of symptoms, changes in pulmonary function, and
the increase in bronchial reactivity may be related and caused by a change in
the activity of afferent nerve endings in the airway epithelium.
10-59
-------
Kulle et al. (1982b) also evaluated the effects of sequential 0~ exposure
on bronchial reactivity. Nonsmoking subjects (n = 24) were exposed for 3 hr
on five consecutive days each week to filtered air during week 1 and to 784
3
jjg/m (0.4 ppm) 0_ during week 2. During week 3, they exposed 11 subjects to
3
filtered air on the first day and to 784 (jg/m (0.4 ppm) 0~ on the second day,
while they exposed the remaining 13 subjects for 4 days to filtered air and
2
then to 784 pg/m (0.4 ppm) 03 on the fifth day. A 15-min period of exercise
at 100 W (VV = 4 to 5 times resting VV) was performed 1 hr prior to the end of
each exposure. After each exposure, a provocative bronchial challenge test
was performed to determine bronchial reactivity to methacholine, defined as
the log of the methacholine dose that provoked a 35 percent decrease in SG
from control. Bronchial reactivity to methacholine observed after exposure to
£U on the initial 2 to 3 days was significantly increased over that observed
after exposure to filtered air. On the fourth and fifth consecutive days of
0« exposure and with reexposure 7 days later, bronchial reactivity to methacho-
line was not significantly changed. The duration of the attenuated bronchial
reactivity response was therefore much longer than that observed for FVC and
FEV-, Q in the same subjects, as noted earlier in this section.
An issue that merits attention is whether attenuated pulmonary respon-
siveness is beneficial or detrimental in that it may reflect the presence or
development of underlying changes in neural responses or basic injury to lung
tissues. Whether the attenuation of pulmonary function responses after repeated
chamber exposures to 0, is suggestive of reduced pulmonary responsiveness for
chronically exposed residents of high-oxidant communities also remains unre-
solved.
10.4 EFFECTS OF OZONE ON VIGILANCE AND EXERCISE PERFORMANCE
Results from animal studies suggest that 0_ causes alterations in motor
activity and behavior, but whether these responses result from odor perception,
irritation, or a direct effect on the central nervous system (Chapter 9) is
unknown. In fact, modification of the inclination to respond was suggested as
possibly being more important than changes in the physiological capacity to
perform simple or complex tasks. Very few human studies are available to help
resolve this issue.
10-60
-------
Henschler et al. (1960) determined the olfactory threshold in 10 to 14
male subjects exposed for 30 min to various 03 concentrations. In a subgroup
of 10 subjects, 9 individuals reported detection when the ambient concentration
3
was as low as 39,2 ug/m (0.02 ppm of 0,). Perception at this low level did
not persist, being seldom noted after some 0.5 to 12 min of exposure. The
odor of Og became more intense at concentrations of 98 ng/m (0.05 ppm),
according to 13 of 14 subjects tested, and it persisted for'a longer period of
time. No explanation was provided for the olfactory fatigue.
Eglite (1968) studied the effects of low 0~ concentrations on the olfactory
threshold and on the electrical activity of the cerebral cortex. He found in
his 20 subjects that the minimum perceptible concentration (olfactory threshold)
3
for 03 was between 0.015 and 0.04 mg/m (0.008 and 0.02 ppm). The few subjects
on whom electroencephalograms (EEGs) were recorded showed a 30 to 40 percent
3
reduction of cerebral electrical activity during 3 min of exposure to 0.02 mg/m
(0.01 ppm) of 03. The data are presented inadequately and can be considered '
only suggestive.
Gliner et al. (1979) determined the effects of 2-hr exposures to 0.0,
490, 980, or 1470 |jg/m (0.0, 0.25, 0.50, or 0.75 ppm) of 03 on sustained
visual and auditory attention tasks (vigilance performance). Eight male and
seven female subjects performed tasks consisting of judging and responding to
a series of 1-s light pulses which appeared every 3 s. The light pulses were
either nonsignals (dimmer) or signals (brighter). When the ratio of signals
to nonsignals was low (15 subjects), approximately 1 out of 30 performances
was not altered regardless of the ambient level of 0^. However, when the
ratio of signals was increased (five subjects), a deficit in performance
3
beyond that of the normal vigilance decline was observed during the 1470-(jg/m
(0.75-pptn) 0- exposure. The results obtained were interpreted within the
framework of an arousal hypothesis, suggesting that a high concentration of 0~
may produce overarousal.
Five individuals (four men, one woman) served as subjects (Gliner et al.,
1980) in studies designed to evaluate the effects of 0., on the electrical
activity of the brain by monitoring the EEG during psychomotor performance.
In the first experiment, a 2-hr visual sustained attention task was unaffected
3
by exposure to filtered air or 1470 |jg/m (0.75 ppm) of 0-. The second experi-
ment involved performing a divided-attention task, which combined a visual
choice reaction time situation with an auditory sustained attention task. The
10-61
-------
3
Og concentrations were either 0.0, 588, or 1470 ug/m (0.0, 0.3, or 0.75 ppm).
Spectral and discriminant function analyses were performed on the EEGs collec-
ted during these studies. There was no clear discrimination between 03 expo-
sure and filtered air using the different parameters obtained from the EEC
spectral analysis. Given the inability to obtain a discrimination between
o
clean air and 1470 |jg/m (0.75 ppm) of 03 using these techniques, EEC analysis
does not appear to hold any promise as a quantitative method of assessing
2
health effects of low-concentration (i.e., < 1484-[jg/m ; 0.3-ppm) 0~ exposure.
Mihevic et al. (1981) examined the effects of 0, exposure (0.0, 588,
q <3
980 pg/m ; 0.00, 0.30, and 0.50 ppm) in 14 young subjects who initially rested,
then exercised for 40 min at heart rates of 124 to 130 beats/min, and finally
rested for an additional 40 min. Pulmonary function measurements (FVC, FEV-^,
and MEF£5-75^ were mac'e Curing res^ periods and after exercise. The primary
objective of the study was to examine the effects of exposure during exercise
on perception of effort and to evaluate perceptual sensitivity to pulmonary
responses. As expected, decrements in FVC, FEV-i, and ^^yS-75 were Si9m'fi~
cantly greater (P <0.01) immediately after exercise than in the rest condition
Q
during either the 588- or 980-ug/m (0.30- or 0.50-ppm) 0, exposures. The
work output remained the same in all conditions. However, the ratings of
perceived exertion revealed that the subjects felt they were working harder or
making a greater effort when exercising in the 0.50-ppm 03 condition as compared
to in-room air. The increased effort was perceived as a "central" effect
(i.e., not related to effort or fatigue in the exercising muscles), which may
suggest the perception of increased respiratory effort. The subjects also
performed a test of magnitude estimation and production of inspired volume in
which they either gave estimates of the percentage of increase in inspiratory
capacity or attempted to produce breaths of a given size. From these tests an
exponent was derived (by geometric regression analysis), which indicated the
"perceptual sensitivity" to change in lung volume. The increase in this
exponent following Og exposure (588, 980 ug/m ; 0.30, 0.50 ppm) indicated that
the subject's sensitivity to a change in lung volume was greater than it was
following filtered-air exposure.
Early epidemiological studies on high school athletes (Chapter 11) pro-
vided suggestive information that exercise performance in an oxidant environ-
ment is depressed. The reports suggested that the effects may have been
related to increased airway resistance or to the associated discomfort in
breathing, thus limiting runners' motivation to perform at anticipated high
10-62
-------
levels. In controlled human studies, exercise performance has been evaluated
during short-term maximal exercise or continuous exercise for periods up to
1 hr (Table 10-6). Folinsbee et al. (1977a) observed that maximal aerobic
capacity (max VCL) decreased 10 percent, maximum attained work load was reduced
by 10 percent, maximum ventilation (max VF) decreased 16 percent, and maximum
3
heart rate dropped 6 percent after a 2-hr Og exposure (1470 ug/m ; 0.75 ppm)
with alternate rest and light exercise. A psychological impact related to the
increased pain (difficulty) induced by maximal inspirations may have been the
important factor in reduction in performance. Savin and Adams (1979) exposed
nine exercising subjects for 30 min to 294 and 588 ug/m (0.15 and 0.30 ppm)
0- (mouthpiece inhalation). No effects on maximum work rate or max Vn? were
found, although a significant reduction in max V,- was observed during the
"2 El
588-ug/m (0.30-ppm) exposure. Similarly, max Vn9 was not impaired in men and
3
women after 2-hr exposure and at-rest exposure to 0.0, 980, and 1470 ug/m
(0.00, 0.50, and 0.75 ppm) of 03 (Horvath et al., 1979).
Six well-trained men and one well-trained woman (all except one male
being a competitive distance cyclist) exercised continuously on a bicycle
q
ergometer for 1 hr while breathing filtered air or 412 ug/m (0.21 ppm) of 0,
(Folinsbee et al., 1984). They worked at 75 percent max V-,, with mean minute
ventilations of 81 L/min. As previously noted (Section 10.2.3), pulmonary
function decrements as well as symptoms of laryngeal and/or trachea! irritation,
chest soreness, and chest tightness were observed upon taking a deep breath.
Anecdotal reports obtained from the cyclists supported the contention that
performance may be impaired during competition at similar ambient Q~ levels.
Adams and Schelegle (1983) exposed 10 well-trained distance runners to
0.0, 392, and 686 ug/m3 (0.0, 0.20, and 0.35 ppm) of 03 while the runners
exercised on a bicycle ergometer at work loads simulating either a 1-hr steady
state training bout or a 30-min warmup followed immediately by a 30-min compe-
titive bout. These exercise levels were of sufficient magnitude (68 percent
of their max VQ2) to increase mean VV to 80 L/min. In the last 30 min of the
competitive exercise bout, minute ventilations were approximately 105 L/min.
Subjective symptoms increased as a function of 0, concentration for both
continuous and competitive levels. In the competitive exposure, four runners
(0.20 ppm) and nine runners (0.35 ppm) indicated that they could not have per-
formed at their maximal levels. Three subjects were unable to complete both
the training and competitive simulation exercise bouts at 0.35 ppm 0,, while a
10-63
-------
TABLE 10-6. EFFECTS OF OZONE ON EXERCISE
Ozone
concentration
ug/m3 pjS
294 0.15
588 0.30
392 0. 20
686 0.35
H
^ 412 0.21
490 0. 25
980 0.50
1470 0.75
1470 0, 75
Measurement3 '
method
UV,
NBKI
UV,
UV
UV,
UV
CHEM,
NBKI
MAST,
NBKI
, Exposure
duration and
activity0
30 Bin (mouthpiece)
R & CE (8xR)
@ progressive work
loads to exhaustion
1 hr (mouthpiece)
IE (77. i) @ vari-
able competitive
intervals
CE (77.5)
1 hr
CE (81)
2 hr
R (8) & CE
@ progressive work
loads to exhaustion
2 hr
IE (2.5xR)
@ 15-min intervals
Observed effect(s)
No effect on maximum work rate, anaerobic
threshold, or pulmonary function; max V_
decreased with 0.30 ppm 03.
FVC, FEVx-o, and FEF2s_?s decreased,
subjective symptoms increased with 03
concentration at 68% max V02; fB in-
creased and VT decreased during CE., No
significant^! effects on exercise VOg,
HR, Vc) or V.. No exposure mode effect.
t n
Decreases in FVC (6.9%), FEVt-o (14.8%),
FEF2S_7S% (M%), 1C (11%), and MW (17%) at
75% max VOg. Symptoms reported: laryngeal
and tracheal irritation, soreness, and chest
tightness on inspiration.
No effect on maximum exercise performance
(max V02 , HR, and total performance time).
HR , VE, VT, V02 , and maximum workload
alt aecrlasea. At maximum workload only,
fR increased (45%) and VT decreased (29%).
No. and sex
of subjects
9 male
(runners)
10 male
(distance runners)
6 male
1 female
(distance cyclists)
8 male
7 female
13 male
Reference
Savin and Adams, 1979
Adams and Schelegle, 1983
Folinsbee et al., 1984
Horvath et al . , 1979
Folinsbee et al., 1977a
Measurement method: CHEH = gas-phase chemiluminescence; UV = ultraviolet photometry.
Calibration method: NBKI = neutral buffered potassium iodide; UV = UV photometry.
Activity level: R = rest; CE = continuous exercise; IE = intermittent exercise; minute ventilation (V_) given in L/nin or as a multiple of resting
ventilation.
See Glossary for the definition of symbols.
-------
fourth failed to complete only the competitive ride. As previously noted
(Section 10.2.3), the high ventilation volumes resulted in marked pulmonary
function impairment and altered ventilatory patterns. The decrements were the
result of physiologically induced subjective limitations of performance due to
respiratory discomfort. The authors found it necessary to reduce the 68 percent
max Vgp work load by some 20 to 30 percent in two of their subjects for them
to complete the final 15 min (of the 30-min work time) in their competitive
test.
Although studies on athletes (not all top-quality performers) have sug-
gested some decrement in performance associated with 03 exposure, too limited
a data base is available at this time to provide judgmental decisions concern-
ing the magnitude of such impairment. Subjective statements by individuals
engaged in various sport activities indicate that these individuals may volun-
tarily limit strenuous exercise during high-oxidant concentrations. However,
increased ambient temperature and relative humidity are also associated with
episodes of high-oxidant concentrations, and these environmental conditions
may also enhance subjective symptoms and physiological impairment during 03
exposure (see Section 10.2.9.3). Therefore, it may be difficult to differen-
tiate any performance effects due to ozone from those due to other conditions
in the environment. Several reviews on exercising subjects have appeared in
the literature, (Horvath, 1981; Folinsbee, 1981; McCafferty, 1981; Folinsbee
and Raven, 1984).
10.5 INTERACTIONS BETWEEN OZONE AND OTHER POLLUTANTS
An important issue is whether or not 03 interacts with other pollutants
to produce additive as well as greater than additive effects beyond those
resulting from exposure to 0, or the other pollutants alone. Also important
to determine is whether no interactions occur when several pollutants are
present simultaneously. Table 10-7 presents a summary of data on interactions
between 0~ and other pollutants.
10.5.1 Ozone Plus Sulfates or Sulfuric Acid
Several studies have addressed the possible interaction between 0,, and
sulfur compounds. Bates and Hazucha (1973) and Hazucha and Bates (1975)
3
exposed eight volunteer male subjects to a mixture of 725 pg/rn (0.37 ppm) of
10-65
-------
TABLE 10-7. INTERACTIONS BETWEEN OZONE AND OTHER POLLUTANTS
CTi
Ozone
concentration
ug/*J
ppm
Pollutant3
Measurement >c
method
Exposure
duration and
activity0
No. and sex
Observed effect(s) of subjects
Reference
A. 03 + S02:
294
393
588
2620
725
970
725
970
725
970
100
784
104B
784
1048
0.15
0.15
0.3
1.0
0.37
0.37
0.37
0.37
0.37
0.37
0.4
0.4
0.4
0.4
03
S02
03
S02
03
S02
03
S02
03
S02
H2S04
03
S02 -
03
S02
CHEM, NBKI
EC
UV, UV
FP
HAST, NBKI
EC
CHEH, NBKI
FP
UV, NBKI
FP
1C
CHEH, NBKI
FP
CHEH, NBKI
FP
2 hr
. IE(25)
@ 15-min
intervals
2 hr
IE (38);
alternating
30-min
exercise and
10-min rest
periods
2 hr
IE(2xR)
@ 15-min
intervals
2 hr
IE(2xR)
@ 15-min
intervals
2 hr
IE(2xR)
@ 15-min
intervals
2 hr
IE(30)
@ 15-min
intervals
2 hr
IE(30)
@ 15-min
intervals
SG decreased; possible synergism is ques- 6 male
tionable. Statistical approach is weak.
FVC, FEVj, and FEF25.75X decreased after 22 male
exposure to 03 alone; wnen combined with
S02, similar but smaller decreases were
observed. No additive or synergistic
effects were found.
Decrement in spirometric variables (FVC, MEFR 8 male
50%); synergism reported. Interpretation com-
plicated by the probable presence of H2S04.
Decreased forced expiratory function 4 normal (L.A)
(FEV^o, FVC) relative to 03 exposure alone 5 sensitive (L.A.)
in combined group of normal and sensitive 4 normal (Montreal)
L.A. subjects; more severe symptoms and
greater decrement of FEV^o in Montreal
(5.2%) than L.A. sensitive (3.7%) subjects.
Small decreases in pulmonary function (FVC, 19 male
FEV,,2,3, MMFR, V 50, V 25) and slight
increase in symptoms due primarily to 03
alone; H2S04 was 93% neutralized.
Decreased forced expiratory function (FVC, 9 male
FEVj.o, FEF25_75v, FEF50v) following expo-
sure to either 03 or 03 * S02; no differences
observed between 03 alone and 03 + S02.
Observed decrement in pulmonary .function 8 male
(FEV^o, FVC, FEF25.75%, FEFSO%> ERV, TLC)
and increase in symptoms reflected changes
due to 03; no synergism was found.
Kagawa and Tsuru, 1979c
Folinsbee et al., 1985
Hazucha, 1973
Bates and Hazucha, 1973
Hazucha and Bates, 1975
Bell et al., 1977
Kleinman et al. , 1981
Bedi et al., 1979
Bedi et al., 1982
B. 03 + H2S04:
294
200
0.15
03
H2S04
CHEM, NBKI
1C
2 hr
IE @15-min
intervals
SGaw decreased; no interaction reported. 7 male
Questionable statistics.
Kagawa, 1983a
-------
TABLE 10-7 (continued). INTERACTIONS BETWEEN OZONE AND OTHER POLLUTANTS
H
?
(Ti
Ozone
concentration
ug/nr5 ppm
588 0.3
100
784 0.4
100
133
116
80
Pollutant3
03
H2S04
03
H2S04
(NH4)2S04
NH4HS04
NH4N03
Measurement 'c
method
HAST, NBKI
& CHEM, NBKI
TS
CHEM, NBKI
Exposure
duration and
activity
2 hr
IE(35)
for 15 min
4 hr
IE(35)
• for 15 min
2-4 hr
IE
for two 15-min
periods
Observed effect(s)6
No significant 03-related changes in pulmo-
nary function or bronchial reactivity to
methacholine. Bronchial reactivity decreased
following a 4-hr exposure to H2S04.
Decrement in pulmonary function due to
03 alone; more apparent after 4 hr than
2 hr; no interaction; recovery within 24 hr.
• No. and sex
of subjects Reference
7 male Kulle et al. , 1982a
5 female
124 male Stacy et al., 1983
(divided into
10 exposure
groups)
C. 03 + CO:
588 0.3
115000 100.0
03
CO
MAST, BAKI
IR
1 hr (mouth-
piece) CE (51
for male and
34.7 for female
subjects).
Decrement in pulmonary function due to
03 alone: FVC, FEVj.o and FEF25_75^
decreased; fg increased and V,. decreased
with exercise.
12 male DeLucia et al. , 1983
12 .female
(equally divided
by smoking history)
D. 03 + N02:
196 0. 1
9400 5.0
294 0. 15
280 0. 15
490- 0.25-
980 0. 5
560 0.3
35000 30.0
980 0. 5
940 0.5
03
N02
Oa
N02
03
N02
CO
03
N02
CHEM, NBKI
MAST (N02)
MAST, NBKI
and CHEM, NBKI
MAST, (N02)
and CHEM, C
CHEM, NBKI
CHEM, C
IR
CHEM, NBKI
CHEM, C
2 hr
IE(2xR)
@ 15-min
intervals
2 hr
IE(25)
@ 15-min
intervals
2-4 hr
R & IE(2xR)
@15-min
intervals
2 hr
IE (40)
for 30 min
Decreases in Pa02 and increases in Raw
due predominantly to N02 alone. No
interaction reported.
SGaw decreased in 5/6 subjects during 03
exposure, 3/6 subjects during N02 expo-
sure, and in all subjects during the
combined exposure. More than additive
effect reported in 3/6 subjects. Coughing,
chest pains, and chest discomfort related
to 03 exposure.
No interaction reported. Changes observed
in spirometry, lung mechanics, and small
airway function in non-reactors (IE) and
hyperreactors (R) at 0.5 ppm 03.
Decreases in FVC, FEVj.0> FEF25_75y, and
FEF50y; ventilatory and metabolic variables
were not changed; response was similar to
that observed in 03 exposure alone. Tight-
ness in the chest and difficulty taking deep
a breath was reported along with cough, sub-
sternal soreness, and shortness of breath.
12 male von Nieding et al., 1977
von Nieding et al. , 1979
6 male Kagawa and Tsuru, 1979b
16 normal and Hackney et al., 1975a,b,c
reactive subjects
8 male Folinsbee et al., 1981
-------
TABLE 10-7 (continued). INTERACTIONS BETWEEN OZONE.AND OTHER POLLUTANTS
Ozone
concentration
ug/i3 ppra
H.
o
o\
00
980-
1372
940
1320
49-
196
100-
9000
314
13000
157
300
900
19S
9400
13100
294
280
393
0,5-
0.7
0.5-
0.7
0.025-
0.1
0.06-
5.0
0.12-
5.0
0.08
0.16
0.34
0.1
5.0 -
5.0
0.15
0.15
0,15
Heasureaent 'c
Pollutant method
N02
03
N02
S02
03
N02
S02
03
N02
S02
oa
N02
S02
HAST, NflKI and
CHEH, NBKI
HAST (N02)
and CHEM, C
CHEH, NBKI
MAST (N02)
TS
CHEH, NBKI
and GS, CHEH
CHEM, C
CHEH, NBKI
GS, CHEM
CHEM, C
CHEH, NBKI
CHEH, C
EC
Exposure
duration and
activity
1 hr
(mouthpiece)
R
2 hr
IE (2xR)
6 15-min
intervals
8 hr
R
2 hr
IE
2 hr
IE
@ 15-min
intervals
No. and sex
Observed effect(s) of subjects
No significant changes in SGaw, Vmax 50%, or 5 male
vmax 25%.
E. 03 + N02 + SQZ:
Decreases in Pa02 and increases in Raw due 11 male
to N02 alone at maximum concentrations; no
effect at minimum concentrations. No inter-
action reported.
No effect on lung function, blood gases, or 15 male
blood chemistry; questionable statistics.
Random effects reported; questionable 24 male
statistics; unknown exercise level. (divided into
3 age groups)
Decreases in SG due to 03 alone. No 7 male
interaction reported. Questionable
statistics.
Reference
Toyama et al. , 1981
von Nieding et al,, 1979
Islam and Ulmer, 1979b
Islam and Ulmer, 1979a
Kagawa, 1983a, 1983b
Pollutants studied for interactive effects: 0 = ozone; SO = sulfur dioxide; H2S04 = sulfuric acid; (NH4)2S04 = ammonium sulfate; NH4HS04 = ammonium bisulfate;
NH4N03 = ammonium nitrate; CO = carbon monoxide; N02 = nitrogen dioxide. ' / '
Measurement method: HAST =-Kl-Coulotetric (Mast meter); HAST (N02) = microcoulometric N02 analyzer; CHEH = gas-phase chemiluminescence; UV = ultraviolet
photometry; GS-CHEM =.gas solid chentiluminescence; 1C = ion chromatography; EC = electrical conductivity S02 analyzer; Ff> = flame photometry S02 analyzer;
TS = total sulfur analyzer; IR = infrared CO analyzer.
Calibration method: NBKI = neutral buffered potassium iodide; BAKI = boric acid potassium iodide; C = coloriietric (Saltzman).
Activity level: R = rest; CE = continuous exercise; IE = intermittent exercise; minute ventilation (V ) given in L/min or as a multiple of resting
.V • • , E ' :
See Glossary for the definition of symbols.
Part of a larger study of 231 subjects.
-------
0~ and 0.37 ppm of sulfur dioxide (SOp) for 2 hr. Temperature, humidity,
concentrations, and particle sizes of ambient aerosols (if any) were not
measured. Sulfur dioxide alone had no detectable effect on lung function,
while exposure to 0, alone resulted in decrements in pulmonary function. The
combination of gases resulted in more severe respiratory symptoms and pulmonary
changes than did 03 alone. Using the maximal expiratory flow rate at 50 percent
vital capacity as the most sensitive indicator, no change occurred after 2 hr
3
of exposure to 0.37 ppm S0? alone. However, during exposure to 725 M0/m
(0.37 ppm) 0,, a 13 percent reduction occurred, while exposure to the mixture
3
of 725 jjg/m (0.37 ppm) 0- and 0,37 ppm SOp resulted in a reduction of 37 per-
cent in this measure of pulmonary function. The effects resulting from 03 and
SOp in combination appeared in 30 min, in contrast to a 2-hr time lag for
exposure to 0~ alone.
Bell et al. (1977) attempted to corroborate these studies using four
normal and four 03~sensitive subjects. They showed that the 0- + S0? mixture
had an overall greater effect on pulmonary function measures than did 03
alone. Differences ranging from 1.2 percent for FVC to 16.8 percent for V25
were detected during 03 + S02 exposure relative to 03 exposure alone in normal
subjects. The mean FEV1<0 decreased 4.7 percent after 0, + S09 exposure
10 £
relative to 03 alone in the sensitive subjects. When normals and sensitives
were combined, the mean FEV1>0 and FVC were both significantly lower after the
03 + SQy exposure. Four of the Hazucha and Bates (1975) study subjects were
also studied by Bell et al. (1977). Two of these subjects had unusually large
decrements in FVC (40 percent) and FEV-, (44 percent) in the first study (Bates
and Hazucha, 1973), while the other two had small but statistically significant
decrements. None of the subjects responded in a similar manner in the Bell
et al. (1977) study.
To determine why some of the Montreal subjects were less reactive to the
S09-Q- mixture when studied in Los Angeles compared to Montreal, Bell et al.
£ «J
(1977) compared exposure dynamics in the two chambers. Analysis of the design
of the Montreal chamber and pollutant delivery system indicated that concen-
trated streams of S02 and 03 could have reacted rapidly with each other and
with ambient impurities like olefins, to form a large number of sulfuric acid
(HpSO») nuclei which grew by homogeneous condensation, coagulation, and absorp-
tion of ammonia (NH3) during their 2-min average residence time in the chamber.
A retrospective sampling of the aerosol composition used for the original
S0«-0, study in Montreal (Hazucha and Bates, 1975) using particle samplers and
C. 3
10-69
-------
chemical analysis in the chamber showed that acid sulfate particles could have
been io- to 100-fold higher (100 to 200 ng/m ), and thus might have been
responsible for the synergistic effects observed. However, recent studies
conducted by Kleinman et al. (1981) involving identical concentrations of SO,,
3
and Og showed that the presence of 100 |jg/m HpSO- did not alter the response
obtained with the SOg-Og mixture alone. (See later discussion in this section.)
Bedi et al. (1979) exposed nine young healthy nonsmoking men (18 to 27
2
years old) to 784 yg/m (0-4 ppm) 0- and 0.4 ppm S09 singly and in combination
w f~
for 2 hr in an inhalation chamber at 25°C and 45 percent rh. The subjects
exercised intermittently for one-half of the exposure period. Pulmonary
function was measured before, during, and after the exposure. Subjects exposed
to filtered air or to 0.4 ppm SOp showed no significant changes in pulmonary
function. When exposed to either 03 or 03 plus S02, the subjects showed
statistically significant decreases in maximum expiratory flow (FEV-, Q,
FEFpc^-jgvj and FEFgQy) and FVC. There were no significant differences between
the effects of 03 alone and the combination of 03 + S02; thus, no synergistic
effects were discernible in their subjects. , Although parti cul ate matter was
not present in the inlet air, whether particles developed in the chamber at a
later point is not known.
Chamber studies were also conducted by Kagawa and Tsuru (1979c), who
exposed six subjects for 2 hr with intermittent exercise (50 W; i.e., ventila-
tion of 25 L/min) for periods of 15 min of exercise separated by periods of
15 rain of rest. The exposures were performed weekly in the following sequence:
filtered air, 0.15 ppm of 03; filtered air, 0.15 ppm of S02; filtered air; and
finally 0.15 ppm of 03 + 0.15 ppm of S02. Pulmonary function measurements
were obtained prior to exposure, after 1 hr in the chamber, and after leaving
the chamber. Although a number of pulmonary function tests were performed,
change in SG was used as the most sensitive test of change in function.
They reported a significant decrease in five of the six young male subjects
exposed to 0<, alone. In three of the subjects, they reported a significantly
greater decrease in SG after exposure to the combination of pollutants than
with 03 exposure alone. Two other subjects had similar decreases with either
03 or 03 + SO- exposure. Subjective symptoms of cough and bronchial irrita-
tion were reported to occur in subjects exposed to either 03 or the 0^ + S02
combination. The authors suggested that the combined effect of the two gases
10-70
-------
on SG is more than simply additive in some exercising subjects. This conclu-
sion is questionable, however, because of the small number of subjects respond-
ing and the use of t-tests of paired observations to test the significance of
pollutant-exposure effects. The statistical approach is weak despite the fact
that the author selected a significance level of P <0.01. The question of
potential synergistic interaction between SOp and 0-, therefore remains unresol-
ved by this study.
Bedi et al. (1982) attempted to explain the conflict of opinion over the
cause of synergistic effects reported by Hazucha and Bates (1975) and Kagawa
and Tsuru (1979c) for humans exposed to the combination of 0- and S09. While
O IM
intermittently exercising (VV ~30 L/min), eight young adult nonsmoking males
were randomly exposed on separate occasions for 2 hr to filtered air, 0.4 ppm
SQ2, 748 jjg/m3 (0.4 ppm) of 03, and 0.4 ppm of S02 plus 784 ug/m3 (0.4 ppm) of
Og at 35°C and 85 percent rh. No functional changes in FEV-, Q occurred as a
result of exposure to filtered air or 0.4 ppm of SOp, but decreases in FEV-, „
occurred following exposure to either 784 jjg/m (0.4 ppm) of 0, (6.9 percent)
3
or the combination of 784 ug/m (0.4 ppm) of 0- plus 0.4 ppm of SQp (7.4 per-
cent). Thoracic gas volume (TGV) increased and FEF50<£ decreased in the 0^
exposures, while FVC, ^^^25-757' ^^50%' ^^' anc* "^ a^ decreased in the
0,,/SOp and Q~ exposures. However, no significant differences were found
between the 0, exposure and the 03 plus SOp exposure. In this study, statisti-
cal analyses were performed using ANOVA procedures.
An analysis of the data obtained in the 1982 study and a prior study
(Bedi et al., 1979) was also made using t-tests to compare data from these two
studies with data obtained by Kagawa and Tsuru (1979c), who reported a syner-
gistic effect consequent to exposure to 0.15 ppm of SOp and 294 ug/m (0.15
ppm) of 03 using t-tests. The experimental designs of the Bedi et al. and the
Kagawa and Tsuru studies were essentially similar. Reanalysis of the Bedi et
al. data using t-tests and expressing data as relative changes indicated that
the SG was not altered in the 25°C-45 percent rh environment but decreased
aw
10.6 percent (P < 0.05) in the S02 exposure and 19 percent (P <'Q.G1) in 03
plus SOp exposure in hot, wet conditions. These investigators concluded that
in one sense they confirmed the findings (based on t-tests) of Kagawa and
Tsuru, but under different conditions. This might suggest a small potential
effect on SG . They then stated, "Nonetheless, we believe that the use of a
more stringent statistical approach provides for better analysis of collected
data and that we are correct in stating that synergism had not occurred."
10-71
-------
Folinsbee et al. (1985) exposed 22 healthy nonsmoking men (23,6 ±8.1
2
years of age) for 2 hr to a combination of 588 yg/m (0.3 ppm) CL and 1.0 ppm
SOn as well as to each gas individually. The subjects alternated 30-min
periods of treadmill exercise at a ventilation of 38 L/min with 10-min rest
periods during the exposure. Forced expiratory maneuvers were performed
before exposure and 5 min after each of three exercise periods; MVV, FRC, R ,
and TGV were measured before and after exposure. After 03 exposure alone,
there were significant decreases in FVC, FEV.,, and FEF25_75^. There were no
significant changes in pulmonary function after SCL exposure alone. Combined
exposure to S02 + 0» produced similar but smaller changes compared to those
found after 03 exposure alone. These small differences were not in a direction
that would support the hypothesis of either a synergistic or additive effect
on pulmonary function. In general, there were no important health-related
differences between the effects of 03 alone and 03 + S02.
Few studies have been reported in which subjects were exposed to 03 and
H«SO*. Kagawa (1983a) summarized some results obtained on seven subjects
intermittently resting and exercising during a 2-hr exposure to 294 ug/m
3
(0.15 ppm) of 03 and 0.2 mg/m of H^SO.. Using t-tests,to analyze his data,
he reported a highly significant (P < 0.01) decrease (10.2 percent) in SG .
However, not enough details are provided to allow adequate analysis.
Kleinman et al. (1981) conducted studies in which 19 volunteers with
normal pulmonary function and no history of asthma were exposed on two separate
3
days to clean air and to an atmospheric mixture containing 03 (725 ug/m » 0.37
ppm), S02 (0.37 ppm), and HgSO^ aerosol (100 MS/m3* MMAD =0.5 urn; cr = 3.0).
Chemical speciation data indicated that 93 percent of the H2SO- aerosol had
been partially neutralized to ammonium bisulfate. Additional data suggested
that the acidity of the aerosol in the chamber decreased as a function of time
during exposure, so that at the beginning of the exposures subjects were
exposed to higher concentrations of HpSO* than they were at the end of expo-
sures. During this 2-hr period, the subjects alternately exercised for 15 min,
at a level calibrated to double minute ventilation, and rested for 15 min.
Statistical analysis of the group average data suggested that the mixture may
have been slightly more irritating to the subjects than 03 alone. A large
percentage (13 of 19) of the subjects exhibited small decrements in pulmonary
function following exposure to the mixture. The group average FEV, ~ on the
exposure day was depressed by 3.7 percent of the control value. However, the
magnitudes of the FEV, „ changes were not higher than those observed in subjects
10-72
-------
exposed to 03 alone (expected decreases of 2.8 percent). The authors con-
cluded that the presence of HLSO, aerosols did not substantially alter the
irritability resulting from Q~-SQy-
Stacy et al. (1983) studied 234 healthy men (18 to 40 years old) exposed
for 4 hr to air, Q3, NG2, or SQ2; to HpSO,, ammonium sulfate [(NH-^SO.],
ammonium bisul fate (NHJHSO,), or ammonium nitrate (NH^NO™) aerosols; or to
mixtures of these gaseous and aerosol pollutants. The subjects were divided
into 20 groups so that each group contained 9 to 15 subjects. The exposure
3
groups of interest were filtered air (n = 10); 784 M9/m (0.4 ppm) of 03
(n = 12); 100 pg/m3 of H2$04 (n = 11); 133 MO/m3 of (NH4)2S04 (n - 13);
116 ug/m3 of NH4HS04 (n = 15); 80 yg/m3 of NH4N03 (n = 12); and the mixtures
°3 + H2S04 (n = 13)' °3 + (NH4)2S04 (n = 15)' °3 + NH4HS04 (n = U)> and °3 +
NH4N03 (n = 12). Ambient conditions were 3Q°C db, 85 percent rh because of
the need to maintain the aerosol particles in proper suspension. Two 15-min
bouts of treadmill exercise were performed, one beginning at 100 min into the
exposure and the second beginning at 220 min. Minute ventilations were not
reported. Pulmonary function was measured during a rest period before expo-
sure, 5 to 6 min following the termination of the exercise, and 24 hr later.
Data were analyzed by multivariate analyses of variance. Airway resistance,
lung volume, and flow rates showed a statistically significant effect of the
gaseous pollutant (0-,) with greater changes reported at 4 hr than at 2 hr of
exposure. None of the particulates significantly altered pulmonary functions
compared with the filtered-air exposure, and there was no indication of inter-
action between 0, and the particulates. Exposure to 0., alone and with particles
was also associated with symptoms of irritation, such as shortness of breath,
coughing, and minor throat irritation. At 24 hr post-exposure, all pulmonary
values had returned to pre-exposure levels.
Kulle et al. (1982a) studied the responses of 12 healthy nonsmokers
(seven men, five women) exposed to 0- and H0SO/1 aerosols. Ozone concentra-
3 3
tions were 588 ug/m (0.3 ppm) and H2SQ4 aerosol levels were 100 ug/m (MMAD =
0.13 urn; a = 2.4). These studies were conducted over a 3-week period; a 2-hr
exposure to 03 during the first week, a 4-hr exposure to H2SO, during the
second week, and a 2-hr exposure to 0~ followed by a 4-hr exposure to H~S(L
during the third week. The protocol followed in each of these weekly exposure
regimes was day 1 - filtered air, day 2 - pollutant, and day 3 - filtered air.
A methacholine aerosol challenge was made at the completion of each exposure
day. Subjects were exercised for 15 min 1 hr prior to the completion of the
10-73
-------
exposure. The work load was 100 W at 60 rpm, with an assumed VV of approxi-
mately 30 to 35 L. No discernible risk was apparent as a consequence of
exposing the nonsmoking healthy young adults to 0~ followed by respirable
HoSO^ aerosol. Bronchial reactivity decreased with H^SO, aerosol exposure at
a statistical level approaching significance (0.05 < p <0.10). Pulmonary
function changes (SG , FVC, FEV-,, FEVo, and bronchial reactivity to methacho-
line) following the 0~ exposure were not significant. However, some subjects
did report typical symptoms observed in other 03 exposures.
10.5.2 Ozone and Carbon Monoxide
DeLucia et al. (1983) reported the only study in which subjects were
exposed to carbon monoxide (CO) and 03. Subjects exercised at 50 percent max
v"n« for 1 hr in the following ambient conditions: filtered air, 100 ppm of
U£ o q
CO, 588 ug/m (0.30 ppm) of 03, and 100 ppm of CO plus 588 yg/m (0.30 ppm) of
0~. These gas mixtures were administered directly, the subjects inhaling them
orally for the entire exposure period. Twelve nonsmokers, six men and six
women, and 12 smokers (not categorized as to smoking habits), equally divided
by sex, served as subjects. There were relatively large differences in fitness
between men and women as well as between smokers and nonsmokers, which could
be responsible for some of the differences reported. Cardiorespiratory perform-
ance, heart rate, oxygen uptake, and minute ventilation were not substantially
higher during exercise bouts where 0~ was present. All subjects exercised at
50 percent max VLp, equivalent to a mean VV of 45.0 to 51.8 L/min for the men
and 29.7 to 36.8 L/min for the women. The women, therefore, probably inhaled
less 03 than the men. Carboxyhemoglobin (COHb) levels attained at the end of
the exercise period were similar for the two sexes, an average increase of
5.8 percent. Smokers' final COHb values were 9.3 ± 1.2 percent, compared with
nonsmokers1 levels of 7.3 ± 0.8 percent.
Based on the limited data available, exposure to CO and 03 does not
appear to result in any interactions. The effects noted appear to be related
primarily to 03.
10.5.3 Ozone and Nitrogen Dioxide
Studies describing the responses of subjects to the combination of these
two pollutants are summarized in Table 10-7. Hackney et al. (1975a,b,c) and
von Nieding et al. (1977, 1979) noted that no interactions were observed and
that the pulmonary function changes were due to 03 alone for the concentrations
10-74
-------
present. Kagawa and Tsuru (1979b) evaluated the reactions of six subjects
o
(one smoker) to 294 ug/m (0.15 ppm) Q3 and 0.15 ppm NQ2, singly and in com-
bination. They used the standard exposure time of 2 hr with alternating
15-min periods of rest and exercise at 50 W. SG was determined prior to
flow .volume measurements and prior to and at two intervals during the exposure
period. A fixed sequence of pollutant exposures was followed at weekly inter-
3
vals, i.e., filtered air, 294 |jg/m (0.15 ppm) of Q3, filtered air, 0.15 ppm
of N02, filtered air, 0.15 ppm (03 + N02), and filtered air. Statistical
analyses were by t-tests. Subjective symptoms were reported in some subjects
only when 0,, was present. Significant decreases in SG occurred in five of
«3 Q.W
six subjects exposed to 03, three of six subjects exposed to N02, and six of
six subjects exposed to 03 + NO^.
Kagawa (1983a) briefly reported that under the conditions of his exposure
(2 hr to 0.15 ppm QS + 0.15 ppm N02) SGgw, V5Q^} and VC decreased. However,
no significant differences were observed between 03 alone and the combination
of 03 + N02. Subjective symptoms were equivalent in both 03 exposures.
Five subjects sitting in a body pi ethysmograph inhaled orally either
filtered air, 0.7 ppm of N02, 1372 (jg/rn3 (0.7 ppm) of 03, or 0.5 ppm of 03 +
0.5 ppm of N02 for 1 hr (Toyama et a!., 1981). Specific airway conductance
and isovolume flows (V x ~y/ anc* ^max 509^ were measured before and at the
end of exposure, and 1 hr later. No significant changes were observed for any
of the ambient conditions and consequently no interactions could be detected.
Folinsbee et al. (1981) exposed eight healthy men for 2 hr to either
o
filtered air or 980 ug/m (0.5 ppm) of 03 plus 0.5 ppm of N02 in filtered air
under four different environmental conditions: (1) 25°C, 45 percent rh;
(2) 30°C, 85 percent rh; (3) 35°C, 40 percent rh; and (4) 40°C, 50 percent rh.
Subjects rested for the first hour, exercised at a VV of 40 L/min during the
next half hour, and then rested for the final 30 min of exposure. Pulmonary
function measurements were made prior to exposure, immediately after the
exercise period, and again at the end of the 2-^hr period. Significant
decreases occurred in FVC, FEV-, g, FE'r25-75f' anc* ^Fgfw during the 03-N02
exposure. Ventilatory and metabolic variables, expired ventilation, oxygen
uptake, tidal volume, and respiratory frequency were unaffected by 0., and NO,,
exposure. Thermal conditions modified heart rate, ventilation, and FVC.
Greater changes in pulmonary functions were seen in both groups following the
exercise period with recovery of the decrements toward the pre-exposure value
during the succeeding half hour of rest. In this study, no synergism or
10-75
-------
interaction between 03 and NOp was observed over the entire range of ambient
temperatures and relative humidities.
10.5.4 Ozone and Other Mixed Pollutants
Von Nieding et al. (1979) exposed 11 subjects to 03, N0p, and SOp singly
and in various combinations. The subjects were exposed for 2 hr with 1 hr
devoted to exercise (intermittent), which doubled their ventilation. The work
periods were of 15 min duration alternating with 15-min periods at rest. In
the actual exposure experiments, no significant alterations were observed for
POp, PCOp, and pH in arterialized capillary blood or in TGV. Arterial oxygen
tension (PaOp) was decreased (7 to 8 torr) by exposure to 5.0 ppm of NOp but
was not further decreased following exposures to 5.0 ppm of N09 and 5.0 ppm of
•3 *•
SOp or 5.0 ppm of NO,,, 5.0 ppm of SOp and 196 [jg/m (0.1 ppm) of 03 or 5.0 ppm
of NOp and 196 ug/m (0.1 ppm) of 0,. Airway resistance increased significant-
ly (0.5 to 1.5 cm HpO/L/s) in the combination experiments to the same extent
as in the exposures to NOp alone. In the 1-hr post-exposure period of the
NOp, SOp, and 0- experiment, R, continued to increase. Subjects were also
exposed to a mixture of 0.06 ppm NOp, 0.12 ppm of SOp, and 49 (jg/m (0.025 ppm)
of 0-. No changes in any of the measured parameters were observed. These
same subjects were challenged with 1-, 2-, and 3-percent aerosolized solutions
of ACh following control (filtered-air) exposure and exposure to 5.0-ppm NOp,
5.0-ppm SOp, and 0.1-ppm 03 mixture, as well as after the 0.06-ppm NOp, 0.12-
ppm S02, and 49-ug/m (0.025-ppm) 03 mixture exposures. Individual pollutant
gases were not evaluated separately. ACh challenge caused the expected rise
in airway resistance in the control study. Specific airway resistance (R x
Q.W
TGV) was significantly greater following the combined pollutant exposures than
in the control study.
In another study of simultaneous exposure to SOp, NOp, and 0^, three
groups of eight subjects, each of different ages (<30, >49, and between 30 to
40 years) were exposed for 2 hr each day in a chamber on three successive days
(Islam and Ulmer, 1979a). On the first day, subjects breathed filtered air
and exercised intermittently (levels not given); on the second day they were
3
exposed at rest to 5.0 ppm of SO,,, 5.0 ppm of NO,,, and 196 |jg/m (0.1 ppm) of
0~; and on the third day the environment was again 5.0 ppm of S09, 5.0 ppm of
3
NOp, and 196 [jg/m (0.1 ppm) of 03, but the subjects exercised intermittently
during the exposure. Statistical evaluation of data for the 11 lung-function
test parameters and two blood gas parameters (PaOp and PaCOp) was not reported.
10-76
-------
These measurements were made before exposure, immediately post-exposure, and
3 hr post-exposure. Individual variability was quite marked. The investi-
gators concluded that no synergistic effects occurred in their healthy subjects.
However, since they did not systematically expose these subjects to the indi-
vidual components of their mixed pollutant environment, the conclusion can
only be justified in that they apparently saw no consistent changes. There
were some apparent changes in certain individuals related to exercise (unknown
level) and age, but the data were not adequately presented or analyzed.
Islam and Ulmer (19?9b) studied 15 young healthy males during chamber
*3 Q "2
exposures to 0.9 mg/m (0.34 ppm) S02, 0.3 mg/m (0.16 ppm) N02, and 0.15 mg/m
(0.08 ppm) 03> Ten subjects were exposed to 1 day of filtered air and four
successive days of the gas mixture. Another group of five subjects was exposed
for 4 days to the pollutant mixture followed by 1 day to filtered air. Each
exposure lasted 8 hr. Following each exposure, the subjects were challenged
by an ACh aerosol. Eight pulmonary function tests and four blood tests (PaOp,
PaCQp, hemoglobin, and lactate dehydrogenase) were performed before and after
the exposure. No impairments of lung functions, blood gases, or blood chemis-
try were found, but statistical analysis of the data was not reported.
10.6 EXTRAPULMONARY EFFECTS OF OZONE
The high oxidation potential of 03 has led early investigators to suspect
that the major damage from inhalation of this compound resulted from oxidation
of labile components in biological systems to produce structural or biochemical
lesions (Chapter 10). Initial studies by Buckley et al. (1975) suggested that
statistically significant changes (P < 0.05) occurred in erythrocytes and sera
3
of seven young adult men following exposure to 980 ug/m (0.50 ppm) of 03 for
2.75 hr. Erythroeyte membrane fragility, glucose-6-phosphate dehydrogenase,
and lactate dehydrogenase enzyme activities increased, while erythrocyte
acetylcholinesterase activity and reduced gluthathione levels decreased.
Serum gluthathione activity decreased significantly, while serum vitamin E and
lipid peroxidation levels increased significantly. These changes were transi-
tory and tended to disappear within several weeks. Although these changes
were significant, that the alterations were such as to modify physiological
systems or mechanisms is doubtful (see later reports in Table 10-8).
10-77
-------
TABLE 10-8. HUMAN EXTRAPULHONARY EFFECTS OF OZONE EXPOSURE
Ozone
concentration
ug/mj
294
588
392
392
490
H725
^J
CO
784
784
784
784
ppm
0.15
0.30
0.2
0.2
0.25
0.37
0.4
0.4
0.4
0.4
Measurement3'
method
UV,
NBKI
NO
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
Exposure
duration and
activityc
1 hr (mouthpiece)
R (11) & CE
(29, 43, 66)
0.5-1 hr
2 hr
IE (2xR)
@ 15-min intervals
2 hr
IE (2xR)
@ 15-min intervals
4 hr
IE for two
15-min periods
4 hr
R
4 hr
IE for two
15-min periods
2.25 hr
IE (2xR)
@ 15-min intervals
Observed effect(s)
No effect on NPSH, G-6-PD, 6-PG-D, GRase,
Hb.
Spherocytosis.
Hb levels decreased. RBC enzymes: LDH in-
creased, G-6-PD increased, AChE decreased.
RBC fragility increased. All observed
effects were stress related (heat).
RBC fragility increased and serum vitamin E
increased in Canadians only. RBC enzymes:
AChE decreased in both groups.
Mild suppression PHA-induced lymphocyte
transformation. Questionable decrease in
PMN phagocytosis and intracellular killing.
No statistically significant depression in T-
lymphocyte rosette formation. B-lymphocyte
rosette formation with sensitized human
erythrocytes was depressed immediately after
but not 72 hr and 2 weeks after ozone
exposure.
No detectable cytogenetic effect.
RBC fragility increased. RBC enzymes: AChE
decreased; LDH increased in new arrivals.
Serum glutathione reductase increased in
new arrivals.
No. and sex
of subjects Reference
6 male DeLucia and Adams, 1977
e Brinkman et al., 1964
20 male Linn et al., 1978
2 female
(asthma)
2 male (Toronto) Hackney et al., 1977b
2 female (Toronto)
3 male (L.A.)
1 female (L.A.)
21 male Peterson et al. (1978a,b)
8 male Savino et al., 1978
26 male McKenzie et al., 1977
6 female (L.A.) Hackney et al., 1976
7 female (new arrival)
2 male (new arrival)
-------
TABLE 10-8 (continued). EXTRAPULMONARY EFFECTS OF OZONE EXPOSURE
Ozone
concentration
pg/m3 ppm
784 0.
784 0.
1176 0,
980 0.
980 0.
980 0,
980 0.
980 0,
4
4
6
5
5
5
5
5
Measurement3'
method
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
uv,
NBKI
Exposure
duration and
activity
4 days
4 hr/day
IE for two
15-nin periods
4 days
4 hr/day
2 hr
IE for two
15-min periods
2 hr
IE (2xR)
@ 15-min intervals
± Vit E
2 hr
IE (2xR)
@ 15-min intervals
intervals
2.75 hr
IE (2xR)
@ 15-min intervals
4 days
2.5 hr/day
IE (2xR)
@ 15-n"n intervals
2 hr
IE (2xR)
@ 15-min intervals
Observed effect(s)
RBC G-6-PD increased. Serum vitamin E
increased. Complement C3 increased.
No detectable cytogenetic effects.
No significant effects.
No significant effects.
RBC fragility increased, RBC enzymes: LDH
increased, G-6-PD increased, AChE decreased,
GSH decreased. Serum: GSSRase decreased,
vitamin E increased, lipid peroxiaation
levels increased.
Hb decreased after second exposure. RBC
enzymes: GSH decreased after second expo-
sure, 2,3-DPG increased and AChE decreased
with successive exposures. Levels tended
to stabilize with repeated exposure but
did not return to control values.
No effect on circulating lymphocytes.
No, and sex
of subjects
74 male
(divided into
four exposure
groups)
30 male
29 male
and female
9 male
28 female
7 aale
6 male (Atopic)
31 male and
female
Reference
Chaney et al . , 1979
McKenzie, 1982
Hamburger et al,, 1979
Posin et al., 1979
Buckley et al., 1975
Hackney et al. , 1978
Guerrero et al . , 1979
i — — — j
-------
TABLE 10-8 (continued). HUMAN EXTRAPULMONARY EFFECTS OF OZONE EXPOSURE
Ozone
concentration
ufl/m3 ppm
980 0.5
H
-------
In the most comprehensive studies to date concerning the cytogenetic
effects of inhaled 0- in human subjects, McKenzie and co-workers have investi-
gated both chromosome and chromatid aberrations (McKenzie et al., 1977) as
well as sister chromatid exchange (SCE) frequencies (McKenzie, 1982). Blood
samples from 26 normal male volunteers were collected before 0- exposure;
immediately after exposure; and 3 days, 2 weeks, and 4 weeks after exposure to
3
784 |jg/m (0.4 ppm) of 0- for 4 hr. Each subject served as his own control
since pre-exposure blood samples were collected. A total of 13,000 human
lymphocytes were analyzed cytogenetically. One hundred well-spread, intact
metaphase plates were examined per subject per treatment time for chromosome
number, breaks, gaps, deletions, fragments, rings, dicentrics, translocations,
inversions, triradials, and quadriradials. The data indicated no apparent
detectable cytogenetic effect resulting from exposure to 03 under the condi-
tions of the experiments.
In later studies, McKenzie (1982) investigated the SCE frequency, in
addition to the number of chromosomal aberrations in peripheral lymphocytes of
3
human subjects exposed to 784 yg/m (0.4 ppm) of 0- for 4 hr on one day and
3
for 4 hr/day on four consecutive days, or to 1176 fjg/m (0.6 ppm) for 2 hr on
one day only. One hundred metaphases per blood sample per subject for chromo-
some aberrations, and 50 metaphases per blood sample per subject were analyzed
for SCEs. Each study was conducted on 10 to 30 healthy, nonsmoking human
subjects. No statistically significant differences were observed in the
frequencies of numerical aberrations, structural aberrations, or SCEs between
0- pre-exposure and post-exposure values. The nonsignificant differences were
observed at all concentrations and durations tested, and in the multiple
exposures as well as in the single 03 exposures.
Chromosome and chromatid aberrations were investigated by Merz et al.
3
(1975) in lymphocytes collected from subjects exposed to 980 |jg/m (0.5 ppm)
of 03 for 6 to 10 hr. Increases in the frequency of chromatid aberrations
(achromatic lesions and chromatid deletions) were observed in lymphocytes
after 03 exposure, with a peak in the number of aberrations 2 weeks after
exposure. No increase was observed in the number of chromosome aberrations.
While these results suggest human genotoxicity after 0- exposure, the results
did not differ significantly from pre-03 chromatid aberration frequencies
because of the small number (six) of subjects investigated.
10-81
-------
Guerrero et al. (1979) exposed 31 male and female subjects to filtered
q
air followed on a second day by 2-hr exposure to 980 jjg/m (0.5 ppm) of Q-.
Subjects "lightly" exercised 15 min out of every 30 min. Blood samples were,
unfortunately, obtained only at the termination of the exposures. An SCE
analysis performed on the circulating lymphocytes showed no change in lympho-
cyte chromosomes in either condition. However, SCE analysis performed on
diploid human fetal lung cells (WI-38) exposed to 0.0, 490, 1470, and 1960 ug/m3
(0.0, 0.25, 0.75, and 1.00 ppm) of .03 for 1 hr i_n vitro was shown to have a
dose-related increase in SCEs. The investigators suggested that the lack of
SCE changes in lymphocytes iji vivo was attributable to the protective effect
of serum and/or another agent.
Peterson and co-workers conducted three studies designed to evaluate the
influence of 0- exposures on leukocyte and lymphocyte function. In 1978,
Peterson et al. (1978a) evaluated bactericidal and phagocytic rates in poly-
morphonuclear leukocytes from blood obtained before each exposure, 4 hr after
exposure, as well as 3 and 14 days post-exposure. The 21 subjects were exposed
o
for 4 hr to to 784 jjg/m (0.40 ppm) of 03 at,rest with the exception of two
15-rain periods of exercise (700 kgm/min, resulting in a doubling of heart
rate). The phagocytic rate and intracellular killing of respirable-size
bacteria (Staphylococcus epidermis) was significantly reduced 72 hr after 0,
exposure. No significant effect on the phagocytic rate or intracellular
killing was observed immediately after 03 exposure, or at 2 weeks after 03
exposure. The nadir of neutrophil function was observed at 72 hours after 03
exposure. Since the neutrophil has an average lifespan of 6.5 hr, the mecha-
nism by which 03 produces an effect on the neutrophil at 72 hr is open to
speculation. Ozone may produce indirect effects on neutrophils through toxicity
to granulocytic stem cells, or by altering humoral factors that facilitate
phagocytosis. A similar experimental protocol was used in a subsequent study
on 11 subjects with the addition of a clean-air exposure with four subjects
(Peterson et al., 1978b). The experimental description is confusing, because
variable numbers of subjects were studied under different conditions. In the
o
0 764-|jg/m (0.39-ppm) exposure (20 subjects), lymphocyte transformation,
responses to 2 |jg/ml and 20 |jg/ml of phytohemagglutinin (PHA) in cultures
indicated significant (P < 0.01) suppression to 2 ug/ml of PHA in blood obtained
immediately post-exposure but no effects with 20 ug/ml of PHA. The data*
presented only in graphical form, suggested a wide variability in response,
and consequently the significance of the observations may be minor. A third
10-82
-------
study was conducted by these investigators (Peterson et al., 1981) on 16
3
subjects exposed to 1176 |jg/m (0.6 ppm) of 03. The protocol of rest, exercise,
and blood sampling was similar to that used in their earlier studies except
that one additional blood sample was obtained at least 1 to 2 months after the
exposure. The relative frequency of lymphocytes in blood and the i_n vitro
blastogenic response of the lymphocytes to PHA, concanavalin A (con A), pole-
weed mitogen (PWM), and Candida albicans were determined. In the second- and
fourth-week blood samples, a significant (P < 0.05) reduced response to PHA
was observed. No other alterations in function were observed. The signifi-
cance of these findings remains somewhat tenuous.
Savino et al. (1978) observed that while peripheral blood T-lymphocyte
rosette formation was unchanged following exposure of human subjects to
2
784 ug/m (0.4 ppm) 0,~ for 4 hr, B-lymphocyte rosette formation was signifi-
cantly depressed. Rosette formation is an i_n vitro method that measures the
binding of antigenic red blood cells with surface membrane sites on lymphocytes.
Different antigenic red cells are used to distinguish T from B lymphocytes. A
normal B-lymphocyte response was restored by 72 hr after Q3 exposure.
Biochemical parameters (erythrocyte fragility, hematocrit, hemoglobin,
erythrocyte glutathione, acetylcholinesterase, glucose-6-phosphate dehydro-
genase, and lactic acid dehydrogenase) were determined in blood obtained from
subjects given either vitamin E or a placebo (Posin et al., 1979). Exposure
3
conditions were filtered air on day 1 and 980 ug/m (0.50 ppm) 0- on day 2;
2 hr of exposure alternating with 15 min of exercise (double the resting
minute ventilation) and 15 min of rest. Vitamin E intakes for nine or more
weeks were 800 or 1600 IU. The number of subjects and the percent of men and
women differed in each of the three studies conducted. No significant differ-
ences between the responses of the supplemented and placebo groups to the 03
exposure were found for any of the parameters measured. Hamburger et al.
(1979) obtained blood from the 29 subjects in one of the above three experi-
ments (800 IU vitamin E and placebo). Blood was obtained before and after the
3
2-hr exposures to filtered air or 980 ug/m (0.5 ppm) of 03. No statistically
significant change in erythrocyte agglutinability by concanavalin A was found.
In summary, the overall impression of available human data raises doubts
that cellular damage or altered function to circulating cells occurs as a
consequence of exposure to 0- concentration under 980 ug/m (0.5 ppm).
10-83
-------
10.7 PEROXYACETYL NITRATE
Subjects exposed to peroxyacetyl nitrate (PAN) complain of eye irritation,
blurred vision, eye fatigue, and of the compound's distinctive odor. Smith
(1965) had 32 young male subjects breathe orally 0.30 ppm PAN for 5 min at
rest and continue to inhale this pollutant during a subsequent 5-min period of
light exercise. Oxygen uptake during exercise was found to be statistically
higher while breathing PAN than while breathing filtered air. These observa-
tions were not confirmed in subsequent studies (Table 10-9). Gliner et al.
(1975) studied 10 young men (22 to 26 years of age) and nine older men (44 to
45 years) while they walked at 35 percent max V02 for 3.5 hr of a 4-hr exposure
to PAN. The ambient conditions in the chamber were either 25°C or 35°C dry
bulb at 30 percent rh and the PAN concentration was either 0.0 or 0.24 ppm.
Various measures of cardiorespiratory function were similar in both PAN and
filtered-air exposures. A study of 16 older men (40 to 57 years) breathing
0.27 ppm PAN for 40 min found no changes in oxygen uptake during light work
(Raven et al.» 1974a).
The potential influence of PAN on V00 m=v was determined in 20 young men
-------
TABLE 10-9, ACUTE EXPOSURE TO PEROXYACETYL NITRATE
H
O
CO
tn
Concentration
jjg/m3 ppa
1187 0.24
1187 0.24
1336 0.27
1336 0.27
1336 0.27
1484 0.30
1484 0,30
Exposure
duration and
activity
4 hr
IE (20-30) for
50 min of each hr.
4 hr
IE (20-30) for
50 rain of each hr
40 min
IE (progressive) for
20 min
40 min
IE (progressive) for
20 min
40 min (mouthpiece)
IE (progressive) for
20 rain
10 min (mouthpiece)
IE for 5 rain
2 hr
IE(27) with
alternating 15-min
rest and 20-min
exercise
h No. and sex
Observed effect(s) of subjects
FVC decreased 4% in 10 young subjects after 19 male
exercise. No significant change in pulmonary
function in nine middle-aged subjects. No in-
teraction between exposure, temperature (25° &
35°C), or smoking habit.
No significant changes in submaximal work at 19 male
35% vQ, in 10 young and nine middle-aged
subjects. No interaction between exposure
and temperature (25° & 35°C).
No significant change in V02 in young non- 20 male
smokers (n = 10) or smokers ffi = 10) during
treadmill walk at 35°.
No significant change in VO- in middle- 16 male
aged nonsmokers (n = 9) or smoRers (n = 7)
during treadmill walk at 25°C and 35°C.
No significant change in V0-m x in 20 male
young nonsmokers (n = 10) of smokers
(n = 10) during treadmill walk at 25°C.
Oxygen uptake increased with exercise. 32 male
Maximum expiratory flow rate decreased
after exercise.
No significant, changes in pulmonary 10 male
function or exercise ventilation with PAN.
Simultaneous effect of PAN and 0.45 ppm
Oa; decrements in TLC, FVC, FEVj.o. and
FEF2s_?sv were significantly greater (10X)
with PAN/03 when compared with 03 alone.
Reference
Raven et al . , 1976
Gliner et al., 1975
Dri nkwater et al . ,
1974
Raven et al . , 1974a
Raven et al . , 1974b
Smith, 1965
Dreehsler-Parks
et al., 1984
Activity level: IE = Intermittent exercise; minute ventilation (vV) given in L/min.
See Glossary for the definition of symbols.
-------
periods of rest and 20-min periods of moderate exercise (VV = 27 L/min) on a
bicycle ergometer during the exposure. Forced expiratory volume and flow were
determined before and after exposure and 5 min after each exercise period.
Functional residual capacity was determined pre- and postexposure. Heart rate
was measured throughout the exposure, and Vv, VCL, fR, and VT were measured
during the last 2 min of each exercise period. There were no significant
changes in exercise V0« or heart rate during any of the pollutant exposures.
The changes in breathing patterns occurring during exercise were significant
decreases in Vy with exposure to 0~ and PAN/CU and significant increases in fp
with PAN/03 exposure. No effects on lung function or respiratory symptoms
were reported after exposure to filtered air or PAN. Exposure to 03 and
PAN/Og produced significant decrements in FVC, FEVp FEV2, FEV3» FEF25~75%>
1C, ERV, and TLC. The decrements in TLC, FVC, FEV.^ and FEF25-75% were signi-
ficantly greater (10 percent) with PAN/On exposure and occurred in a shorter
period of time when compared with exposure to 0- alone. A wide range of
individual responsiveness to 0, and PAN/03 was noted among subjects; four
subjects had greater than 30 percent decrements in FEV.. while one subject
showed no change at all. Symptoms reported after 0^ and PAN/0~ exposures were
similar, although a greater number of symptoms were reported after the PAN/0,
exposure. The results by Drechsler-Parks et al. (1984) suggest a simultaneous
effect of the oxidants PAN and 03. However, because the large individual
responsiveness to 03 makes direct comparisons to extant data difficult to
perform, it is not clear if the greater decrements observed after PAN/0-
exposure are related to total oxidant load. Additional research is needed to
further clarify the relationship between PAN and 0™ at concentrations found in
ambient air.
The interaction of PAN and CO was also evaluated in the series of studies
on healthy young and middle-aged men exercising on a treadmill (Raven et al.,
1974a, 1974b; Drinkwater et al., 1974; Gliner et al., 1975). Both smokers and
nonsmokers were exposed to 0.27 ppm PAN and 50 ppm CO. No interactions between
CO and PAN were found. Hetabolic, body temperature, and cardiorespiratory
responses of healthy middle-aged men, nine smokers and seven nonsmokers, were
obtained during tests of maximal aerobic power (max VQ2) at ambient tempera-
tures of 25°C and 35°C, rh = 20 percent (Raven et al., 1974a). These subjects
were randomly exposed for 40 min in an environmental chamber to each of four
conditions, i.e., filtered air, 50 ppm CO, 0.27 ppm PAN, and a combination of
50 ppnt of CO and 0.27 ppm of PAN. Carboxyhemoglobin was measured in these
10-86
-------
subjects. There was no significant change in maximal aerobic power related to
the presence of these air pollutants, although total exercising time was
lowered in the 25°C environment while exposed to CO. ' A decrement in max VQ2
was found in middle-aged smokers breathing 50 ppm of CO. Another study con-
ducted under similar pollutant conditions at an ambient temperature of 35°C,
20 percent rh was carried out on 20 young male subjects (10 smokers and 10
nonsmokers) (Drinkwater et al., 1974). Maximal aerobic power was not affected
by any pollutant condition. Exposure to CO was effective in reducing work
time of the smokers. The same subjects were also involved in a study conducted
at 25°C, 20 percent rh under similar pollutant conditions except that they
inhaled the pollutants orally for 40 min (Raven et al. , 1974b). Exposure to
the two pollutants singly or in combination produced only minor, nonsignificant
alterations in cardiorespiratory and temperature regulatory parameters. The
influence of PAN and CO, singly or in combination, was evaluated in 10 young
(22 to 26 years) and nine middle-aged (45 to 55 years) men performing submaxi-
mal work (35 percent max VQ2) for 210 min (Gliner et al., 1975). Five subjects
in each age group were smokers. Studies were conducted at two different
ambient temperatures, i.e., 25°C and 35°C, rh 30 percent. The pollutant
concentrations were 0.25 ppm of PAN and 50 ppm of CO. Two physiological
alterations were reported. Stroke volume decreased during long-term work,
being enhanced in the higher ambient temperatures. Heart rate was significantly
(P <0.05) higher when exercise was being performed during the CO exposures.
No other alterations were found in relation to the pollutants. There were no
differences in response related to age.
10.8 SUMMARY
A number of important controlled studies discussed in this chapter have
reported significant decrements in pulmonary function associated with 0-
exposure (Table 10-10). In most of the studies reported, greatest attention
has been accorded decrements in FEV-, n, as this variable represents a summation
of changes in both volume and resistance. While this is true, it must be
pointed out that for exposure concentrations critical to the standard-setting
process (i.e., <0.3 ppm 03), the observed decrements in FEV-, Q primarily
reflect FVC decrements of similar magnitude, with little or no contribution
from changes in resistance.
10-87
-------
TABLE 10-10 SUMMARY TABLE: CONTROLLED HUMAN EXPOSURE TO OZONE
H
o
CO
CO
Ozone3 b
concentration Measurement ' Exposure
ug/«tj
ppra method duration
Activity11 •
level (VE)
Observed effects(s)
No. and sex
of subjects
Reference
HEALTHY ADULT SUBJECTS AT REST
627
1960
980
980
1470
0.32 HAST, NBKI 2 hr
1.0
0.5 CHEM, NBKI 2 hr
0.50 CHEM, NBKI 2 hr
0.75
R
R (10)
R (8)
Spcific airway resistance increased with
acetylcholine challenge; subjective symptoms
in 3/14 at 0.32 ppw and 8/14 at 1.0 ppm.
Decrement in forced expiratory volume and
flow.
Decrement in forced expiratory volume and
f 1 ow.
13 male
1 female
40 male
(divided into four
exposure groups)
8 male
7 female
KBnig et al., 1980
Folinsbee et al. ,
1978
Horvath et al . ,
1979
EXERCISING HEALTHY ADULTS
235
353
470
588
784
314
470
627
353
470
588
784
392
686
0.12 CHEM, UV 2.5 hr
0.18
0.24 '
0.30
0.40
0.16 UV, UV 1 hr
0.24
0.32
0.18 CHEM, UV 2.5 hr
0.24
0.30
0.40
0.20 UV, UV 1 hr
0.35 (mouth-
piece)
IE (65)
8 15-nin intervals
CE (57)
IE (65)
@15-min intervals
IE (77.5) i vari-
able competitive
intervals
CE (77.5)
Decrement in forced expiratory volume and
flow suggested at 0.12 ppm with larger
decrements at >_ 0.18 ppm; respiratory
frequency and specific airway resistance
increased and tidal volume decreased at
> 0.24 pprn; coughing reported at all
concentrations, pain and shortness of
breath at £ 0.24 ppm.
Small decrements in forced expiratory
volume at 0.16 ppm with larger decrements
at X).24 ppm; lower-respiratory symptoms
increased at >0.16 ppm.
Individual responses to 03 were highly
reproducible for periods as long as 10
months; large intersubject variability
in response due to intrinsic responsiveness
to Q3.
Decrement in forced expiratory volume and
flow with IE and CE; subjective symptoms
increased with 03 concentration and nay
limit performance; respiratory frequency
increased and tidal volume decreased with
CE.
135 male
(divided into six
exposure groups)
42 male
8 female
(competitive
bicyclists)
32 male
10 male
(distance runners)
McDonnel 1 et al . ,
1983
Avol et al . , 1984
McDonnell et al. ,
1985a
Adams and Schelegle,
1983
-------
TABLE 10-10 (continued). SUMMARY TABLE: CONTROLLED HUMAN EXPOSURE TO OZONE
Ozone3 b
concentration Measurement ' Exposure
Hg/nr'
392
823
980
392
490
412
0490
CO
588
980
725
980
1470
ppm method duration
0.2 UV, UV 2 hr
0.42
0.50
0.20 UV, UV 2 hr
0.25
0.21 UV, UV 1 hr
0.25 UV, UV 1 hr
0.3 CHEM, NBKI 2 hr
0.5
0.37 MAST, NBKI 2 hr
0.50
0.75
Activityd '
level (VE)
IE (30 for male,
18 for female
subjects)
@ 15-min intervals
IE (68)
(4) 14-min periods
CE (81)
CE (63)
R (10), IE (31,
50, 67)
& 15-min intervals
R (11) & IE (29)
8 15-min intervals
Observed effects(s)
Repeated daily exposure to 0.2 ppm did not
affect response at higher exposure concen-
trations (0.42 or 0.50 ppm);. large inter-
subject variability but individual
pulmonary function responses were highly
reproducible.
Large intersubject variability in response;
significant concentration- response relation-
ships for pulmonary function and respiratory
symptoms.
Decrement in forced expiratory volume and
flow.; subjective symptoms may limit per-,,
formance. . .
Increased responsiveness to 03 lasts for
24 hr, may persist in some subjects for
48 hr, but is generally lost within 72 hr.
Decrement in forced expiratory volume and
flow; the magnitude of the change was
related to 03 concentration and Vg.
Total lung capacity and inspiratory
capacity decreased with IE (50, 67); no
change in airway resistance or residual
volume even at highest IE (67). No
significant changes in pulmonary function
were observed at 0.1 ppm.
Good correlation between dose (concen-.
tration x VV) and decrement in forced
expiratory Volume and flow.
No. and sex
of subjects
8 male
13 female
20 male
6 male
1 female
(distance cyclists)
19 male
7 female
40 male
(divided into four
exposure groups)
20 male
8 female (divided into
six exposure groups)
Reference
Gliner et al., 1983
Kulle et al., 1985
Folinsbee et al. ,
1984
Folinsbee and
Horvath, 1986
Folinsbee et al,,
1978
Silverman et al. ,
1976
784 0.4
UV, NBKI 2 hr
IE (2xR)
@ 15-min intervals
Specific airway resistance increased with
histamine challenge; no changes were
observed at concentrations of 0.2 ppm.
12 male "
7 female
(divided into three
exposure groups)
Dimeo et al., 1981
784 0.4
CHEM, NBKI & 3 hr
MAST, NBKI
IE (4-5xR)
Decrement in forced expiratory volume and
SG was greatest on the 2nd of 5 exposure
days; attenuated response by the 4th day
of exposure.
10 male
4 female
Farrel1 et al., 1979
-------
TABLE 10-10 (continued). SUMMARY TABLE; CONTROLLED EXPOSURE TO OZONE
Ozone3 .
concentration Measurement » Exposure
jjg7m3 pp«i method duration
784 0,4 CHEH, UV 3 hr
784 0.4 CHEM, UV 2.5 hr
o 823 0.42 UV, UV 2 hr
882 0.45 UV, UV 2 hr
921 0.47 UV, NBKI 2 hr
980 0.5 MAST, NBKI 6 hr
1176 0.6 UV, NBKI 2 hr
(noseclip)
1470 0.75 MAST, NBKI 2 hr
Activity •
level (VE)
IE (4-5xR)
for 15 win
IE (71)
@ 15-nin intervals
IE (30)
IE (27)
@ 20-nin intervals
IE (3xR)
IE (44) for two
15-min periods
IE (2xR)
@ 15-min intervals
IE (2xR)
@ 15-min intervals
^Observed effects(s)
Decrement in forced expiratory volume was
greatest on the 2nd of 5 exposure days;
attenuation of response occurred by the
5th day and persisted for 4 to 7 days.
Enhanced bronchoreactivity with
methacholine on the first 3 days;
attenuation of response occurred by
the 4th and 5th day and persisted
for > 7 days.
Atroplne pretreatment prevented the
increased R observed with Og exposure,
partially blocked the decreased forced
•expiratory flow, but did not prevent the
03-induced decreases in FVC and TIC,
changes in exercise ventilation, or
respiratory symptoms.
Decrement in forced expiratory volune and
flow greatest on the 2nd of 5 exposure
days; attenuation of response occurred by
the 5th day and persisted for < 14 days with
considerable intersubject variability.
Increased responsiveness to 03 was found
with a 2nd 03 challenge given 48 hr after
the initial exposure.
Decrement in forced expiratory volume and
flow greatest on the 2nd of 4 exposure
days; attenuation of response occurred by
the 4th day and persisted for 4 days.
Small decrements in forced expiratory
volume and specific airway conductance.
Specific airway resistance increased in 7
nonatopic subjects with hi stand ne and
methacholine and in 9 atopic subjects
with histaniine.
Decrements in spirometric variables
(20X-55%); residual voluite and closing
capacity increased.
No. and sex
of subjects
13 Male
11 female
(divided into two
exposure groups)
8 male
24 male
1 male
5 female
8 male
3 female
19 male
1 female
11 male
5 female (divided
by history of atopy)
12 male
Reference
Kulle et al., 1982b
Beckett et al. ,
1985
Horvath et al., 1981
Bedi et al . , 1985
Linn et al., 1982b
Kerr et al . , 1975
Holtzman et al. ,
1979
Hazucha et al. ,
1973
-------
TABLE 10-10. (continued) SUMMARY TABLE: CONTROLLED HUMAN EXPOSURE TO OZONE
Ozone3 k
concentration Measurement '
|jg7m3 ppm method
Exposure
duration
Activity11
level (VE)
Observed effects(s)
No. and sex
of subjects Reference
EXERCISING HEALTHY CHILDREN
235 0.12 CHEM, UV
2.5 hr
IE (39)
@15-rain intervals
Small decrements in forced expiratory
volume, persisting for 24 hr. No subjec-
tive symptoms.
23 male McDonnell et al.,
(8-11 yrs) 1985b,c
ADULT ASTHMATICS
392 0.2 CHEM, NBKI
490 0.25 CHEM, NBKI
2 hr
2 hr
IE (2xR)
@ 15-min intervals
R
No significant changes in pulmonary func-
tion. Small changes in blood biochemistry.
Increase in symptom frequency reported.
No significant changes in pulmonary func-
tion.
20 male Linn et al., 1978
2 female
5 males Silverman, 1979
12 female
£ ADOLESCENT ASTHMATICS .. . . .
1 - ;
}S 235 0.12 UV
SUBJECTS WITH CHRONIC OBSTRUCTIVE
235 0.12 UV, NBKI
353 0.18 UV, NBKI
490 0.25
392 0.2 CHEM, NBKI
588 .0.3
784 0.41 UV, UV
1 hr
(mouthpiece)
LUNG DISEASE
1 hr
1 hr
2 hr
3 hr
R
IE (variable)
@ 15-iln intervals
IE (variable)
@ 15-min intervals
IE (28) for
7.5 nrin each
half hour
IE (4-5xR)
for 15 min
No significant changes in pulmonary function
or symptoms.
No significant changes in forced expiratory
•performance or symptoms. Decreased arterial
oxygen saturation during exercise was
observed.
No significant changes in forced expiratory
performance or symptoms. Group mean arterial
oxygen saturation was not altered by 0$
exposure.
No significant changes in pulmonary function
or symptoms. Decreased arterial oxygen
saturation during exposure to 0.2 ppm.
Small decreases in FVC and FEV3.<).
4 male Koenig et al. , 1985
6 female
(11-18 yrs)
18 male Linn et al., 1982a
7 female
15 male Linn et al., 1983
13 female
13 male • Solic et al., 1982
Kehrl et al., 1983,
1985
17 male Kulle et al., 1984
3 female
Ranked by lowest observed effect level.
Measurement method; MAST = Kl-Coulometric (Mast meter); CHEM = gas phase chemiluminescence; UV = ultraviolet photometry.
Calibration method: NBKI = neutral buffered potassium iodide; UV = ultraviolet photometry.
Minute ventilation reported in L/min or as a multiple of resting ventilation. R = rest; IE = intermittent exercise; CE = continuous exercise.
-------
Results from studies of at-rest exposures to 0, have demonstrated decre-
o
ments in forced expiratory volumes and flows occurring at and above 980 ug/m
(0.5 ppm) of 03 (Folinsbee et a!., 1978; Horvath et a!., 1979). Airway resis-
tance is not clearly affected at these 0Q concentrations. At or below 588
•a -3
jjg/m (0.3 ppm) of 03, changes in pulmonary function do not occur during at
rest exposure (Folinsbee et a!., 1978), but the occurrence of some On-induced
pulmonary symptoms has been suggested (Konig et a!., 1980).
With moderate intermittent exercise at a 1L of 30 to 50 L/min, decrements
in forced expiratory volumes and flows have been observed at and above 588
q
{jg/ra (0.30 ppm) of 03 (Folinsbee et al., 1978). With heavy intermittent
exercise (VV = 65 L/min), pulmonary symptoms are present and decrements in
forced expiratory volumes and flows are suggested to occur following 2-hr
exposures to 235 pg/m (0.12 ppm) of 03 (McDonnell et al., 1983). Symptoms
are present and decrements in forced expiratory volumes and flows definitely
q
occur at 314 to 470 ng/m (0.16 to 0.24 ppm) of Og following 1 hr of continuous
heavy exercise at a $r of 57 L/min (Avol et al., 1984) or very heavy exercise
at a VE of 80 to 90 L/min (Adams and Schelegle, 1983; Folinsbee et al., 1984)
and following 2 hr of intermittent heavy exercise at a vV of 65 to 68 L/min
(McDonnell et al., 1983; Kulle et al., 1985). Airway resistance is only
modestly affected with moderate exercise (Kerr et al., 1975; Parrel! et al.,
3
1979) or even with heavy exercise while exposed at levels as high as 980 jjg/m
(0.50 ppm) 03 (Folinsbee et al., 1978; McDonnell et al., 1983). Increased fR
and decreased V-p while maintaining the same VV, occur with prolonged heavy
exercise when exposed at 392 to 470 M9/m3 (0.20 to 0.24 ppm) of 03 (McDonnell
et al., 1983; Adams and Schelegle, 1983). While an increase in RV has been
q
reported to result from exposure to 1470 ng/m (0.75 ppm) of 03 (Hazucha et
al., 1973), changes in RV have not been observed following exposures to
q
980 pg/m (0.50 ppm) of 0., or less, even with heavy exercise (Folinsbee et
al., 1978). Decreases in TLC and 1C have been observed to result from expo-
q
sures to 980 (jg/m (0.50 ppm) of 03 or less, with moderate and heavy exercise
(Folinsbee et al., 1978).
Recovery of the lung from the effects of 03 exposure consists of return
of pulmonary function (FVC, FEV-,, and SR ) to preexposure levels. The time
course of this recovery is related to the magnitude of the 03~induced functional
decrement (i.e., recovery from small decrements is rapid). Despite apparent
functional recovery of most subjects within 24 hr, an enhanced responsiveness
10-92
-------
to a second 03 challenge may persist in some subjects for up to 48 hr (Bedi
et a!., 1985; Folinsbee and Horvath, 1986).
Group mean decrements in pulmonary function can be predicted with some
degree of accuracy when expressed as a function of effective dose of Oo, the
simple product of 03 concentration, VE, and exposure duration (Silverman et
al., 1976). The relative contribution of these variables to pulmonary decre-
ments is greater for 03 concentration than for ^r. A greater degree of predic-
tive accuracy is obtained if the contribution of these variables is appropri-
ately weighted (Folinsbee et al., 1978). However, several additional factors
make the interpretation of prediction equations more difficult. There is
considerable intersubject variability in the magnitude of individual pulmonary
function responses to 03 (Horvath et al., 1981; Gliner et al, 1983; McDonnell
et al., 1983; Kulle et al., 1985). Individual responses to a given On concen-
tration have been shown to be quite reproducible (Gliner et al., 1983; McDonnell
et al., 1985a), indicating that some individuals are consistently more respon-
sive to 03 than are others. No information is available to account for these
differences. Considering the great variability in individual pulmonary re-
sponses to Og exposure, prediction equations that only use some form of effec-
tive dose are not adequate for predicting individual responses to 0^,
In addition to overt changes in pulmonary function, enhanced nonspecific
bronchial reactivity has been observed following exposures to 0, concentrations
O O
>588 M0/m (0.3 ppm) (Holtzman et al., 1979; Konig et al., 1980; Dimeo et al.,
3
1981). Exposure to 392 \ig/m (0.2 ppm) of 0,, with intermittent light exercise
does not affect nonspecific bronchial reactivity (Dimeo et al., 1981).
Changes in forced expiratory volumes and flows resulting from 03 exposure
reflect reduced maximal inspiratory position (inspiratory capacity) (Folinsbee
et al., 1978). These changes, as well as altered ventilatory control and the
occurrence of respiratory symptoms, most likely result from sensitization or
stimulation of airway irritant receptors (Folinsbee et al., 1978; Holtzman et
al., 1979; McDonnell et al., 1983). The increased airways resistance observed
following 03 exposure is probably initiated by a similar mechanism. Different
efferent pathways have been proposed (Beckett et al., 1985) to account for the
lack of correlation between individual changes in SR and FVC (McDonnell
et al., 1983). The increased responsiveness of airways to histamine and
methacholine following CL exposure most likely results from an On-induced
increase in airways permeability or from an alteration of smooth muscle charac-
teristics.
10-93
-------
Decrements in pulmonary function were not observed for adult asthmatics
exposed for 2 hours at rest (Silverman, 1979) or with intermittent light
o
exercise (Linn et al., 1978) to 0- concentrations of 490 pg/m (0.25 ppm) and
less. Likewise, no significant changes in pulmonary function or symptoms were
3
found in adolescent asthmatics exposed for 1 hr at rest to 235 pg/m (0.12
ppm) of 03 (Koenig et al.3 1985). Although these results indicate that asthma-
tics are not more responsive to 0~ than are healthy subjects, experimental-design
considerations in reported studies suggest that this issue is still unresolved.
For patients with COLD performing light to moderate intermittent exercise, no
decrements in pulmonary function are observed for 1- and 2-hr exposures to 0~
concentrations of 588 pg/m3 (0.30 ppm) and less (Linn et a!., 1982a, 1983;
Solic et al., 1982; Kehrl et a!., 1983, 1985) and only small decreases in
forced expiratory volume are observed for 3-hr exposures of chronic bronchitics
to 804 ug/m (0.41 ppm) (Kulle et al., 1984). Small decreases in Sa02 have
also been observed in some of these studies but not in others; therefore,
interpretation of these decreases and their clinical significance is uncertain.
Many variables have not been adequately addressed in the available clini-
cal data. Information derived from Q~ exposure of smokers and nonsmokers is
sparse and somewhat inconsistent, perhaps partly because of undocumented
Variability in smoking histories. Although some degree of attenuation appears
to occur in smokers, all current results should be interpreted with caution.
Further and more precise studies are required to answer the complex problems
associated with personal and ambient pollutant exposures. Possible age differ-
ences in response to 03 have not been explored systematically. Young adults
usually provide the subject population, and where subjects of differing age
are combined, the groups studied are often too small in number to make adequate
statistical comparisons. Children (boys, aged 8 to 11 yr) have been the
subjects in only one study (McDonnell et al., 1985b) and nonstatistical compari-
son with adult males exposed under identical conditions has indicated that the
effects of 0, on lung spirometry were very similar (McDonnell et al., 1985c).
While a few studies have investigated sex differences, they have not conclu-
sively demonstrated that men and women respond differently to Og, and consid-
eration of differences in pulmonary capacities have not been adequately taken
into account. Environmental conditions such as heat and relative humidity may
enhance subjective symptoms and physiological impairment following 03 exposure,
but the results so far indicate that the effects are no more than additive.
10-94
-------
In addition, there may be considerable interaction between these variables
that may result in modification- of interpretations made based on available
information.
During repeated daily exposures to 0-,, decrements in pulmonary function
are greatest on the second exposure day (Farrell et al., 1979; Horvath et al.,
1981; Kulie et al., 1982b; Linn et al., 1982b); thereafter, pulmonary respon-
siveness to Og is attenuated with smaller decrements on each successive day
than on the day before until the fourth or fifth exposure day when small
decrements or no changes are observed. Following a sequence of repeated daily
exposures, this attenuated pulmonary responsiveness persists for 3 (Kulle
et al., 1982b; Linn et al., 1982b) to 7 (Horvath et al., 1981) days. Repeated
daily exposures to a given low effective dose of 0., does not affect the magni-
tude of decrements in pulmonary function resulting from exposure at a higher
effective dose of 03 (Gliner et al., 1983).
There is some evidence suggesting that exercise performance may be limited
by exposure to O^. Decrements in forced expiratory flow occurring with 0,
exposure during prolonged heavy exercise (VV - 65 to 81 L/min) along with
increased f,, and decreased Vj might be expected to produce ventilatory limita-
tions at near maximal exercise. Results from exposure to ozone during high
exercise levels (68 to 75 percent of max VQ2) indicate that discomfort associ-
ated with maximal ventilation may be an important factor in limiting perfor-
mance (Adams and Schelegle, 1983; Folinsbee et al., 1984). However, there is
not enough data available to adequately address this issue.
No consistent cytogenetic or functional changes have been demonstrated in
circulating cells from human subjects exposed to CL concentrations as high as
3
784 to 1176 (jg/m (0.4 to 0.6 ppm). Chromosome or chromatid aberrations would
therefore be unlikely at lower 0~ levels. Limited data have indicated that 0~
can interfere with biochemical mechanisms in blood erythrocytes and sera but
the physiological significance of these studies is questionable.
No significant enhancement of respiratory effects has been consistently
demonstrated for combined exposures of 0~ with S09, N05, and sulfuric acid or
O ^ £.
particulate aerosols or with multiple combinations of these pollutants. Most
of the available studies with other photochemical oxidants have been limited
to studies on the effects of peroxyacetyl nitrate (PAN) on healthy young and
middle-aged males during intermittent moderate exercise. No significant
effects were observed at PAN concentrations of 0.25 to 0.30 ppm, which are
10-95
-------
higher than the daily maximum concentrations of PAN reported for relatively
high oxidant areas (0.047 ppm). One study (Drechsler-Parks et al., 1984)
suggested a possible simultaneous effect of PAN and 03; however, there are not
enough data to evaluate the significance of this effect. Further studies are
also required to evaluate the relationships between 0» and the more complex
mix of pollutants found in the natural environment.
10-96
-------
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/
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10-107
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11. FIELD AND EPIDEMIOLOGICAL STUDIES OF THE EFFECTS OF OZONE
AND OTHER PHOTOCHEMICAL OXIDANTS
11.1 INTRODUCTION
This chapter critically assesses field and epidemiological studies of
health effects linked to ambient air exposure to ozone and other photochemical
oxidants. In order to characterize the nature and extent of such effects, the
chapter (1) delineates types of health effects associated with exposures to
ozone or photochemical oxidants in ambient air; (2) assesses the degree to
which relationships between exposures to these agents and observed effects are
quantitative; and (3) identifies population groups at greatest risk for such
health effects. Studies of both acute and chronic exposure effects are summar-
ized and discussed. Tables are provided to give the reader an overview of the
studies reviewed in this chapter.
In many of the epidemiological studies available in the literature,
exposure data or health endpoint measurements were used that were inadequate
or unreliable for quantifying exposure-effect relationships. Also, results
from these studies have often been confounded by factors such as variations in
activity levels and time spent out of doors, cigarette smoking, coexisting
pollutants, weather, and socioeconomic status. Thus, selection of those
studies thought to be most useful in deriving health criteria for ozone or
oxidants is of critical importance. Assessment of the relative scientific
quality of epidemiological studies for standard-setting purposes is a difficult
and often controversial problem; therefore, the following general guidelines
(as modified from U.S. Environmental Protection Agency, 1982) have been sug-
gested as useful for appraising individual studies:
1. The aerometric data are adequate for characterizing geographic
or temporal differences in pollutant exposures of study popula-
tions in the range(s) of pollutant concentrations evaluated.
2. The study populations are well defined and allow for statisti-
cally adequate comparisons between groups or temporal analyses
within groups.
3. The health endpoints are scientifically plausible for the
pollutant being studied, and the methods for measuring those
endpoints are adequately characterized and implemented.
4. The statistical analyses are appropriate and properly per-
formed, and the data analyzed have been subjected to adequate
quality control.
11-1
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5, Potentially confounding or covarying factors are adequately
controlled for or taken into account.
6. The reported findings are internally consistent and biologically
plausible.
For present purposes, studies most fully satisfying these suggested
criteria provide the most useful information on exposure-effect or exposure-
response relationships associated with ambient air levels of ozone or photo-
chemical oxidants likely to occur in the United States during the next 5
years. Accordingly, the following additional guidelines were used to select
studies for detailed discussion: (1) the results provide information on
quantitative relationships between health effects and ambient air ozone or
oxidant concentrations with emphasis on concentrations less than or equal to
0.5 ppm (measurement methods and calibrations are reported when available);
and (2) the report has been peer-reviewed and is in the open literature or is
in press. A number of recent studies not meeting the above guidelines but
considered to be sources of additional supportive information are also discussed
below and their limitations noted.
The remaining studies not rigorously meeting all of these guidelines are
tabulated chronologically by year of publication within 'each subject area.
Since the lack of quantitative exposure data is a frequently noted limitation
of epidemiological studies, an attempt has been made to provide as detailed a
description as possible of the photochemical oxidant concentrations and averag-
ing times reported in the original manuscripts. In addition, the tables
summarize comments on earlier studies described in detail in the 1978 EPA
criteria document for ozone and other photochemical oxidants (U.S. Environmental
Protection Agency, 1978).
11.2 FIELD STUDIES OF EFFECTS OF ACUTE EXPOSURE TO OZONE AND OTHER PHOTO-
CHEMICAL OXIDANTS
For the purposes of this document, field studies are defined as laboratory
experiments where the postulated cause of an effect in the population or
environment is tested by removing it under controlled conditions (Morris,
1975; Mausner and Bahn, 1974; American Thoracic Society, 1978; World Health
Organization, 1983). Field studies of symptoms and pulmonary function contain
elements of both controlled human exposure studies (Chapter 10) and of epidemi-
ologic studies. These studies employ observations made in the field along
11-2
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with the methods and better experimental control typical of controlled exposure
studies. Studies classified here as field studies used exposure chambers but
exposed subjects to ambient air containing the pollutants of interest rather
than to artificially generated pollutants, as well as to clean air as a control.
These studies thus form a bridge or continuum between the studies discussed in
the preceding chapter (Chapter 10) and the epidemiological studies assessed
later in this chapter.
11.2.1 Symptoms and Pulmonary Function in Field Studies of Ambient Air Exposures
Researchers at the Ranches Los Amigos Hospital in California (Linn et
al., 1980, 1982, 1983; Avol et al., 1983, 1984, 1985a,b) have used a mobile
laboratory containing an exposure chamber to study the effects of ambient air
exposures on symptoms and pulmonary function in high-oxidant (Duarte) and
low-oxidant (Hawthorne) areas of the Los Angeles Basin. In these field studies,
pre- and post-exercise measurements of pulmonary function, often used in
controlled human exposure studies, were made to compare the effects of short-
term exposures to ozone and oxidants in ambient air versus clean air (sham
control) exposures. The subject characteristics and experimental conditions
in the respective studies are summarized in Table 11-1. The mobile laboratory
has been described previously (Avol et al., 1979), as have the methods for
studies of lung function.
In 1978 Linn et al. (1980, 1983) evaluated 30 asthmatic and 34 normal
subjects exposed to ambient and purified air in a mobile laboratory in Duarte,
CA, during two periods separated by 3 weeks. Only five subjects were smokers,
and the two groups were similar with respect to the age, height, and sex of
subjects. Asthmatic subjects had heterogeneous disease characteristics, as
determined by questionnaire responses. Of the "normal" group, 25 subjects
were considered allergic based on a history of upper respiratory allergy or
reported undiagnosed wheeze that they called "allergic." No definitive clinical
evaluations were performed to verify the allergic status of these subjects.
Ozone, nitrogen oxides (NO ), sulfur dioxide (S0?), sulfates, and total sus-
f\, £-
pended particulate matter (TSP) were monitored inside and outside the chamber
at 5-min intervals. Measurements of 0- by the ultraviolet (UV) method were
calibrated against California Air Resources Board (CARB) reference standards
and were corrected to those obtained by the KI method.
Ozone and particulate pollutants predominated in the ambient air mixture,
as shown in Table 11-1 for the 1978 study (Linn et al., 1980, 1983). Ozone
11-3
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TABLE 11-1. SUBJECT CHARACTERISTICS AND EXPERIMENTAL CONDITIONS IN THE MOBILE LABORATORY STUDIES
Year and place of study
Subjects/conditions
Subject characteristics:
Total number
Males
Asthmatics
Smokers
Avg. age, yr ± SD
Avg. ht, cm ± SD
Avg. wt, kg ± SD
Experimental conditions:
Exercise level
Exposure duration
jlj Pollutant concentration,
1 mean ± SD
03, ppm9
862 , ppm
N02, ppm
CO, ppm
Particulate:
Total, ug/a3
504, jag/m3
NOg, Mg/m3
aLinn et al. (1980, 1983).
bLinn et al. (1982, 1983).
cLinn et al. (1983); Avol et
"1 Inn n& ->1 /1OQ3\. £,,„! ™4-
1978, Duarte3
64
26
30
5
30 + 10
170 ± 10
70 t 14
light intermittent
2 hr (p.m.)
0.174 i 0.068
0.012 ± 0.003
0.069 ± 0.014
2.9 '+. 1.1
182 ± 42
16 ±7
h
al. (1983).
-,i /i«a^%
1979, Hawthorne15
64
26
21
14
34 ± 11
170 ± 12
69 ± 16
light intermittent
2 hr (.a.m.)
0.022 ± 0.011
0.018 + 0.099
0.056 + 0.033
1.6 ± 0.9
112 ± 45
13 ± 6
19 ± 10
1980, Duartec
60
45
7
8
30 ± 11
173 ± 15
69 ± 10
heavy continuous
1 hr (p.m.)
0.165 ± 0.059
0.009 i 0.005
0.050 ± 0.028
3.1 ±2.0
227 ± 76
17 ± 12
22 ± 9
1981, Duarted
98
57
50
7
28 ± 8
172 ± 9
67 ± 11
heavy continuous
1 hr (p.». )
0.156 + 0.055
0.005 ± 0.033
0.062 ± 0.023
2.2 ± 0.7
166 + 52
9 + 4
32 + 10
1982, Duarte6
50
42
0
3
26 ± 7
177 ± 8
70 ± 10
heavy continuous
1 hr (p.m. )
0.153 ± 0.025
0.006 ± 0.004
0.040 ± 0.016
2.2 ± 0.8
295 ± 52
13 ± 8
40 ± 10
1983, Duarte'
59
46
2
0
14 ± 1
162 ± 13
54 ± 13
moderate continuous
1 hr (p.m. )
0.144 ± 0.043
0.006 ± 0.001
0.055 ± 0.011
1.1 ±0.3
152 ± 29
5 ± 4
19 ± 4
eAvol et al. (1984, 1985c).
fAvol et al. (1985a,b).
^Ultraviolet photometer calibration method.
Measurements unsatisfactory due to artifact nitrate formation on filters.
Source: Adapted from Linn et al. (1983).
-------
3
levels (corrected to the KI method) averaged 427 |jg/m (0.22 ppm) inside the
mobile laboratory chamber and 509 (jg/m (0.26 ppm) outside the laboratory
o
during ambient air exposures; and 7.8 |jg/m (0.004 ppm) during purified air
o
exposures. The respective maximum 0- concentrations were 498 ± 186 |jg/m
(0.25 ± 0.10 ppm) inside; 597 ± 217 |jg/m3 (0.31 ± 0.11 ppm) outside; and
19 ± 17 ug/m (0.01 ± 0.009 ppm) in purified air. Levels of TSP averaged
3 3
182 |jg/m inside the chamber and 244 |jg/m outside the laboratory during
3
ambient air exposures, but 49 (jg/m inside the chamber during purified-air
exposures. Average NOp, SOp, CO, and sulfate levels inside the chamber were
uniformly low during ambient-air exposures (as shown in Table 11-1) and were
even lower during purified-air exposures (i.e., 0.015 ppm for NO^; 0.009 ppm
for S02; 2.8 ppm for CO; 0.9 ppm for sulfates). Gases were monitored continu-
ously, with inside and outside air sampled alternately for 5-min periods.
Particles were measured during testing inside and outside the laboratory.
Temperature and humidity were controlled inside the laboratory.
During the exposure studies (Tuesday through Friday), four subjects
(maximum) were tested sequentially in the morning at 15-min intervals, each
first breathing purified air at rest followed by "pre-exposure" lung-function
tests. Ambient-air chamber tests were performed in the early afternoon (after
odors were masked by a brief outside exposure). The ambient-air exposure
period lasted 2 hr and included exercise on bicycle ergometers for the first
15 min of each half-hour; this was followed by "post-exposure" lung function
testing during continuing ambient-air exposure. Ergometer workloads ranged
from 150 to 300 kg-m/min and were sufficient to double the respiratory minute
ventilation relative to resting level. Lung function measures before and
after exposure were compared by t-tests and nonparametric methods. The
purified-air control study for each subject took place at least 3 weeks after
the ambient-air exposure session, with identical procedures except for purified
air in place of the ambient. Note that 12 healthy subjects from the project
staff were tested apart from the study cohort in order to validate various
aspects of the study. The validation tests were performed to determine whether
there were any gross differences in response to indoor and outdoor ambient
exposures. While no significant differences were found in this comparison,
small differences would have been difficult to detect because of the small
number of subjects tested.
In the main set of experiments (Linn et al. ,- 1980, 1983), the asthmatic
group experienced greater changes from baseline in residual volume (RV) and
11-5
-------
peak flow measurements with exercise than did the "normals," based on data
adjusted for subject age, height, and weight. The magnitude of these changes
did not correlate with age. Both groups showed similar changes in most of the
other lung-function measurements. Regression analysis showed no significant
associations of functional changes with TSP, total sulfate, total MM,, or N09.
*5 £*.
Increasing CU was correlated with decreasing peak flow and 1-sec forced expira-
tory volume (FEV..). No explanation was given for the observed association of
increasing CO with increasing RV and with the slope of the alveolar plateau
(SBNT). Increasing SO,, was significantly associated with increasing RV and
total lung capacity (TLC). In multiple regression analysis, 0~ was the variable
contributing the most variation in FEV., and maximum expiratory flow (.^maX2B7^'
as well as in the FEV-j^ normalized for forced vital capacity (FEV-j/FVC%), TLC,
and pulmonary resistance (R.) in the normal/allergic group. Although other
pollutant variables contributed to the observed effects, none did so consis-
tently. Apart from 03, functional changes on control days (intraindividual
variability), smoking habits, and age appeared to explain the functional
changes in normals/ allergies during exposure. In asthmatics, all pollutant
variables except TSP were significant in one or more analyses, but not all
consistently. Asthmatics and normals/allergies also had significantly increased
symptom scores during ambient air exposure sessions (Figure 11-1).
Nine of 12 subjects from this study (Linn et al., 1980, 1983) known to be
highly reactive to 0- (four from the normal/allergic group and five asthmatics,
a similar proportion from each group), who had experienced a fall in FEV-, greater
than 200 ml during ambient exposure (compared to purified-air exposure), under-
3
went a controlled 2-hr exposure experiment at 392 ug/m (0.2 ppm) with intermit-
tent exercise. Among these nine reactive subjects, the mean FEV-, change in the
ambient exposure was -273 ± 196 ml (-7.8 ±6.3 percent of pre-exposure). This
change was significantly greater than the mean change of -72 ± 173 ml (3.1 ±
6.6 percent pre-exposure) in the control setting. Although the authors sug-
gested the possibility that ambient photochemical pollution may be more toxic
than chamber exposures to purified air containing only ozone, other explanations
for the differences were given, including the effect of regression toward the
mean. More direct comparative findings published recently by Avol et al.
(1984) (see following text) showed no differences in response between chamber
exposures to oxiriant-polluted ambient air and purified air containing a
controlled concentration of 0-. Normal/allergic subjects in the validation
11-6
-------
30
§ 20
O
eo
10
1 f
AMBIENT AIR
PURIFIED AIR
I
I
PE 1C LD
ALL
PE 1C LD
NORMAL
AND
ALLERGIC
PE 1C LD
ASTHMATIC
Figure 11-1. Changes in mean symptom score with
exposure for all subjects, for normal and allergic subjects,
and for asthmatic subjects. PE = pre-exposure; IC = in
chamber (near end of exposure period); LD = later in day.
Circles ( O or •) indicate total symptom scores; triangles
( A or A ) Indicate lower-respiratory symptom scores. Solid
symbols indicate that ambient exposure score is
significantly higher for indicated time period and/or
increased significantly more relative to pre-exposure value.
Open symbols indicate that the difference between
ambient and purified air scores was not significant.
Source: Adapted from Unn et al. (1980).
11-7
-------
studies also showed similar findings in the exposure chambers compared to the
outside ambient air when the levels were similar inside and out.
Linn et al. (1982, 1983) repeated the initial experiment (Linn et a!.,
1980) with 64 different subjects, ages 18 to 55, in Hawthorne, CA, which had
low 03 levels (0.04 ± 0.02 ppm, 82 ± 39 ug/m3) but elevated levels of other
pollutants. They found no statistically significant lung-function or symptom
changes, and they concluded that 0- was primarily responsible for the effects
seen in the original study.
In 1980, a third experiment (Linn et al., 1983; Avol et al., 1983) was
conducted at the original oxident-polluted location (Duarte) with 60 physi-
cally fit subjects, aged 18 to 55, who exercised heavily (four to five times
resting minute ventilation) and continuously for 1 hr. The mean 0™ concentra-
3
tion was 314 ug/m (0.16 ppm) in ambient air (measured by the UV method).
Total reported symptoms, did not differ significantly between exposure and
control (purified-air) conditions. For the complete group, small functional
decrements in FEV, were found (3.3 percent loss, P < 0.01), more or less
comparable to those in the original (1978) study. A number of the subjects
showed functional losses during exposure that were still present after a 1-hr
recovery period at rest in filtered air. Those in the most reactive quartile
(those who experienced 320 to 1120-ml losses, versus control) were compared
with the least reactive quartile (increases of 60 to 350 ml). They did not
differ by age, height, sex, smoking, medication use, prevalence of atopy, or
asthma. Negative FEV- changes occurred more frequently (34 of 47 cases) at 0,
3
exposure concentrations above 235 ug/m (0.12 ppm), up to the maximum observed
3
(549 ug/m ; 0.28 ppm) in the total study group (P = 0.02). Even at the upper
end of this range, however, a number of subjects showed no decrement in func-
tion. The authors stated that the marked functional losses measured in the
most reactive subjects in this study were not necessarily accompanied by
symptoms, nor were they related to obvious prior physical or clinical status.
In 1981, a fourth study (Linn et al., 1983; Avol et al., 1983) presented
data on 98 subjects, including 50 asthmatics, who were exposed in Duarte to
mean CL levels of 306 ug/m3 (0.156 ppm) and 166 ug/m3 TSP (lower than in
3
1980). The highest 0- exposure concentration was 431 pg/m (0.22 ppm), which
was lower than the levels measured in 1980. The subjects were exposed to
heavy, continuous exercise (though at slightly lower exercise ventilation
levels than in 1980). The normal subjects showed a pattern of forced expira-
tory changes that were similar to those reported in 1980; however, the mean
11-8
-------
FEV, decrease with exposure to ambient air was much smaller. The only signi-
ficant change reported for this group was for FVC (P <0.003). The asthmatics
had decrements in forced expiratory performance during both exposures, but the
mean FEV.. decrease remained depressed for up to 3 hr after exposure to ambient
air. Maximum mean changes in FVC and FEV.. for asthmatics after exposure to
ambient air were 122 ml and 89 ml, respectively, with the former returning
more quickly to control levels. The value for VmaxcQV was more variable with
a maximum mean change of 132 L/s after exposure to ambient air. There were
also significant interactions of ambient and purified air after exposure in
asthmatics for FEV, and Vm^Ktw
1 max50%
The subject population was expanded in the summer of 1982 to include
well-conditioned athletes undergoing 1 hr of continuous heavy exercise (six to
ten times resting minute ventilation) (Avol et a!., 1984, 1985c) Volunteer
competitive bicyclists (n=50) were exposed in the mobile chamber to purified
air containing 0, 157, 314, 470, and 627 ug/m3 (0, 0.08, 0.16, 0.24, and 0.32
ppm) Og and to ambient air in the Duarte location. Pollution conditions were
milder than in previous summers so that comparable ambient exposure data were
available for only 48 subjects (Table 11-1). Mean concentrations during
3
ambient exposures were 294 ug/m (0.15 ppm) 0, with a range of 235 to 372
3 3
ug/m (0.12 to 0.19 ppm) and 295 ug/m total suspended particulate matter
3
(TSP). Mean particulate nitrate and sulfate concentrations were 40 (jg/m and
3
13 ug/m , respectively. For the controlled exposure studies, no functional
3
decrements in FEV1 were found at 0 or 157 ug/m (0 or 0.08 ppm) 0-»; however,
3
statistically significant decrements were found at 314, 470, and 627 ug/m
(0.16, 0.24, and 0.32 ppm) 0, (see Section 10.2.3). Symptom increases general-
ly paralleled the FEV., decrements (Figure 11-2). Statistically significant
decrements in FEV, were also observed during the ambient exposure studies (5
percent) and were not significantly different from those obtained with 0.16
ppm 03. At the generated 0, concentrations of 0.24 and 0.32 ppm, an increasing
number of subjects could not complete the 1 hr of exercise without reducing
their workloads. Exposure to ambient air or 0.16 ppm 0- produced no decreases
in workloads, even though statistically significant decrements in lung function
and increased symptoms did occur. Comparisons on an individual basis showed
that ambient exposure responses differed only randomly from predictions based
on the generated 0~ concentration-response information. Symptom increases
during ambient exposure were slightly less than predicted. Thus, no evidence
11-9
-------
40 r
100 -r
0.16
0.32
Ozone Concentration, ppm
Figure 11 -2. Changes in group mean responses, including
FEV1 0, symptoms, and exercise performance in 50
competitive cyclists exercising continuously for 1 hr while
exposed to ozone.
Source: Adapted from Avol et al. (1985c).
11-10
-------
was found to suggest that any pollutant other than 0, contributed to the
observed effects produced by ambient air.
The mobile laboratory was used again in Duarte, CA, during the summer of
1983 to determine if younger subjects were affected by exposure to ambient
levels of photochemical oxidants. Avol et al. (1985a,b) studied forced expira-
tory function and symptom responses in 59 healthy adolescents, 12 to 15 years
of age (Table 11-1). Each subject received a screening examination including
medical history, pulmonary function tests, resting EKG, and exercise stress
test. All subjects denied smoking regularly. Fifteen of the subjects had a
history of allergy and two of the subjects gave a history of childhood asthma
but denied recent asthmatic symptoms. The subjects were randomly exposed to
3
purified air and to ambient air containing 282 yg/m (0.144 ppm) CL and 153
3
ug/m total suspended particulates while continuously exercising on bicycle
ergometers at moderate levels (V> = 32 L/min) for 1 hr. Pulmonary function
tests were performed pre- and post-exposure. Symptoms were recorded at 15-min
intervals and immediately post-exercise. Following the exposure period, the
subjects rested in purified air for 1 hr, after which symptoms and pulmonary
function were measured again. After ambient exposure, there were statistically
significant decrements in FVC (2.1 percent), FE\/Q -,^ (4.0 percent), FEV-, Q
(3.7 percent), and PEFR (4.4 percent) relative to control exposure. Although
some reversal of these changes was evident at 1 hr post-exposure, decrements
in pulmonary function were still present compared to the preexposure levels.
A linear regression analysis showed that individual FEV-, Q responses were
negatively correlated (r = 0.37, P <0.01) with Individual ambient (k exposure
concentrations. Analysis of the data set revealed no significant differences
in responses between the fifteen "allergic" subjects and the rest of the
group. In addition, although girls tended to show larger decreases in FEV-, „
with ambient exposure than boys (7.5 percent and 3.4 percent, respectively),
the difference was not statistically significant. The authors attributed the
lack of significance as possibly due to the smallnumber (n = 13) of girls in
the study. There were no significant increases in symptoms with ambient
exposure relative to control. The lack of symptoms in adolescents at ambient
0- concentrations that produce statistically significant decrements in pulmonary
function is an interesting and potentially important observation from this
study, since adults exposed in the mobile laboratory under similar conditions
report symptoms of lower respiratory irritation accompanying decrements in
forced expiratory function (Linn et al., 1980, 1983; Avol et al., 1983, 1984).
11-11
-------
Factors contributing to the differences in response between adolescents and
adults are not yet known.
11.2.2 Symptoms and Pulmonary Function in Field or Simulated High-Altitude
Studies
Early reports of high 0^ concentrations in aircraft flying at high alti-
tudes prompted a series of field and high-altitude simulation studies. In
1973, Bischof reported that 0, concentrations (measured by a Comhyr ECC meter)
during 14 spring polar flights (1967-1971) varied from 0.1 to 0.7 ppm, with 1-hr
peaks above 1.0 ppm occurring, despite ventilation. More recently, Daubs (1980)
reported 03 concentrations in Boeing 747 aircraft ranging from 0.04 to 0.65 ppm,
with short-term (2 to 3 min) levels as high as 1.035 ppm. Other reports (U.S.
House of Representatives, 1980; Broad, 1979) have indicated that 0^ concentra-
tions in high-altitude aircraft can reach excessively high levels; for example,
on a flight from New York to Tokyo a time-weighted concentration of 0.438 ppm
was recorded, with a maximum of 1.689 ppm and a 2-hr exposure of 0.328 ppm.*
Flight attendants and passengers in high-altitude aircraft have complained
of certain symptoms (chest pain, substernal pain, cough), which are,identical
to those typically reported in subjects exposed to 0., and other photochemical
oxidants (see 11.3.1.1). The symptoms were most prevalent during late winter
and early spring flights. Similar symptoms have also been observed in more
systematic studies of high-altitude effects, such as (1) the study by Reed
et al. (1980), in which symptoms among 1,330 flight attendants were found to
be related to aircraft aircraft type and altitude duration but not to sex,
medical history, residence, or years of work; and (2) the Tashkin et al.
(1983) study, in which increased Og-related symptoms were reported by flight
attendants on Boeing 747SP (higher-altitude) flights in comparison to atten-
dants on lower-flying 747 flights. In neither of these two studies, however,
were concentrations of 03 or other photochemical oxidants measured in the
aircraft.
*Note that, as ambient pressure decreases at high altitude, 03 concentra-
tions remain the same as expressed in terms of ppm levels, but 03 mass concen-
trations (in ug/m3) decrease in direct proportion to increasing altitudes.
Therefore, knowledge of prevailing atmosphere pressure and temperature is
generally needed for correct conversion of ppm 03 readings to ug/m3 03 concen-
trations under specific measurement conditions.
11-12
-------
In a series of altitude-simulation studies, Lategola and, associates
(198Qa,b) attempted a more quantitative evaluation of effects on cardiopulmonary
function and symptoms associated with 0- exposures of male and female flight
attendants, crew, and passengers. Two studies (Lategola et al., 198Qa) were
conducted on young surrogates of a mildly exercising flight attendant popula-
tion, while a third study (Lategola et al., 1980b) evaluated older surrogates
for ^sedentary airline passengers and cockpit crew. All studies simulated
in-flight environmental conditions at 1829 m (6000 ft) and all subjects served
as their own controls. The results indicate increased symptoms and pulmonary
function decrements among nonsmoking normal adult subjects at 0.30 ppm, but
not 0.2 ppm under light exercise conditions. It should be noted that the 0™
levels used in the Lategola studies are generally lower than 0, concentrations
reported to occur in certain aircraft at high altitudes, as are the simulated
altitudes employed in the studies.
11.3 EPIDEMIQLQGICAL STUDIES OF EFFECTS OF ACUTE EXPOSURE
Effects of the acute exposure of communities to photochemical oxidants
are generally assessed by comparing the functional or clinical status of
residents during periods of high and low 0~ or oxidant concentrations. Occa-
sionally, two or more communities with different concentrations are compared.
The concentrations measured have been 24-hr averages, maximum hourly averages,
or instantaneous peaks.
11.3.1. Acute Exposure Morbidlty Effects
For purposes of this document, indices of acute morbidity associated with
photochemical oxidants include the incidence of acute respiratory illnesses;
symptom aggravation in healthy subjects and in patients with asthma and other
chronic lung diseases; and effects on pulmonary function, athletic performance,
auto accident rates, school absenteeism, and hospital admissions.
11.3.1.1 Symptom Aggravation in Healthy Populations. Various symptoms,
including eye irritation, headache, and respiratory irritation, have been
reported during ambient air exposure in a number of studies (Table 11-2). Eye
irritation, however, has not been associated with 0, exposure in controlled
laboratory studies (Chapter 10). This symptom has been associated with other
photochemical oxidants such as peroxyacetyl nitrate (PAN) and with formaldehyde,
acrolein, and other organic photochemical reaction products (National Air
Pollution Control Administration, 1970; Altshuller, 1977; U.S. Environmental
11-13
-------
Protection Agency, 1978; National Research Council, 1977; Okawada et al.5
1979). Of the biological effects caused by or aggravated by photochemical air
pollution, eye irritation appears to have one of the lowest thresholds. It
also appears to be a short-term, reversible effect, however, since damage to
conjunctiva and subjacent tissue has not been reported.
Qualitatively, the occurrence of an association between photochemical
oxidant exposure and symptoms such as cough, chest discomfort, and headache is
plausible, given similar findings of occupational exposure to oxidants (see
11.3.1.7) and of controlled human exposure studies (Chapter 10). The primary
issues in question, however, in the studies cited in Table 11-2, are: (1) the
composition of the mixture to which the subjects were exposed; (2) the concen-
trations and averaging times for oxidants in ambient air; and (3) the adequacy
of methodologic controls for other pollutants, meteorological variables, and
non-environmental factors in the analysis. For these reasons, the studies are
of limited use for developing quantitative exposure-response relationships for
ambient oxidant exposures.
11.3.1.2 Altered Performance. The possible effects of photochemical oxidant
pollution on athletic and driving performance have been examined in studies
described in Table 11-3. The absence of definitive monitoring data for impor-
tant pollutants as well as confounding by environmental conditions such as
temperature and relative humidity detracts from the quantitative usefulness of
these studies. Qualitatively, however, the epidemiological findings relative to
athletic performance are consistent with the evidence from field studies
(Section 11.2.1) and from controlled human exposure studies (Section 10.4)
indicating that exercise performance may be limited by exposure to 0,.
11.3.1.3 Acute Effects on Pulmonary Function. A summary of studies on the
acute pulmonary function effects of photochemical oxidant pollution is given
in Table 11-4. Previously reviewed studies (U.S. Environmental Protection
Agency, 1978) suggested a possible association between decrements in pulmonary
function in children and ambient ozone concentrations in Tucson, Arizona
(Lebowitz et a!., 1974) and Tokyo, Japan (Kagawa and Toyama, 1975; Kagawa et
a!., 1976). An additional study (McMillan et al.5 1969) comparing acute
effects in children residing in high- and low-oxidant areas of Los Angeles
failed to show any significant differences in pulmonary function. None of
these studies, however, meets the criteria necessary for developing quanti-
tative exposure-response relationships for ambient ozone exposures.
11-14
-------
TABLE 11-2. SYMPTOM AGGRAVATION IN HEALTHY POPULATIONS EXPOSED TO PHOTOCHEMICAL OXIDANT POLLUTION
Concentration(s)
ppm
'Pollutant
Study description
Results and comments
Reference
0.08-0.50 max 1-hr/day
(1954)
0.04-0.78 max 1-hr/day
(1955)
0.05-0.49 max 1-hr/day
(1956)
Oxidant Panel studies of office and factory
•workers in Los Angeles during 1954-..
- 1956.
Eye irritation increased with oxidant concen-
tration; no discrete oxidant threshold.
Although oxidants explained a higher propor-
tion of the variation in eye irritation,
other pollutants were associated with this
symptom.
Renzetti and Gobran, 1957d
<0.27 (@ 11:00 a.m.
~ daily)
Oxidant Effectiveness of air filtration for
removing eye irritants in 40 female
telephone company employees over 123
work days in Los Angeles from May to
November 1956.
Increased eye irritation associated with
oxidant concentration and temperature in
the nonfiltered room; severity increased
above 0.10 ppm. No correlations with N02
or PM; however, other pollutants were not
measured.
Richardson and Middleton,
1957a, 1958a
H<0.04-0.50
I max 1-hr/day
ui
Oxidant Symptom rates from daily diaries of
students at two nursing schools in
Los Angeles from October 1961 to
June 1964. Maximum hourly oxidant
concentrations from two monitors
located within 0.9 to 2 miles of
both hospitals.
Eye discomfort reported at oxidant levels
between 0.15 and 0.19 ppm, cough at 0.30
to 0.39 ppm, headache and chest discomfort
at 0.25 to 0.29 ppm. Symptom frequencies
related more closely to oxidants than CO,
N02, or temperature, although rigorous statis-
tical treatment is lacking.
Hammer et al., 1974a
£0.3 max l-hr(?)/day
Oxidant Daily symptom rates from 854 students
in Tokyo during July 1972 to June :
1973. Measurement methods for oxidant,
NO, N02, S02, and PM were not reported.
Highest correlations reported between symp-
toms and oxidants; increased rates for eye
irritation, cough, headache, and sore throat
on days with max. hourly oxidant >0.10 ppm;
no significant correlations with S02, N02 or
NO, although some symptoms were correlated with
temperature. Effects of acute respiratory
illness were not considered; measurement meth-
ods not reported.
Makino and Mizoguchi, 1975
0.07-0.19
max 1-hr/day
Oxidant Questionnaire survey on subjective
symptom rates at two junior high
schools in Osaka, Japan during the
fall of 1972. ,
Symptoms classified as (a) eye irritation,
(b) cough and sore throat, and (c) nausea,
dizziness, and numbness of the extremities;
symptom rate and distribution correlated with
physical exercise. Findings point out vari-
able symptom distribution from multiple
pollutants in ambient air.
Shiraizu, 1975a
-------
TABLE 11-2 (continued). SYMPTOM AGGRAVATION IN HEALTHY POPULATIONS EXPOSED TO PHOTOCHEMICAL OXIOANT POLLUTION
Concentration(s)
ppm
Pollutant
Study description
Results and coanents
Reference
<0.39 max
~ (undefined)
Oxidant Survey of student health during 180
days in 1975.
Number of students reporting symptoms
increased with increasing oxidant concen-
tration. No symptom rates reported;
questionnaire use presented likely bias;
other pollutants were not considered.
Japanese Environmental
Agency, 1976a
<0.23
max 1-hr/day
H
V
Oxidant Questionnaire survey on subjective
symptoms in 515 students at a junior
high school in Tokyo from May to
July 1974; maximum hourly oxidant
concentrations by KI.
Differences between high- and low-oxidant
days in symptom rates for eye irritation
and lacrimation, sore throat, and dyspnea.
Other pollutants, particularly S02. SO >
or acrolein, may have been contributing
factors.
Increased symptom rates for eye irritation,
sore throat, headache, and cough on days with
oxidant >0.15 ppm compared to days with oxi-
dant <0.10 ppm. Some symptoms were corre-
lated with SQ2, PM, and rh; however, not all
possible environmental variables were consi-
dered.
Shimizu et al., 1976a
Mizoguchi et al., 1977d
0.02-0.21 daily
maxima
(undefined)
Oxidant Association between eye irritation
and photochemical oxidants in 71
Tokyo hifh school students for 7 days
during two summer sessions; daily
maximum oxidartt concentrations by KI;
tear lysozyrae, pH, and eye exam
measured daily.
Tear lysozyme and pH decreased on two highest
oxidant days compared to two lowest oxidant
days; eye irritation incidence rates increased
with oxidant concentrations >0.1 ppm; eye
irritation produced by HCHO, PAN, and PBZN.
Okawada et al., 1979
Reviewed in U.S. Environmental Protection Agency (1978).
-------
TABLE 11-3. ALTERED PERFORMANCE ASSOCIATED WITH EXPOSURE TO PHOTOCHEMICAL OXIDANT POLLUTION
Concentration^)
ppm
Pollutant
Study description
Results and comments
Reference
0.03-0.30
max 1-hr/day
0.06-0.38
l_> max 1-hr/day
Oxidant Athletic performance of student
cross-country track runners in
21 competitive meets at a high
school in Los Angeles County
from 1959 to 1968. Daily maximum
hourly concentrations of oxidants,
NO, NQ2, CO, and PM by LA-APCD.
Data extended to include the seasons
of 1966 to 1968.
Percentage of team members failing to improve their
performance increased with increasing oxidant
concentration in the hour before the race; however,
convincing individual linear relationships were not
demonstrated.
Inverse relationship between running speed and
speed and oxidant after correcting for average
speed, time, season, and temperature. No correla-
tion with NO , CO, or PM; however, SQ^ was not
examined.
Wayne et al., 1967"
Herman, 1972
0.02-0.24
max 1-hr/day
Oxidant Association of automobile acci-
dents with days of elevated
hourly oxidant concentrations
in Los Angeles from August
through October for 1963 and
1965.
Association of automobile acci-
dents in Los Angeles with elevated
oxidant concentrations from the
summers of 1963 and 1965 and
with CO concentrations from the
winters of 1964-1965 and 1965-
1966.
Accident rates were higher on days with hourly
oxidant levels >0.15 ppm compared to days <0.10
ppm. Other pollutants were not evaluated.
Sample size reduced by excluding accidents in-
volving alcohol, drugs, mechanical failure, rain,
or fog.
Strong relationship between accident rates and
oxidant levels; temporal pattern suggests
the importance of oxidant precursors; no
consistent relationship with lagged oxidant
concentration or with CO concentrations. Other
pollutants, possibly NO and SO , may have
confounded the association; questionable effect
of traffic density.
Ury, 1968"
Ury et al., 1972d
Reviewed in U.S. Environmental Protection Agency (1978).
-------
TABLE 11-4. ACUTE EFFECTS OF PHOTOCHEMICAL QXIDANT POLLUTION ON PULMONARY FUNCTION OF CHILDREN AND ADULTS
Coneentration(s)
ppm
Pollutant
Stwjy description
Results and cowtients
Reference
0.01-0,67
daily maxima
(undefined)
Oxidant Comparison of ventilatory performance
in two groups of third-grade children
residing in high (n=50) and low (n=28)
oxidant areas of Los Angeles fron
November 1966 to October 1967,
Ho correlation between acute effects on PEFR
(Wright Peak Flow Meter) and oxidant concen-
centrations; however, persistently higher
PEFR and greater variance were obtained
from the children residing in the high oxidant
area; possible confounding by respiratory
infections.
McMillan et al.,
1969a
0.01-0,12 range
of hourly averages
for 1 day
Oxidant Combined effects of air pollution and
weather on the ventilatory function
of exercising children, adolescents,
and adults in Tucson, Arizona during
the spring and summer of 1972.
B
Significant post-exercise decreases in lung
function were observed in adolescents but not
adults; however, differences in exercise
regimens suggest a possible exercise effect.
Monitors recording hourly peak oxidant con-
centrations for adolescents and adults were
at least 3 miles away; no oxidant data given
for children's study. TSP nay have contri-
buted to the observed effect.
Lebowitz et al.,
1974a
0.01-0.15
max 1-hr/day
0.03-0.17
max 1-hr/day
Ozone Effects of environmental factors on
the pulmonary function of 21 children,
aged 11 yrs, at an elementary school
Oxidant in Tokyo, Japan from June to December
1972; hourly average concentrations
of oxidant (MBKI), 08 (CHEM), N02t NO,
HC, and PM measured on top of the three-
story school.
Pulmonary function correlated with temperature
far more than any other environmental variable;
03, NO, S02, and HC were the pollutants most
frequently correlated with changes in pulmonary
function; 03 was correlated with Raw, SGaw, and
FVC in only 2SX of the subjects. Partial
analyses after correcting for temperature
reduced the number of significant
correlations.
Kagawa
1975a
and Toy ana,
<0.30 averaged over
each 2-hr study
period
Ozone Effects of high- and low-temperature
seasons on the pulmonary function of
19 children at an elementary school in
Tokyo, Japan from November 1972 to October
1973; hourly average concentrations of
Oa, NO, N02, S02, and PM were measured
at the school.
Temperature was positively correlated with
Raw, Vso, and v^s. and negatively correlated
with SGaw; however, the effect of temperature
on Raw was season-dependent. 03 was positively
correlated with Raw and negatively correlated
with SGaw in both high- and low-temperature
seasons; however, correlations were more consis-
tent in the low-temperature period when 03 was
lowest (<0.10 ppm); partial analyses after
correcting for temperature still revealed signi-
ficant 03 correlations with Raw. Five subjects
showed correlations of function and multiple
environmental factors, indicating selective
sensitivity in the population.
Kagawa et al.
1976a
-------
TABLE 11-4 (continued). ACUTE EFFECTS OF PHOTOCHEMICAL OXIOANT POLLUTION ON PULMONARY FUNCTION OF CHILDREN AND ADULTS
Concentrati on(s)
ppm
Pollutant
Study description
Results and comments
Reference
0.046-0.122
max 1-hr/day
Ozone Effects of ambient photochemical oxidant
exposure on pulmonary function of 83
children (aged 8 to 13) at a 2-week
day camp in Indiana, PA during the summer
of 1980; 1-hr peak 03 concentrations were
estimated by regional exposure modeling
techniques; 6-hr ambient TSP and H2S04
were monitored at the campsite.
Significant relationship for peak flow
(Wright Peak Flow Meter) and daily peak 0,
for 23 children; FVC and FEV, were J
significantly lower on 1 day when the 0,
peak was 0.11 ppm compared to days when the
0, peak was <0.08 ppm. Analysis of regres-
sion slopes does not demonstrate any conclusive
associations for sex, other pollutants, or
ambient temperature. Questionable exposure
modelling raises uncertainty about the
quantitative interpretation of these results.
Lippmann et al.,
1983°
0.09-0.12
max 1-hr/day
1
H
Ozone As part of a community population sample
of 117 families from Tucson, AZ, venti-
latory function was studied in 24 healthy
children and young adults (aged 8 to 25
yrs) for an 11-month period in 1979 and
1980; 1-hr maximum concentrations of
03 (CHEM), N02, CO, and daily levels of
TSP, allergens, and weather variables
were monitored at central stations within
k mile of each cluster of subjects.
Correlation of peak flow (Wright Peak Flow
Meter) with average maximum hourly Os was not
significant; after correcting for season and
other pollutants, 03 and TSP were negatively
correlated with peak flow; use of multifactor
analysis to control for person days, weather
variables, CO, N02, and TSP showed significant
independent correlations of 03 with peak flow
and significant interactions between 03 and TSP
and 03 and temperature. Regressions of resi-
dual and predicted Vmax with 03 were also
significant. Small number of subjects and
interaction with other environmental condi-
tions limit the quantitative interpretations
of these studies.
Lebowatz et al.
1983°, 1985°;.
Lebowitz, 1984
0.02-0.14
max 1-hr/day
Ozone Effects of ambient photochemical oxidant
exposure on pulmonary function of healthy
active children (aged 7 to 12) at a summer
day camp in Mendham, NJ from July 12 to
August 12,. 1982; state regional .pollution
monitoring of 03 (CHEM), TSP (H , S04,
and NOg), temperature, and rh at a station
6 km from the camp.
Linear regression and correlation coefficient
analyses between 03 and pulmonary function (FVC,
FEV, PEFR, and MMEF) showed a significant asso-
ciation for PEFR only. Girls appeared to be more
susceptible than boys but there was no statistical
treatment of the differences. Large variability
in regression slopes suggests effects Jron other
environmental conditions (temp, S04, H ); results
of aerosol sampling were not reported and other
pollutants were not considered. Lack of signi-
ficant effect for FEVj and FVC which have lower
coefficients of variation than PEFR is question-
able. In addition, difficulty in judging the
relationship between 03 and acid sulfates or
other environmental conditions limits the
quantitative use of these studies.
lann and Lioy,
1985"; Bock et al.,
1985°; Lioy et al.,
1985°.
-------
TABLE 11-4 (continued). ACUTE EFFECTS OF PHOTOCHEMICAL OXIDANT POLLUTION ON PULMONARY FUNCTION OF CHILDREN AND ADULTS
Concentration(s)
ppm
Pollutant
Study description
Results and comments
Reference
H
E
, o
0.004-0.135
yvg time-weighted
15-min max
Ozone Pulmonary function of healthy adults
exercising vigorously at a high
school track near Houston, TX during
May-October, 1981. Continuous moni-
toring of 03 (CHEH), S02, N02, CO,
temperature, and rh at the track
averaged over 15-min intervals
during the time of running; 12-hr
averages for fine inhalable
particulates.
Simple linear regression analysis showed a
significant association between decreased lung
function and increasing 03 concentration; how-
ever, after adjusting for rh, the changes were
no longer statistically significant. Weighted
multiple linear regression analysis adjusted
for temperature and rh was not significant for
00. Other pollutants were not considered.
Selwyn et al., 1985U
Reviewed in U.S. Environmental Protection Agency (1978).
See text for discussion.
-------
Lippmann et al, (1983) studied 83 nonsmoking, middle-class, healthy
children (ages 8 to 13) during a 2-week summer day camp program in Indiana,
PA. The children exercised outdoors most of the time. Afternoon measurements
included baseline and post-exercise spirometry (water-filled, no noseclips).
®
Peak flow rates were obtained by Mini-Wright Peak Flow Meter at the beginning
of the day or at lunch, adjusted for both age and height. No day-of-week
effect was seen. Ambient air levels of TSP, hydrogen ions, and sulfates were
monitored by a high-volume sampler on the rooftop of the day camp building.
Ozone concentrations1 were estimated as a weighted average of data extrapolated
from a monitoring site 20 mi south and a site 60 mi west, using two models
2
that yielded 0,, estimates within ±16 ug/m (0.008 ppm) on the average. Esti-
3
mated 1-hr peak 0, levels (early afternoon) varied from 90 to 249 ug/m (0.046
3
to 0.122 ppm), and TSP levels were <103 ug/m (6-hr samples) and maximum
q
sulfuric acid (HgSO*) concentrations were £6.3 ug/m .
Lippmann et al. (1983) reported significant inverse correlations between
FVC and FEV-. and estimated maximum 1-hr 0- levels for 4 or more days on which
0,, concentrations covered a twofold range. Differences in correlations (i.e.,
slopes) were not related to other pollutants (TSP, H^SO*) or ambient tempera-
tures. Qualitatively, the Lippmann et al. (1983) study results suggest low-
level 03 effects; however, because exposure modeling (rather than on-site
monitoring) was used to estimate 0, levels, and because the effects were seen
almost entirely on one day of the study, there is uncertainty about the precise
quantitative interpretation of these findings.
A similar group of children was studied during the summer at a day camp
in Mendham, NJ (Lippmann and Lioy, 1985; Bock et al., 1985; Lioy et al.,
1985). Pulmonary function data were obtained from the children, aged 7 to 13
years, during 16 days of a 5-week period from July 12 to August 12, 1982. In
order to provide better air monitoring data, 0, concentrations were measured
(UV) at the Mendham camp site and at a NJ sampling station 3.5 mi away. Only
data from the sampling station were used in the analysis. The average highest
3
peak 1-hr 0- concentration measured on a study day was 280 ug/m (0.143 ppm);
values ranged from 39 to 353 ug/m3 (0.02 to 0.19 ppm) 03 during the 5-week
period., Daily averages for ambient temperature, relative humidity, and precipi-
tation were provided by the National Weather Service.' Ambient aerosol samples
were also analyzed on a daily basis, but the results were not reported. A
linear regression was calculated for each child between peak 1-hr 0~ and each
of four measures: FVC, FEV-,, PEFR, and MMEF. In addition, a summary weighted
11-21
-------
correlation coefficient was calculated for all subjects. No adjustments were
made for covariates. Linear regressions were negative except for FVC in boys.
Decrements in PEFR were significantly correlated with peak 0- exposure but
• O ' '
there were no significant correlations with FVC, FEV-, or MMEF.
Several comparisons can be made between the data reported by Lippmann et
al. (1983) and those reported by Lippmann and Lioy (1985), Bock et al. ,(1985),
and Lioy et al. (1985). There were 39 children (22 girls, 17 boys) in, the
follow-up study for whom sufficient data existed for linear regression analysis.
The children in Mendham, NJ, were not as physically active as the children
studied in the previous study in Indiana, PA, which may account for some
observed differences in results from the two studies. While 0--dependent
changes in PEFR were reported in both studies, the authors did not observe the
Oy-dependent change in FVC and FEV.^ in the follow-up study that they found in
the previous study. This lack of a significant effect for FVC and FEVp which
are known to have smaller coefficients of variation than PEFR, is surprising,
especially considering the higher 03 concentrations reported in Mendham, NJ.
Concentrations of inhalable particulate matter were also reported to be higher
in association with a large-scale regional photochemical smog episode which
may have had some effect on baseline lung function (Lioy et al., 1985). In
addition, adjustments for covariates such as temperature and relative humidity,
which might influence lung function, would have strengthened the reported
results. The differences in transient reponses to 03, the lack of definitive
exposure data for other pollutants (particularly ambient aerosols), and the
lack of adjustment for covariates limit the usefulness of these studies for
determining quantitative exposure-response relationships for 0,.
Lebowitz et al. (1983, 1985) and Lebowitz (1984) measured daily lung
function in 24 Tucson, AZ, residents, aged 5 to 25 years. The subjects were
part of a stratified sample of families from geographic clusters of a large
community population under study. Over an 11-month period in 1979 and 1980,
randomly chosen subsets of these subjects were tested during each season of
the year. Measurements of peak flow were made in the late afternoon, using a
Mini-Wright® Peak Flow Meter (Wright, 1978; Williams, 1979; van As, 1982;
Lebowitz et al., 1982b). All age- and height-adjusted baseline peak.flows
were within the published normal range. To adjust for seasonal effects and
for inter-individual differences in means and variances, the daily peak flow
for each person was transformed into a standard normal variable. Seasonal
11-22
-------
means and standard deviations were then used to generate daily z-scores, or
standardized deviations from seasonal averages.
Regional ambient 0~ (measured by UV), CO, and NOp were monitored daily at
three sites in the Tucson basin (Lebowitz et a!., 1984). Every 6 days, 24-hr
TSP was measured at 12 sites, including stations at the center of each cluster
of subjects within a 0.25- to 0.5-mi radius. Since previous ambient monitoring
showed significant homogeneity of 03 in the basin, average regional values
were used for analysis of all geographic clusters, and closest-station values
for individual clusters. Comparisons showed no significant changes in results
when using regional averages or closest daily hourly maximum values. Indoor
and outdoor monitoring was conducted in a random cluster sample of 41 represen-
tative houses. Measurements of air pollutants, pollen, bacilli, fungi, algae,
temperature, and humidity were recorded once in each home for 72 hr during the
two-year study period; Regional daily ambient maximum hourly 0~ went up to
3 -
239 ug/m (0.12 ppm) and was highest in the summer months. Indoor 0~ concen-
3
trations were between 0 and 69 ug/m (0 and 0.035 ppm). Levels of CO were
less than 2.4 ppm (2736 g/m3) indoors and 3.8 to 4.9 ppm (4332 to 5586 g/m )
outdoors. Indoor CO was correlated with gas-stove use only. Daily average
ambient N09 ranged from 0.001 to 0.331 ppm (2 to 662 ug/m3). Outdoor TSP
3
ranged between 20 and 363 ug/m for all monitoring days and between 27.5 and
3
129 ug/m on days of indoor monitoring. Indoor TSP and respirable suspended
3 3
particle (RSP) ranges were 5.7 to 68.5 ug/m and 0.1 to 49.7 ug/m , respect-
ively, and were correlated with indoor cigarette smoking but not gas-stove
use.
In a preliminary analysis, 03 and TSP levels were negatively correlated
with peak flow, after correction for season and other pollutants. In a multi-
variate analysis of variance, controlling for person-days of observation,
meteorologic factors, CO, NO,,, and TSP, a significant effect of Q~ on peak
flow remained (p <0.001). A significant interaction of 03 with TSP was also
observed (z-scores more negative than predicted by an additive model at high
03 and TSP levels). In multiple regression analyses, the z-scores for person-
days with maximum hourly 03 level and mean 03 level of at least 0.08 ppm were
statistically significant (p <0.007 and p <0.0001, respectively). These
scores represented decreases in mean peak flow of 12.2 percent and 14.8 percent,
respectively. These changes were significantly different (p <0.05) from
changes reported in previously published data (Lebowitz et a!., 1982b) on
normal day-to-day variation in another, comparable group of children.
11-23
-------
Lebowitz et al. (1983, 1985) and Lebowitz (1984) observed a consistent
short-term effect of ambient ozone exposure on peak flow. The quantitative
usefulness of the study, however, for standard setting is limited by several
factors. Sample sizes were small in relation to the number of covariates.
The fixed-station aerometric data employed did not allow quantitation of
individual ambient pollution exposures. Likewise, since the time spent indoors
and outdoors was not measured in the children, the proper relative weights of
indoor and outdoor pollution measurements could not be determined for; quanti-
tation of exposure.
Selwyn et al. (1985) studied changes in ambient 03 concentrations in
relation to changes in the pulmonary function of healthy adults after vigorous
outdoor exercise. From May through October 1981, 24 local residents ran three
miles twice a week between 4:30 and 6:30 PM at a track near Houston, Texas.
Subjects kept their heart rates between 75 and 90 percent of heart rate during
maximal oxygen consumption. Levels of 03, S02, N02, CO, temperature, and
relative humidity (rh) were measured continuously beside the track. For each
run, a subjects' 03 exposure was considered to be the time-weighted 15-min
average of the maximum 03 concentrations measured during the run. Average
inhalable particulate levels were obtained every 12 hr. The average 0Q concen-
O ^ Q
tration during runs was 92 ug/m (0.047 ppm), with a range of 8 to 265 [jg/m
(0.004 to 0.135 ppm). Temperature averaged 85 degrees F., and rh averaged 62
percent during runs. Subjects performed forced expiratory maneuvers (FVC,
FEV-,, FEFpr-yr^, and FEFQ 2_n J before an<^ 15 min after each run. Changes in
the pulmonary function measures (calculated as post-run minus pre-run values)
were regressed against Oo concentration, with adjustment for temperature and
rh. In these regressions, most lung function changes were negatiavely asso-
ciated with 03 concentration, but the coefficients for 03 were not statisti-
cally significant at p = 0.05.
11.3.1.4 Aggravation of Existing Respiratory Diseases. A number of studies
have examined the effects of photochemical oxidants on symptoms and lung func-
tions of patients with asthma, chronic bronchitis, or emphysema. Most of the
earlier studies were evaluated in the 1978 EPA criteria document for ozone and
other photochemical oxidants (U.S. Environmental Protection Agency, 1978). The
results of these as well as more recent studies are summarized in Table 11-5.
For 10 weeks from July to September 1976, Zagraniski et al. (1979) followed
82 patients with asthma or hay fever (patient group) and 192 healthy telephone
company employees (worker group) in New Haven, CT. Subjects were asked to
11-24
-------
TABLE 11-5. AGGRAVATION OF EXISTING RESPIRATORY DISEASES BY PHOTOCHEMICAL OXIDANT POLLUTION
Concentrations J
ppm
0.2-0.7
max 1-hr/day
0.20-0.53
max 1-hr/day
Pollutant
Oxidant
Ozone
Study description
Effects of air filtration on pulmonary
function of 47/66 subjects with emphysema
staying for variable times in a Los Angeles
hospital during a 3k yr period in the late
1950' s; daily maximum hourly concentrations
of oxidant, 03, NO, N02, S02, and CO by
LA-APCD.
Results and comments
Improved lung function in emphysematous
subjects staying in the filtered room for
>40 hr; lack of control for smoking and
other pollutants.
Reference
Motley et al.,
1959a
0.13 median
Oxidant Daily records of the times of onset and
severity of asthma attacks of 137 asthmatics
residing and working in Pasadena, California
between September 3 and December 9, 1956;
daily maximum hourly average oxidant levels
(KI) from LA-APCD.
Of the 3435 attacks reported, <5% were asso-
ciated with smog and most of these occurred in
the same individuals; time-lagged correlations
were lower than concurrent correlations; mean
number of patients having attacks on days
>0.25 ppm was significantly higher than days
<0.25 ppm.
Schoettlin and
Landau, 1961a
(Not reported)
H
I
in
Oxidant Effects of community air pollution,
occupational exposure to air pollution, and
smoking on armed forces veterans with chronic
respiratory disease in the Los Angeles
Basin between August and December 1958;
total oxidant (KI) measured at the site.
No statistically significant effect of air
pollution on respiratory function or symptoms.
Schoettlin, 1962
<0.42 peak
(undefined)
Oxidant Longitudinal study of the effects of environ-
mental variables on pulmonary function of 31
patients with chronic respiratory disease
(predominantly emphysema) in a Los Angeles
hospital over a period of 18 months; total
oxidants (KI), 03, NO, N02, CO, PM, and
environmental conditions monitored at a
station k mile upwind from the hospital.
No consistent pattern of response to episodes
of high pollution exposure; possibility of
selective sensitivity in some subjects.
Unknown measurement method for oxidants. This
was only a preliminary study.
Rokaw and Massey,
1962a
<0.2 peak
(undefined)
Oxidant Effects of air filtration on pulmonary
function of 15 patients with moderately
severe COLD in a Los Angeles County
Hospital between July 1964 and February
1965; total oxidant (KI), NO, and NQ2
monitored five times daily.
Raw decreased and P 02 increased in both Remmers and
smokers and nonsmoklrs after 48 hr in the Balchum, 1965 ;
filtered room. Decreases in Raw were more Balchum, 1973;
strongly related to oxidants than N02 or NO; Ury and Hexter,
however, study lacks rigorous statistical , 1969
treatment. Questionable effects of smoking
and other pollutants.
0.09-0.37 maxima
(undefined)
Ozone Daily diaries for symptoms and medication
of 45 asthmatics (aged 7-72 yr) residing
in Los Angeles from July 1974 to June 1975;
daily average concentrations of 03, NO,
N02, S02, and CO by LA-APCD within the
subjects' residential zone.
No significant relationship between pollutants
and asthma symptoms; increased number of
attacks at >0.28 ppm in a very small number
of subjects; other factors such as animal
dander and other pollutants may be Important.
Kurata et al.,
1976
-------
TABLE 11-5 (continued). AGGRAVATION OF EXISTING RESPIRATORY DISEASES BY PHOTOCHEMICAL OXIDANT POLLUTION
Concentration(s)
ppm
(Not reported)
Pollutant
Ozone
Study description
Daily log for symptoms, medication, and
Results and cowients
Bad weather and high levels of SOg, CO, and
Reference
Khan, 1977
hospital visitation of 80 children with
asthma (aged 8-15 yrs) in the Chicago
area during 1974-1975; air quality data
on S02, CO, PM; partial data for 03,
pollen and climate.
PM exerted a minor influence on asthma,
accounting for only 5-15% of the total vari-
ance; high levels of 03 increased both the
frequency and severity of asthmatic attacks;
pollen density in fall, and winter temperature
variations had no influence. No exposure data
given for quantitative treatment.
0,004-0,235
max 1-hr
to
CTV
Ozone Daily symptom rates in 82 asthmatic and
allergic patients compared to 192 healthy
telephone company employees in New Haven,
CT from July to September 1976; average
maximum hourly levels of 03 and average
daily values for S02, TSP, SOf, pollen,
and weather were monitored witin 0.8 km
of where the subjects were recruited.
Maximum oxidants associated with increased
daily prevalence rates for cough, eye, and
nose irritation in heavy smokers and patients
with predisposing illnesses; pH of particulate
was also associated with eye, nose, and throat
irritation while suspended sulfates were not
associated with any symptoms. Questionable
exposure assessment, use of prevalence rather
than incidence data, lack of correction for
auto regression, and possible bias due to high
dropout rates limit the usefulness of this
study for developing quantitative exposure-
response relationships.
Zagram'ski h
et al., 1979°
<0.21
max 1-hr/day
Ozone Longitudinal study of daily health symptoms
and weekly spirometry in 286 subjects with
COLD in Houston, TX between July and October
1977 ("Houston Area Oxidants Study"); daily
maximum hourly concentration of 03 measured
at site nearest the subjects' residential
zone; partial peak levels of PAN, N02, S02,
HC, CO, PM, allergens, and temperature at some
monitoring sites.
Increased incidence of chest discomfort, eye
irritation, and malaise with increasing
concentrations of PAN; increased incidence
of nasal and respiratory symptoms and in-
creased frequency of medication use with
increasing 03 concentration; FEVt, and FVC
decreased with increasing 03 and total
oxidant (03 +• PAN) concentration. Questionable
exposure assessment and statistical analysis,
weak study design, and lack of control for
confounding variables limit the usefulness of
this study for developing quantitative exposure-
response relationships.
Johnson et al.,
1979°;
Javitz et al.,
1983°
-------
TABLE 11-5 (continued). AGGRAVATION OF EXISTING RESPIRATORY DISEASES BY PHOTOCHEMICAL OXIDANT POLLUTION
Goncentration(s)
ppm
Pollutant
Study description
Results and comments
Reference
0,03-0.15 medians
at 6 sites-
Oxidant Statistical analysis (repeated-measures
design) of CHESS data on daily attack
rates for juvenile and adult asthmatics
residing in six Los Angeles area communi-
ties for 34-week periods (May-December)
during 1972-1975; daily maximum hourly
averages for oxidants (KI) by LA-APCDs,
24-hr averages for TSP, RSP, SO , NO ,
SQ2, and NOZ by EPA, and meteorological
conditions were monitored within 1 to
8 miles of homes in each community.
Daily asthma attack rates increased on days
with high oxidant and particulate levels and
on cool days; presence of attack on the pre-
ceding day, day of week, and day of study
were highly significant predictors of an
attack; questionable exposure assessment in-
cluding lack of control for medication use,
pollen counts, respiratory infections, and
other pollutants and possible reporting biases
limit the usefulness of this study for
developing quantitative exposure-response
relationships.
Whittemore and
Korn, 1980
0.038-0.12
max 1-hr/day
H
H
Ozone As part of a community population sample of
117 families from Tucson, AZ, daily symptoms,
medication use, and ventilatbry function
were studied in adults with asthma, allergies,
or airway obstructive disease (ADD) for an
11-month period in 1979 and 1980; 1-hr maximum
concentrations of 03 (CHEM), N02, CO, and
daily levels of TSP, allergens, and weather
variables were monitored at central stations
within % mile of each cluster of subjects.
In adults with AOD, 03 and TSP were signifi-
cantly associated with peak flow (Wright
Peak Flow Meter) after adjusting for covari-
ables; however, no interaction for Oa + TSP
with peak flow. In adults with asthma, 03
was not significantly related to peak flow
after adjusting for covariables; however,
there was a significant interaction for 03
+ temperature with peak flow and symptoms.
Small number of subjects actually studied and
interaction with other environmental condi-
tions limit the quantitative interpretation
of these studies.
Lebowitz et al,
1982aD, 1983°;
1985D; b
Lebowitz, 1984
0.001-0.127
max 1-hr
Ozone Association of Oa exposure with the probabi-
lity of asthma attacks in subjects (aged 7-55
yrs) residing in two Houston communities during
May-Oct., 1981. Maximum hourly averages for
03 (CHEM), N02> CO, S02, temperature, and rh;
daily 12-hr averages for fine (<2.5 u) and
coarse (2.5-15 u) particles, aldehydes and
aeroallergens; daily 24-hr averages for TSP.
Fixed-rate-monitoring within 2,5 miles of sub-
jects residence; time-specific individual
exposure estimates were developed using
aerometric data and activity data for
individuals.
Increased probability of an asthma attack was
associated with the occurrence of a previous
attack and with exposure to increased Og con-
centration and decreased temperature; only
suggested importance of pollen. Magnitude of
the 03 effect varies with the levels of the
other covariates; however, other stimuli may
be involved including S02 and particulates
which were not analyzed. In addition,
uncertainties about the use of a logistic
regression model limits the usefulness of
this study for developing quantitative
exposure-response relationships.
HolgUjin et al.,
1985 ; Contant
et al., 1985°
Reviewed in U.S. Environmental Protection Agency (1978).
See text for discussion.
-------
complete daily symptom diaries, which were distributed and collected weekly.
The groups differed in their distributions of age, gender, smoking history,
and job type, though these variables, as well as ethnic group, appear to have
been controlled in the statistical analysis.
Air pollution was monitored at two downtown sites 1.2 km apart. Concen-
trations of SOp, TSP, sulfates (from dried glass-fiber filters), and 0, (by
chemi luminescence) were measured, as was the pH of filter samples (using KC1
in distilled water). Previously measured NO^ and CO levels had been low.
Daily maximum temperature was treated as a covariate. Maximum hourly 0,
3
levels ranged from 8 to 461 \ig/m (0.004 to 0.235 ppm) and averaged 157
2
(0.08 ppm). Eight- and 24-hour mean TSP levels were 83 and 73 |jg/m , respec-
2
tively. The 24-hour mean SO, level was 12.5 (jg/m . Ozone and SO, peaks often
occurred simultaneously. Reported outdoor exposure, working, and home condi-
tions were judged to be equivalent for most subjects for most pollutants.
The data were analyzed by pairwise correlation and multiple regression,
in which daily symptom prevalence was the dependent variable. Few associations
of symptoms with pollution levels were observed. The maximum hourly 03,
however, was positively and significantly correlated (p <0.05) with cough and
nasal irritation in heavy smokers, with cough in hay fever patients, and with
nasal irritation in asthmatics. In multiple regression analysis, the 03 level
was associated with cough and eye irritation in heavy smokers, and with cough
in hay fever patients. Cough frequency increased linearly with maximum hourly
03 levels, particularly in heavy smokers and in subjects with pre-existing
illness. Filter pH was negatively associated with eye, nose, and throat
irritation in most groups. Pollen was positively associated with sneezing in
hay fever patients. Sulfate levels were not consistently associated with
symptoms .
Although it suggests a relationship between ambient ozone exposure and
symptom prevalence, the study does not allow quantitative inference as to
pollution exposures of individual subjects, largely because the distances
between monitoring sites and respective homes and workplaces were not reported.
Also, interpretation is limited by the fact that the dependent variable,
symptom prevalence, ignores the potential dependence of present day's symptom
on previous day's symptoms. Use of incidence, or adjustment for previous
day's symptoms, would have been more appropriate than use of prevalence.
Furthermore, the regression models were not clearly described, and thus the
appropriateness of statistical corrections can not be assessed with confidence.
11-28
-------
Whittemore and Korn (1980) applied multiple logistic regression analysis
to asthma panel data collected in six southern California communities during
1972 through 1975. The panels were recruited by the U.S. Environmental Protec-
tion Agency (EPA) as part of the Community Health Environmental Surveillance
System (CHESS). Subjects with physician-diagnosed, active asthma kept symptom
diaries in which they were asked to report the presence or absence of an
asthma attack each day for 34 weeks. Each diary contained information for one
week; diaries not returned after 16 days were excluded from analysis. The EPA
data sets used have undergone quality control to ensure accurate coding of
health responses. There were 16 period- and community-specific panels. In
selecting panelists, preference was given to prospective subjects reporting
frequent asthma attacks; local physicians were consulted before final selection.
• Concentrations of TSP, RSP, SO., and N03 were measured by EPA in each
community. Because a large proportion of EPA ozone measurements were missing,
total oxidant measurements made by the Los Angeles Air Quality Control District
were used instead. Measurements of NOp and S02 were not used in data analysis
because many such measurements were missing. The average distance between
subjects' homes and monitoring stations was 3 miles (range 1 to 8 miles). The
aerometric data were arranged into 24-hour periods (midday to midday). Daily
maximum hourly oxidant levels were used in analysis; panel-specific medians of
these ranged from 0.03 to' 0.15 ppm. Because RSP, SO., and N0» were highly
correlated with TSP, TSP was the only particulate pollutant included in analysis.
Logistic regression analysis was applied to data from 444 person-periods,
231 male and 213 female. Seventy-two percent of the males' reporting periods
were supplied by males under 17 years old; the corresponding percentage of
females'reporting periods was 44 percent. It was possible for an individual's
data to be analyzed more than once, since some asthmatics participated in more
than one panel. The dependent variable was the individual's presence or
absence of an asthma attack on a given day. Independent variables were the
same day's oxidant and TSP levels, minimum temperature, relative humidity,
average windspeed, day of study, and day of week, as well as the individual's
presence or absence of an asthma attack on the previous day (autocorrelation
variable).
Present day's attack status was most closely associated with the autocor-
relation variable, and was also significantly associated with all pollution
and weather variables except windspeed. The results suggested high inter-
individual variability in response to environmental and meteorologic factors.
11-29
-------
The model estimated that a panelist having a baseline attack probability of
0.10 following an attack-free day and a probability of 0.41 on the day after
an attack day would have these probabilities raised to 0.13 and 0,44, respec-
tively, if the oxidant level increased by 0.2 ppm. The model also estimated
an increase of less than 0.01 when the oxidant level rose by 0.1 ppm.
The Whittemore and Korn (1980) analysis suggests an effect of ambient
oxidants on asthma attack rate. The analysis also offers the major advantages
of adjusting for previous day's status and confining the individual's model-
estimated attack probability to the realistic range of zero to one. These
results cannot, however, be considered quantitative. Oxidant measurements,
not ozone measurements, were used, and some subjects' homes were distant from
aerometric sites. The independent variable was a subjective measure, subject
to potential bias. Information on relevant covariates, such as daily medica-
tion use, emotional stress, exercise level, acute respiratory infection, and
other environmental pollutants and pollen counts, was not collected.
Lebowitz et al. (1982a, 1983, 1985) and Lebowitz (1984) conducted serial
studies of Tucson, AZ, adults with asthma, with reported chronic symptoms of
airway obstructive disease (ADD), with reported allergies, and without reported
symptoms. Subjects were drawn from 117 Anglo-white families from a stratified
sample of families in three geographic clusters in a community study population.
Subjects were followed for two years with daily symptom and medication diaries
®
and Mini-Wright peak flow measurements. All families gave information on
their home structure, heating, cooling, appliances, and smoking in the house-
hold. Telephone checks and visits ensured proper use of diaries, and visits
were made to calibrate peak flow meters.
Measurements of air pollutants, pollen, bacilli, fungi, and algae were
made in and directly around a random cluster sample of 41 study households
(Lebowitz et al., 1984). Pollen and TSP (high-volume samplers) were measured
simultaneously in the center of each geographic cluster. Air pollutants were
also measured regionally in the Tucson basin (see discussion in previous
section for details). Indoor pollution was classified according to indoor
smoking and gas-stove use for homes in which indoor monitoring was not done.
Indoor particle and pollen concentrations were 100- to 200-fold lower than
those outdoors. Scanning electron microscopy showed structural differences
between indoor and outdoor dust.
A total of 35 asthmatics provided daily peak flows. For each study
group, a given day was included in analysis only if more than five people had
11-30
-------
provided data on that day. There were 353 such days for asthmatics, 544 for
the ADD group, 494 for the allergy group, and 312 for the asymptomatic group.
A sex-, age-, and height-specific z-score was computed for each-subject's peak
flow. Symptom rates per 100 person-days were calculated separately for asth-
matics and non-asthmatics. Asthmatics' attack incidence could not be analyzed
because there were only 75 newly incident asthma attacks in 3820 person-days.
The data were analyzed by multivariate analysis of variance and regression
analysis. When appropriate, models were adjusted for differences among indivi-
duals' person-days of observation. Of the variables considered, smoking was
most strongly related to peak flow. In the ADD group, 03 and TSP were both
significantly related to symptoms (p <0.01) after adjustment for gas-stove
use, smoking, and relative humidity.
In 23 asthmatics in the geographic cluster where indoor monitoring was
most complete, Qg and temperature had a significant interaction in relation to
peak flow; high temperature had an effect when 03 was low, and 03 had an
effect only at low temperatures. Ozone alone, however, was not independently
related to peak flow after adjustment for other pollutants and covariates.
There was also a temperature-O^ interaction on these asthmatics' symptom
prevalence; 03 had an effect (not statistically significant) only in the
high-temperature range. Ozone was associated with rhinitis in asthmatics
living in homes with gas stoves (p <0.015). Daily medication correlated
highly with asthmatics' symptom exacerbations.
The authors speculated that 03 effects in asthmatics were occurring
mainly at levels of 0.052 ppm or greater, but that 03 appeared to be acting as
a surrogate for other oxidants or in conjunction with other environmental
factors. These studies included good quality control of health data and
unusually extensive environmental monitoring. Like the studies discussed
previously, they suggest an effect of ozone in persons with pre-existing
respiratory illness. Their results are not truly quantitative, however,
largely because sample sizes were often small in relation to the number of
covariates, and because hot all individuals' pollution exposures were known in
detai1.
Javitz et al. (1983) reanalyzed a study of 286 persons with asthma,
chronic bronchitis, or pulmonary emphysema in Houston, TX (Johnson et al.,
1979, unpublished report). Over 114 days from May to October 1977, all subjects
were asked to complete daily symptom diaries, and about one-third of the
subjects underwent weekly spirometric testing at home. Air pollutants were
11-31
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measured at nine fixed stations in the Houston area. The symptom data were
analyzed by logistic regression models, which estimated that the incidence of
chest discomfort, eye irritation, and malaise would increase as the PAN concen-
tration increased up to 0.012 ppm. The models also estimated that the incidence
of combined nasal symptoms, combined respiratory symptoms, and medication use
would increase by 6.0, 3.4, and 5.2 percent, respectively, as the 0., level
3
increased up to 412 pg/m (0.21 ppm). The models estimated no increase in any
specific nasal or respiratory symptoms with increasing 03 exposure.
The spirometric data were analyzed by linear regression models, which
estimated decreases in FVC and FEV*., of 2.8 percent and 1.6 percent, respec-
3
tively, as daily maximum 1-hr 0~ levels rose 412 pg/m (0.21 ppm). These
models estimated somewhat larger decreases in lung function with rising total
oxidant (0^ and PAN) levels. The model-estimated changes in lung function
were of questionable statistical significance.
These results suggest a limited effect of ozone on symptoms and lung
function in persons with pre-existing lung disease, but substantial limitations
in data quality render the results inconclusive. Many aerometric data points
were missing, so that individuals' pollution exposures could not be assessed
at all confidently. Over one-third of the subjects reported respiratory
symptoms on 100 or more days, and over two-thirds reported nasal symptoms on
10 or fewer days. Such skewing of symptom behavior yielded a relatively
insensitive test for pollution effects in the study group.
In a preliminary presentation, Holguin et al. (1985) have evaluated the
association of 03 exposure with the probability of an asthma attack in Houston,
TX, during May to October 1981. The study population of 51 subjects was
carefully selected from individuals residing in the neighborhoods of Clear
Lake and Sunnyside. The subjects were medically diagnosed as probable, uncom-
plicated extrinsic asthmatics, since all had elevated IgE levels, pulmonary
function tests consistent with reversible airway disease, and no evidence of
other chronic cardiopulmonary disease. Baseline pulmonary function status,
however, was not described in detail. Ages of the subjects ranged from 7 to
55 yr but the median age was 13 yr and 41 of the subjects were under 20 yr of
age. All subjects completed log forms twice daily providing 12-hr daytime (7
a.m. to 7 p.m.) and 12-hr nighttime (7 p.m. to 7 a.m.) records of hourly
symptoms, activities, and location. Pulmonary function measurements of peak
flow were also made during the morning and evening reporting times using a
®
Mini-Wright peak flow meter. Symptoms, medication use, and peak flow data
11-32
-------
were examined for patterns that fit the clinical description of asthma and
that represented deviations from an individuals1 baseline profile. Using this
information, a specific definition of an asthma attack was derived for each
subject.
Fixed-site monitors within 2,5 miles of the subjects residences in each
of the two neighborhoods provided: maximum hourly averages for 0, (CHEM),
N02, CO, SOp, temperature, and relative humidity (rh); daily 12-hr averages
for fine (<2.5 pm MMAD) and coarse (2.5-15 pm MMAD) particles, aldehydes, and
aeroallergens; and daily 24-hr averages for total suspended particulates.
Mobile monitoring of indoor/outdoor concentrations of the same pollutants was
collected in 12 residences for 1 week. Detailed measurements of personal 0,
exposure were also obtained by means of portable monitors in 30 of 51 study
subjects. An exposure model that weighted indoor and outdoor location patterns
as well as fixed-site values was used to estimate individual exposures to 03
and other aerometric variables. Over the 12-hr symptom period, the time-weighted
3
1-hr maximum 0., concentrations ranged from 2 to 151 ug/m (0.001 to 0.077 ppm)
3
with a mean concentration of 37 \ig/m (0.019 ppm). Values for the other
environmental variables were not reported.
Logistic regression analysis was applied to 42 subjects, each with more
than five attacks. The analysis adjusted for autocorrelation of present day's
attack probability with the attack probability on the previous day. Regression
coefficients were found to be significantly related to a previous attack, to
increasing 0™ concentration, and to decreasing ambient temperature. Elevated
concentrations of pollen in September and October increased the probability of
an attack in some asthmatics, but this was not statistically significant for
the group. There was no association between attack probability and NO, or rh.
The utilization of a time-weighted exposure model, employing data from
fixed-site as well as mobile monitors, provides an unusually good estimate of
actual exposures. Personal exposure data, however, were used to assess the
validity of the estimates of individual exposures determined by the model but
were not used in the development of the exposure estimate model itself. There
are still some uncertainties associated with this approach since results from
this comparison indicated that exposure estimates obtained from the model
underestimated actual personal exposures by approximately 10 ppb (Contant et
a!., 1985).
The data analysis by Holguin et al. (1985) provides a means of estimating
the increasing probability of an asthma attack on the basis of a previous
11-33
-------
attack, a 40 ppb increase in CU, an 8°C increase in ambient temperature, and a
combination of these factors. Although the authors estimate the increased
attack probabilities associated with incremental 03 increases from given
baseline probabilities, it would be difficult to quantitate these probabilities
at any given 0- concentration since the magnitude of the effect varies as the
levels of the other covariates vary. While confounding variables such as NCU,
pollen, and rh were taken into account, other pollutants such as S02, total
suspended particulates, and inhalable particles (<15 urn MMAD) were not consid-
ered in the analysis. The role of other pollutants, particularly the fine
inhalable particles, in combination with 0,, temperature, and pollen needs to
be evaluated before the results of this study can be used quantitatively.
11.3.1.5 Incidence of Acute Respiratory Illness. Table 11-6 describes studies
relating oxidant levels with the incidence of acute respiratory illnesses.
These studies, however, did not meet the criteria necessary for developing
quantitative exposure-response relationships for ambient oxidant exposures.
11.3.1.6 Physician, Emergency Room,and Hospital Visits. Earlier studies
reviewed in the 1978 EPA criteria document for ozone and other photochemical
oxidants (U.S. Environmental Protection Agency, 1978) were not able to relate
oxidant concentrations to hospital admission rates or clearly separate oxidant
effects from effects of other pollutants (Table 11-7). The effects of social
factors, which produce day-of-week and weekly cyclical variations, and holiday
and seasonal variations, were rarely removed (and then with possible loss of
sensitivity). Relating time of visit to time of exposure was also very diffi-
cult. Studies of visits to medical facilities in the United States usually
lack appropriate denominators since data on the number of individuals at risk
are generally not available and the catchment area (total population) is
unknown. In addition, with the increased use of the emergency room as a
family practice center, visits are becoming less associated with acute exposure
or attack than they once were. Also, emergency room data, like hospital
record data, often lack information on patients' smoking habits, ethnic group,
social class, occupation, and even other medical conditions.
Whether changes in hospital use reflect changes in either illness experi-
ence or illness perception and behavior is still uncertain. People may behave
differently according to individual perceptions of environmental challenges.
The response of the medical-care system is also determined by several factors,
including insurance and availability of physicians, beds, and services (Bennett,
11-34
-------
TABLE 11-6. INCIDENCE OF ACUTE RESPIRATORY ILLNESS ASSOCIATED WITH PHOTOCHEMICAL OXIDANT POLLUTION
Concentration(s)
ppra
Pollutant
Study description
Results and comments
Reference
U)
Ui
<0.23 avg cone
10 a.m.-3 p.m.
(Not reported)
Oxidant Absentee rates from two elementary
schools in Los Angeles throughout
the 1962-63 school year; oxidant
(KI) concentrations measured by
LA-APCD within 2-4.5 miles from
each school.
Absence rates were highest during the
winter when oxidant levels were lowest;
no consistent association between oxidant
level and absenteeism. Other pollutants
were not considered.
Wayne and Wehrle, 1969d
0.
08-0.23
max 1-hr/day
Oxidant Retrospective study on the inci-
dence and duration of influenza-
like illness from December 1968
to March 1969 among 3500 elementary
school children residing in five
Southern California communities.
No relationship between photochemical
. oxidant gradient and illness rates
during an influenze epidemic occurring
in a low-oxidant period; all the
communities had similar levels. Other
pollutants were not considered.
Pearlman et al., 1971a
Oxidant Health service visits for respira-
tory illness in students at five Los
Angeles and two San Francisco
colleges during the 1970-71 school
year peak oxidant and mean S02,
N02, NO, NO CO, HC, PM, and
weather variables were monitored
within 5 miles of each university.
Pharyngitis, bronchitis, tonsilitis,
colds, and sore throat associated
primarily with oxidant, S02, and N02 levels
on same day and on 7 preceding days;
stronger associations in Los Angeles
than in San Fransicso.
Durham, 1974a
0.066 and 0.079
avg of daily maxima
<0.195 maximum
(undefined)
Oxidant Health insurance records from two
locations in Japan during July-
September 1975; maximum oxidant
and S02 levels and weather
variables were monitored daily.
No relationship between oxidant levels and
new acute respiratory diseases. Other
pollutants beside S02 were not considered.
Nagata et al., 1979d
Reviewed in U.S. Environmental Protection Agency (1978).
-------
TABLE 11-7. HOSPITAL ADMISSIONS IN RELATION TO PHOTOCHEMICAL OXIDANT POLLUTION
Concentratlon(s)
PPM
Pollutant
Study description
Results and consents
Reference
0.11 and 0.28
avg »ax 1-hr during
low and high periods,
respectively.
Oxidant Comparison of admissions to Los Angeles
County Hospital for respiratory and
cardiac conditions during snog and s«og-
free periods from August to November 19S4.
No consistent relationship between admissions
and high smog periods; however, statistical
analyses were not reported.
California Depart-
ment of Public
Health, 1955a,
19S6a, 1957a
0.12 avg cone
6 a.M.-l p.m.
Oxidant Respiratory and cardiovascular admissions
to Los Angeles County Hospital for resi-
dents living within 8 miles of downtown LA
between August and December, 1954.
Inconclusive results; partial correlation Brant and Hill,
coefficients between total oxidants and 1964 ;
admissions were variable. Method of patient Brant, 1965
selection was not given. Other pollutants
were not considered.
(Not reported)
Oxidant Admissions of Blue Cross patients to
Los Angeles hospitals with >100 beds
between March and October 1961; daily
average concentrations of oxidant, 03,
CO, SD2, N02, ND, and PM by.LA-APCOs.
Ui
CTl
Correlation coefficients between admissions
for allergies, eye Inflammation, and acute
upper and lower respiratory infections and
all pollutants were statistically significant;
correlations between cardiovascular and other
respiratory diseases were significant for
oxidant, 03, and S02; significant positive
correlations were-noted with length of
hospital stay for S02, N02, and NO .
Correlations were not significant Tor tempera-
ture and relative humidity or for pollutants
with other disease categories.
Sterling et §1.,
1966a, 1967a
(Not reported)
Oxidant Admissions for all adults and children with
acute respiratory illness in 4 Hamilton,
Ontario hospitals during the 12 months from
July 1, 1970 to June 30, 1971; city-average
pollution monitoring for Ox(KI), SQ2, PM,
COH, CO, NO , HC, and temperature, wind
direction and velocity, relative humidity,
and pollen.
Correlation between number of admissions and ,
an air pollution index for SQ2 and COH; negative
correlation between temperature and admissions.
No correlation was found with concentrations of
Ox, CO, HC, and NO or with pollen, relative
humidity, wind direction, and velocity.
Levy et al., 1977
(Not reported)
Ozone Emergency room visits for cardiac and
respiratory disease in two major hospitals
in the city of Chicago during April 1977
to April 1978; 1-hr concentrations of 03,
S02, N02, NO, and CO from an EPA site close
to the hospital, 24-hr concentrations of
TSP, S02, and N02 from the Chicago Air
Sampling Network,
No significant association between admissions
for any disease groups and 03, CO, or TSP;
S02 and NO accounted for part of the variation
of ER visits for respiratory and cardiovascular
admissions. Questionable study design and
analysis including lack of control for con-
founding and weak exposure assessment.
Namekata et al.,
1979°
-------
TABLE 11-7 (continued). HOSPITAL ADKSSSIONS IN RELATION TO PHOTOCHEMICAL OXIDANT POLLUTION
Concentration(s)
Pollutant
Study description
Results and comments
Reference
0.07 and 0.39
avg max 1-hr
during low and high
periods, respectively
Ozone Emergency room visits and hospital
admissions for children with asthma
symptoms during periods of high and
low air pollution in Los Angeles from
August 1979 to January 1980; daily
maximum hourly concentrations of 03)
S02> NO, N02, HC, and COM; weekly _
maximum hourly concentrations of S04
and TSP; biweekly allergens and daily
meterological variables from regional
monitoring stations.
Asthma positively correlated with COM, HC, N02,
and allergens on same day and negatively
correlated with 03 and S02; asthma positively
correlated with N02 on days 2 and 3 after
exposure; correlations were stronger on day
2 for most variables; nonsignificant correla-
tions for S04 and TSP. No indication of
increased symptoms or medication use during
high pollution period; however, peak flow
decreased (no differentiation of pollutants).
Factor analysis suggested possible synergism
between NO, N02, rh, and windspeed; 03, S02,
and temperature; and allergens and windspeed.
Presence of confounding variables, lack of
definitive diagnoses for asthma and question-
able exposure assessment limit the quantita-
tive interpretation of this study.
Richards et al.,
1981b
I
u>
0.03 and 0.11
avg max 1-hr for
low and high areas,
respectively
Oxidant Daily hospital emergency room admissions
in four Southern California communities
during 1974-1975. Maximum hourly average
concentrations of oxidant, N02, NO, CO,
S02, COH;_24-hr average concentrations of
PM and S04; and daily meteorological
conditions from monitoring sites <8 km
from the hospitals.
Admissions associated with oxidant in Azusa
(the highest oxidant pollution), S04 in
Long Beach and Lennox but not Riverside
(the highest sulfate pollution), and with
temperature in all locations. Lack of
sufficient exposure analysis and subject
characterization limit the quantitative use
of this study.
Goldsmith et al.
1983b
0.03-0.12 avg of
max 1-hr/day
for 15 stations
Ozone Admissions to 79 acute-care hospitals in
Southern Ontario for the months of January,
February, July, and August in 1974,
1976-1978. Hourly average concentrations
of particulate (COM), 03, S02, N02, and
daily temperature from 15 air sampling
stations within the region.
Excess respiratory admissions associated
with S02, 03; and temperature during July
and August with 24 and 48 hr lag; only
temperature was associated with excess
respiratory admissions and total hospital
admissions for January and February. Lack
of sufficient exposure analysis limits the
quantitative use of this study.
Bates.and Sizto,
1983°
Reviewed in U.S. Environmental Protection Agency (1978).
See text for discussion.
-------
1981; Ward and Moschandreas, 1978). Artifacts may arise from changing defini-
tions of classifications and varying diagnostic or coding practices as well.
Another frequent problem is that repeated admissions or attendance by a small
number of patients can cause tremendous distortions in the data (Ward and
Moschandreas, 1978). Furthermore, interpretation of hospital admissions data
is hindered because hospital statistics often lack reliability and validity
such that determining disease incidence is difficult; insufficient clinical
data are available for diagnostic classification and grading of severity; and
a number of potential subclassifications of patients may require separation
and attention in the analysis (Ward and Moschandreas, 1978).
Namekata et al. (1979) found no significant association between 03 levels
and emergency room visits for cardiac and respiratory diseases in two Chicago
hospitals during 1977-1978. This study, however, must be considered inadequate
because information collected from the medical records was insufficient for
identifying sources of variability in the data and for controlling confounding
factors of the types noted above. In addition, the 03 data were insufficient
and incomplete and the linear models used could not determine effect levels of
the pollutant.
Richards et al. (1981) evaluated the relationship between asthma emergency
room visits and hospital admissions and indices of air pollution, meteorologi-
cal conditions, and airborne allergens. Questionnaire data were obtained on
all children presenting to the Emergency Room of Childrens Hospital of Los
Angeles for symptoms associated with asthma during a 6-month period (August
1, 1979 to January 31, 1980), encompassing both high and low periods of air
pollution. Air pollution and meteorological data were obtained from monitoring
stations located in the geographical area and weighted according to the density
of patients residing near the monitoring stations. The weighted averages were
used to calculate an average exposure representative of the entire geographical
area. Univariate correlation analyses demonstrated a number of positive and
negative correlations of asthma with air pollutants; however, when asthma
morbidity was regressed on the combined factor scores, 30 percent of the total
variation could be explained by air pollution or meteorological conditions.
Other variables such as restriction of outdoor activity or exposure to other
irritants that were not measured could also have affected asthma morbidity.
In addition, this study suffers from many of the problems enumerated above.
There was difficulty establishing a definitive diagnosis of asthma retrospec-
tively in the patients, inadequate exposure assessment, no clear differentiation
11-38
-------
of (L effects from the effects of other pollutants, and the presence of multiple
confounding variables.
Goldsmith et al. (1983) studied emergency room visits in four Southern
California communities (Long Beach, Lennox, Azusa, and Riverside) during
1974-1975. Logbook data on total admissions were taken from two hospitals in
each of the first three communities and from three hospitals in the fourth.
The hospitals were < 8 km from Southern California Air Quality Management
District stations monitoring TSP, QX, CO, NO, N02, S02, sulfate (S04), and
coefficient of haze (COM). Catchment areas and air monitoring data for resi-
dential and work sites were unknown for the subjects included in the study.
The data were adjusted for day-of-the-week and long-term trends, but not for
seasonal trends. Maximum hourly averages of oxidants and temperature were
reported to be associated with daily admissions in the high-oxidant area
(Azusa) after correction for other variables using correlation coefficients
from path analysis (although the more complete path analysis explained less
variance than the standard regression model). Unfortunately, the lack of popu-
lation denominators and characteristics, the lack of admission characteristics,
and poor characterization of exposure seriously limit the use of these findings.
Bates and Sizto (1983) studied admissions to all 79 acute-care hospitals
in Southern Ontario, Canada (i.e., the whole catchment area of 5.9 million
people) for the months of January, February, July, and August in each of 6
years (1974, 1976-1978, and 1979-1980). Air pollution data for CO, N02> 03,
and particles (COM) were obtained from 15 stations located mostly along the
prevailing wind direction. Temperature was controlled. In July and August,
highly significant assocations (Pearson r, 1-tailed, P < 0.001) were found
between excess (percent deviations from day-of-week and seasonal means) respira-
tory admissions and average maximum hourly SOp and 03 concentrations, and
temperature (with 24- and 48-hr lags between the variables). Nonrespiratory
admissions showed no relation to pollution. Temperature was independently
important (-5.3°C average on winter days in study). Admissions, and admission
correlations with pollutants, were consistent from year to year. Further
analysis showed that asthma was the most significant respiratory problem
driving the admissions up, especially in younger people. Bronchitis and
pneumonia admissions were not significantly related to pollutants. The authors
state that it was difficult to differentiate between the effects of tempera-
ture, S02, and 03. With data extended through 1980 (Bates, 1985), however,
there is preliminary information that sulfate levels accounted for a high
11-39
-------
percentage of explained variations for all respiratory complaints, but that
ozone was still independently associated with asthma. Since the number of
separate people admitted was unknown, a "sensitive" subpopulation could have
affected the results. In addition, actual exposure information can only be
approximated in this type of study so that only qualitative associations can
be drawn between ambient pollutants and morbidity increases in the population.
11.3.1.7 Occupational Studies. Studies of acute effects from occupational
exposure are summarized in Table 11-8. These studies did not meet the criteria
necessary for developing quantitative exposure-response relationships for
ambient oxidant exposures.
11.3.2 Trends in Mortality
The possible association between acute exposure to photochemical oxidants
and increased mortality rates has been investigated a number of times (Table
11-9) and the results have been reviewed at length in previous documents
(National Research Council, 1977; U.S. Environmental Protection Agency, 1978;
World Health Organization, 1978; Ferris, 1978). As yet, no convincing associ-
ation has been demonstrated between daily mortality and daily oxidant concen-
trations. High oxidant levels were usually associated with high temperatures
that were sufficient to account for any excess mortality found in these studies.
11.4 EPIDEMIOLOGICAL STUDIES OF EFFECTS OF CHRONIC EXPOSURE
Only a few prospective studies of the chronic effects of 03 exposure are
available. These studies are usually concerned with the association of symp-
toms, lung function, chromosomal effects, or mortality rates and average
annual levels of photochemical oxidants; or comparisons of chronic effects in
populations residing in low- or high-oxidant areas. The inability to relate
chronic effects with chronic exposure to specific levels of pollutants is a
major limitation of these studies. In addition, given the long periods of
time known to be required for the development of chronic diseases, it is
unlikely that any of these studies can be used to develop quantitative exposure-
response relationships for ambient oxidant exposures. Further study of well-
defined populations over long periods of time is required before any relation-
ship between photochemical oxidants and the progression of chronic diseases
can be conclusively demonstrated from population studies.
11-40
-------
TABLE 11-8. ACUTE EFFECTS FROM OCCUPATIONAL EXPOSURE TO PHOTOCHEMICAL OXIDANTS
Concentrati on(s)
ppnt
Pollutant
Study description
Results and comments
Reference
(Not reported)
Ozone Health complaints of workers in a test
laboratory of a factory for electric
insulators.
Reports of thoracic cage constriction, in-
spiration difficulty, and laryngeal irrita-
tion.. Other pollutants were not controlled.
Truche, 1951
0.25-0.80 peaks
(undefined)
H
Ozone Clinical findings and symptoms in welders
using inert gas-shield consumable elec-
trodes in three plants with ozone measured
at breathing zones.
Increase in chest constriction and throat '
irritation at 1-hr concentrations of 0.3 to
0.8 ppm; no complaints or clinical findings
below 0.25 ppm. Nitrogen dioxide and total
suspended particulate matter were not measured
or controlled.
Kleinfeld et al.,
1957
0.8-1.7 peaks
(undefined)
Ozone
Symptoms in 14 helio-arc welders.
Upper respiratory symptoms in 11 of 14 welders
exposed daily to 0.8 to 1.7 ppm ozone, which
disappeared with exposure to 0.2 ppm. Nitrogen
dioxide was present, but not studied.
Challen et al.,
1958
0.2-0.3 means
Ozone Lung function in seven welders using
argon-shield. Og measured by rubber
cracking.
No changes in function. Nitrogen dioxide was
probably present, but not controlled.
Young et al., 1963
0.56-1.28
(interval not
specified)
Ozone Symptoms in welders and nearby workers
(controls) ages 25-35, with less than
5 years employment.
More'frequent complaints of respiratory irri-
tation, headache, fatigue, and nosebleeds in
welders; exams were normal. Carbon monoxide
and nitrogen dioxide were below permissible
levels. Total suspended particulate matter
was not studied.
Polonskaya, 1968
0.01-0.36 peaks
(undefined)
Ozone Illness in 61 welders, 63 pipefitters, 61
pipecoverers, and 94 new pipefitters,
measured by questionnaires, pulmonary
function, partial physicals, and X-rays.
Lung function obstruction in smokers in first
two groups; third group had restrictive func-
tion. Otherwise, no differences were observed.
Many pollutants were also involved.
Peters et al., 1973
-------
TABLE 11-8 (continued). ACUTE EFFECTS FROM OCCUPATIONAL EXPOSURE TO PHOTOCHEMICAL OXIDANTS
Concentration(s)
ppm
Pollutant
Study description
Results and comments
Reference
0.05-0.5
workshift avg
0.16-0.29
H workshift avg
to
Ozone Pulmonary function in workers in a plastic
bag factory (31 exposed and 31 controls
of sane age, height, smoking habits).
Ozone Extrapulmonary effects in 33 workers
in a plastic bag factory.
Decreased expiratory flow in 8 of 31 subjects
during workshift. Lower flows in exposed
smokers than control smokers. Acute changes
to acetylcholinesterase, peroxidase, and
lactate dehydrogenase. Other pollutants,
including formaldehyde (0.18 to 0.20 ppm)
were not.controlled.
Altered serum enzyme levels in 22 subjects;
peroxidase activity of peripheral leucocytes
increased at the end of the workshift but
returned to normal after a holiday.
Fabbri et al., 1979
Sarto et al.,
1979a,b
0.08
workshift avg
<1.0 peaks
(undefined)
Ozone Health effects in male German metallur-
gical plant workers, as measured by
questionnaire, absenteeism, insurance
records, vital capacity measures,
plethysmographic measures, blood pressure,
and airway resistance. Ozone, nitrogen
oxides, and sulfur oxides were sampled.
Group exposed to high ozone had more absenteeism
and more episodes of bronchitis and pneumonia,
more cough and phlegm, and higher airway resis-
tance than did controls. However, high total
suspended particulate matter levels and
temperature-induced volatilized metals obscured
effects of ozone.
von Nieding and
Wagner, 1980
0.01-0.15 avg
personal exposure
Ozone Changes in immune responses of 30 workers
(average age = 34 yr) exposed an average
of 4.3 yr to 03 when compared to a control
group of ore miners.
Levels of alpha-1-antitrypsin and transferrin
increased after exposure. Comparisons of
relative numbers of changes in serum and
plasma proteins and in the immunological
responses of peripheral lymphocytes in both
groups indicates considerable interindividual
variability.
Ulrich et al., 1980
-------
TABLE 11-9. DAILY MORTALITY ASSOCIATED WITH EXPOSURE TO PHOTOCHEMICAL OXIDANT POLLUTION
Concentration(s)
PP"
Pollutant
Study description
Results and comments
Reference
<1.0 peak
(undefined)
Oxidant
<0.38 max l-hr(?)/day Oxidant
Relationship between daily concentrations
of photochemical oxidants and daily
mortality among residents of Los Angeles
County aged 65 yrs and over the periods
August-November 1954 and July-Novatiber 1955.
Data extended to include the period from
1956 through the end of 1959.
Heat had a significant effect on mortality;
no consistent association between mortality
and high oxidant concentrations in the
absence of high temperature.
California Depart-
ment of Public
Health, 1955a,
1956a, 1957a
Tucker, 1962
(Not reported) Oxidant
0.10-0.42 Ozone
(undefined) for
148 days of 1949
Relationship between daily maximum
oxidant concentrations and daily
cardiac and respiratory mortality in
Los Angeles for the periods 1947-1949,
August 1953 through December 1954, and
January 1955 through September 1955.
Positive relationship between daily maximum
oxidant concentrations and mean daily death
rates on high-smog vs. low-smog days.
questionable exposure analysis including use
of the "SRI smog index."
Mills, 1957aa,ba
(Not reported)
H
r
*>
U)
Oxidant Comparison of daily mortality in two
Los Angeles County areas similar in
temperature but with different levels
of daily maximum and mean oxidant
levels (KI); S02 and CO concentrations
were also measured.
No significant correlations between differences
in mortality and differences in pollutant
levels.
Massey et al., 1961
0.05-0.21
monthly avgs
Oxidant Relationship between daily maximum oxidant
concentrations (KI) and daily mortality
from cardiac and respiratory diseases in
Los Angeles for the years 1956 through
1958.
No significant correlations between pollutants
and mortality for cardiorespiratory diseases;
no correlation for a 1-4 day lag in exposure
and mortality.
Hechter and
Goldsmith, 1961a
(Not reported)
Oxidant Relationship between daily total mortality
from all causes and three Los Angeles heat
waves occurring in 1939, 1955, and 1963;
comparison with mortality during the same
season in 1947 without a heat wave.
High photochemical oxidant concentrations do
not augment the effect of high temperature
on mortality; however, no statistical
relationship was determined between mortality
and oxidant exposure.
Oechsli and
Buechley, 1970a
0,003-0.128
max 1-hr/day
Ozone Relationship between daily mortality and
daily 1-hr maximum concentrations of Og
in Rotterdam, The Netherlands during the
months of July and August of 1974 and 1975.
No significant correlation between 03 c.oncen- Biersteker and
tration and mortality in the absence of high Evendijk, 1976
temperature; no augmentation of mortality
due to increased temperature during heat waves.
Reviewed in U.S. Environmental Protection Agency (1978).
-------
11.4.1 Pulmonary Function and Chronic Lung Disease
Studies of chronic respiratory morbidity are summarized in Table 11-10.
While some of these studies (Detels et al., 1979, 1981; Rokaw et al. , 1980;
Hodgkin et al., 1984) suggest an increase in the prevalence of respiratory
symptoms or possibly impairment of pulmonary function in high-pollutant areas,
the results do not show any consistent relationship with chronic exposure to
ozone or other photochemical oxidants. In addition, as discussed above, these
studies are generally limited by insufficient information about individual
exposures and by their inability to control for the effects of other environ-
mental factors. They do not provide information useful for quantitative
exposure-effect assessment. Thus, to date, insufficient information is avail-
able in the epidemic!ogical literature on possible exposure-effect relationships
between On or other photochemical oxidants and the prevalence of chronic lung
disease. These relationships will need further study.
One of the largest investigations of chronic 03 exposure has been the
series of population studies of chronic obstructive respiratory diseases in
communities with different air pollutant exposures, reported by Detels and
colleagues of the University of California at Los Angeles (UCLA) (Detels et
al., 1979, 1981; Rokaw et al., 1980). The areas studied were characterized by
high levels of photochemical oxidants (Burbank and Glendora, CA); high levels
of SO j particulates, and HCs (Long Beach, CA); and low levels of gaseous
J\
pollutants (Lancaster, CA). The prevalence of symptoms was reported to be
increased in the residents of the highest-polluted area (Glendora). Lung
function was generally better among residents of the low-pollution areas, as
indicated by FEV.,, FVC, maximum expiratory flow rates, closing volume, thoracic
volume, and airway resistance. Maximal mid-expiratory flow rate, considered
to be sensitive to changes in small airways, was similar in the residents of
all three areas, while the mean AN2 was slightly higher among residents of the
high-pollution areas. Although the results suggest that adverse effects of
long-term exposure to photochemical oxidant pollutants may occur primarily in
the larger airways, the usefulness of these studies is limited by a number of
problems. For example, testing in different communities occurred at different
times over a 4-year period. Also, the authors presented no information on
such matters as self-selection and migration in and out of these areas.
Additional comparisons between mobile laboratory and hospital laboratory
test results did not always show adequate reproducibility. The study popula-
tions had mixed ethnic groups, and completion rates were approximately 70 to
11-44
-------
TABLE 11-10. PULMONARY FUNCTION EFFECTS ASSOCIATED WITH CHRONIC PHOTOCHEMICAL OXIDANT EXPOSURE
Concentration(s)
ppm
Pollutant
Study description
Results and comments
Reference
<1.0 peak
~ (undefined)
Oxidant Comparison of weekly surveys of illness
and injury rates between population samples
from Los Angeles County and the rest of
California during 17 weeks from August
through November 1954.
No relationship between incidence of illness
and area in the young. Elderly showed some
increases in Los Angeles but investigators
did not adjust for dfferences in population
density, ethnic characteristics, and socio-
economic level. Pollutants other than ozone
were also higher.
California Depart-
ment -of Public
Health 1955a,
1956a, 1957a
(Not reported)
Oxidant Prevalence of illness in survey of 3545
households throughout California. Chronic
pulmonary disease studied four times,
1957-1959.
Higher prevalence rates in Los Angeles and
San Diego. No quantitative oxidant data.
Questionable study design and data analysis.
Hausknecht and
Breslow, 1960 ;
Hausknecht, 1962
(Not reported)
en
Oxidant Symptoms, measured by questionnaire and
ventilatory function, in outdoor tele-
phone workers 40-59 years of age in San
Francisco and Los Angeles.
Respiratory symptoms were more frequent in the
older age group (50-59 yrs) of Los Angeles but
pulmonary function was similar. No differences
in symptom prevalence between cities in the
younger group (40-49 yrs), although particulate
concentrations were about twice as high in Los
Angeles. No aerometric data.
Deane et a!,, 1963d;
Goldsmith and
Deane, 1965a
0.07 and 0,12 •
avg max 1-hr for
low and high areas,
respectively
Oxidant Comparison of pulmonary function in
nonsmoking Seventh Day Adventists (aged
45-64 yrs) residing in high-oxidant
(San Sabiel Valley) and low-oxidant
(San Diego) areas of California in
January 1970; average maximum oxidant
concentrations were obtained from
September 1969 and January 1970; TSP,
RSP, and S02 were also measured.
No significant difference in prevalence of
respiratory symptoms or in measurements of
pulmonary function; however, the findings
are limited by the similarity of annual
average ambient levels of oxidants in the
two areas.
Cohen et al., 1972d
0.15 and 0.33
max 1-hr for the
low and high areas,
respectively
Oxidant Respiratory symptoms and function in
insurance company workers in Los.Angeles
and San Francisco during the Spring and
Summer of 1973; median concentrations of
oxidant, N02, SQ2, CO, TSP, and weather
were measured from 1969 to-1972 at
central-city monitoring stations.
Sex-specific pulmonary function measurements
were similar in all tests; no difference in
chronic respiratory symptom prevalence between
cities. More frequent reports of nonpersistent
(<2 years) production of, cough and sputum by
women in Los Angeles. Different populations and
different aerometric characteristics complicate
the analysis.
Linn et al., 1976d
-------
TABLE 11-10 (continued). PULMONARY FUNCTION EFFECTS ASSOCIATED WITH CHRONIC PHOTOCHEMICAL OXIDANT EXPOSURE
Concentration(s)
pp*
Pollutant
Stutfy description
Results and comments
Reference
0.07 and 0.09 annual
means of max 1-hr/
day for Lancaster
and Burbank,
respectively
0.04, 0.07, and 0.09
annual means of Max
1-hr/day for Long
Beach, Lancaster, and
Burbank, respectively
0.07 and 0.12 annual means
of max 1-hr/day for
Lancaster and Glendora,
respectively
Oxidant UCLA population studies of the prevalence
of symptoms of chronic obstructive respira-
tory disease (CORD) and of functional
respiratory impairment in residents of
California communities with differing
photochemical oxidant concentrations.
Daily maximum hourly average concen-
trations of oxidant, 03> NO , S02, CO,
and HC; 24-hr_average concentrations
of TSP and 504 from regional SCAQMO
and CARB monitoring stations within 1
to 3 miles of the subjects residential
zone.
Increased prevalence of respiratory symptoms
in the residents of high-pollution areas;
pulmonary functon tests of small airways
showed little or no differences between
areas while results of large airway func-
tion suggests that long-term exposure to
high concentrations of pollutants (oxi-
dants S02, N02, PM, and HC) may result in
measurable impairment. Difficulty in
judging ambient pollution exposure and
lack of control for confounding environmen-
mental conditions migration, smoking
history, and occupational exposure restrict
the quantative interpretation of these studies.
Detels et al.
1979°
Rokaw et al., 1980°
Detels et al.,
1981°
(Not reported)
I
CTl
Oxidant Prevalence of respiratory symptoms in
nonsmoking Seventh Day Adventists
residing for at least 11 yrs in high
(South Coast) and low (San Francisco,
San Diego) photochemical air pollution
areas of California; CARB regional air
basin monitoring data for_oxidants,
N02, S02, CO, TSP, and S04 from 1973
to 1976.
Slightly increased prevalence of respiratory
symptoms in high pollution area; after adjust-
ing for covariables, 15% greater risk for COPD
due to air pollution (not specific to oxidants);
past smokers had greater risk than never
smokers; when past smokers were excluded,
risk factors were similar. Use of symptoms
as risk for COPD without FEVj data is question-
able. In addition, insufficient exposure
assessment and confounding by environmental
conditions limit the quantitative use of this
study.
Hodgkin et al.,
1984
(Not reported)
Oxidant Respiratory symptoms and function in 360
wives and daughters of shipyard workers in
Long Beach, CA compared to a reference
population from Michigan.
Increased prevalence of chronic bronchitis,
reduced expiratory air flow, and altered gas
distribution in the Long Beach cohort; all
subjects in this cohort had family exposure
to asbestos and 31/238 wives and 3/122
daughters had clinical signs of asbestosis.
Questionable effects of smoking and other
pollutants; no oxidant exposure data were
presented.
Kilburn et al.,
1985
aReviewed in U.S. Environmental Protection Agency (1978).
See text for discussion.
-------
79 percent in the three areas. Comparisons of participants with census infor-
mation were fairly close. Analysis of the comparisons of the three communi-
ties for symptoms and pulmonary function results used age- and sex-adjusted
data only from white residents who had no history of change of occupation or
residence because of breathing problems. Those with occupations that may have
involved significant exposure were not necessarily excluded. Analyses were
often made by smoking status and compared means or proportions that fell above
or below certain levels.
A major difficulty in the analyses is that the exposure data presented
are not adequate. Control of migration effects on chronic exposure was insuf-
ficient, and recent exposure information was provided only by ambient levels
from only one monitor, located as far as 3 mi away. A further problem is
that, as in most geographical comparisons, analysis of results assumes no
differences by place, date, or season. This assumption is especially important
since the study periods in each community were different. Furthermore, over
the 4-year period of the study there were many changes, including amounts and
types of cigarettes smoked, respiratory infection epidemics, and other undeter-
minable influences that could have affected the results. Also, the numbers of
subjects changed from one report to another and from one analysis to another.
Interpretation of the UCLA lung function data is complicated by the fact
that fewer smokers had abnormal lung function than might be expected. Also,
some of the tests employed, e.g., flow rates at low Tung volumes and single-
breath nitrogen tests, require stringent measures to avoid observer bias. It
is not clear whether such measures were taken in the UCLA studies.
To test for health effects of air pollution, the investigators often
compared the lower ends (three to five standard deviations below the means) of
the distributions of the study communities' health measurements. It is very
difficult to interpret such comparisons unless the other portions of the
distributions are also presented. Also, numbers of cases were sometimes
relatively small, and some results, e.g., those of the single-breath nitrogen
test, suggested improving lung function with increasing pollution exposure.
It is not clear whether covariates were appropriately treated in data analysis.
Thus, this work is not sufficiently quantitative for air quality standard-
setting purposes.
11-47
-------
11.4.2 Chromosomal Effects
The importance of chromosomal damage depends on whether the effect is
mutagenic or cytogenetic. For example, trans!ocations and trisomies are
inrportant forms of genetic damage, whereas minor chromosomal breakage (such
as that associated with caffeine) and chromatid aberrations are of questionable
significance. Interest in the existence and extent of chromosomal damage in
populations exposed to 0, derives from in vitro cell studies and in v 1 vo
animal studies (Chapter 9). Findings from _in vivo human studies are con-
flicting, but generally negative (Chapter 10).
Chromosomal changes in humans exposed to 0~ have been investigated in
four epidemiological studies, none of which found any evidence that 03 affects
peripheral lymphocytic chromosomes in humans at the reported ambient concentra-
tions. For example, Scott and Burkart (1978) studied chromosome lesions in
peripheral lymphocytes of students exposed to air pollutants in Los Angeles.
In their study of 256 college students, who were followed continuously, chromo-
somal changes found were almost entirely of the simple-breakage type and were
no more numerous than the predicted incidence for a population.
Magie et al. (1982) studied chromosomal aberrations in peripheral lympho-
cytes of college students in Los Angeles: 209 nonsmoking freshmen at a campus
3
with higher smog levels (>0.08 ppm 0,; >160 ug/m ) and 206 freshmen at a
3
campus with lower smog levels (<0.08 ppm 03; <160 ng/m ). Students were
enrolled in the study after completing questionnaires, and were assigned to
groups on the basis of campus location and previous residence. Blood samples
and medical histories (obtained at the beginning of the school year, in
November, in April, and at the beginning of the next school year) were analyzed
for chromosome and chromatid aberrations, but no significant effects on chromo-
somal structure were found in peripheral lymphocytes.
Bloom (1979) studied military recruits before and after welding training.
No chromosomal aberrations were seen in peripheral lymphocytes (0, levels were
negligible and N02 was high). Fredga et al. (1982) studied the incidence of
chromosomal changes in men occupationally exposed to automobile fuels and
exhaust gases in groups of drivers, automobile inspectors, and a control group
matched with respect to age, smoking habits, and length of job employment.
Chromosome preparations from lymphocytes were made and analyzed by standardized
routine methods. Analysis of the data gave no evidence of effects from occupa-
tional exposure.
11-48
-------
11.4.3 Chronic Disease Mortality
Two studies previously reviewed in the 1978 EPA criteria document for
ozone and other photochemical oxidants (U.S. Environmental Protection Agency,
1978) were not able to establish conclusively a relationship between oxidant
exposure and mortality from chronic respiratory diseases and liing cancer.
Buell et al. (1967) studied mortality rates among members of the California
Division of the American Legion for the 5-year period from 1958 through 1962.
Long-term residents of Los Angeles County had slightly lower age- and smoking-
adjusted lung cancer rates than residents of the San Francisco Bay area and
San Diego County. Rates of mortality resulting from chronic respiratory
diseases other than lung cancer were higher in Los Angeles than in San
Francisco or San Diego,, but the rates were highest in the other less urbanized
counties. Mahoney (1971) reported higher total respiratory disease mortality
rates in inland, downwind sections of Los Angeles than in coastal, upwind
sections; however, variables such as smoking, migration within the city, and
variation among zones in population density were not considered. In fact,
socioeconomic, demographic, and behavioral variables were not fully controlled
in either the Buell et al. (1967) or Mahoney (1971) studies and mortality
rates were not related to actual pollution measurements.
11.5 SUMMARY AND CONCLUSIONS
Field and epidemiological studies offer a unique view of health effects
research because they involve the real world, i.e., the study of human popula-
tions in their natural setting. These studies have attendant limitations,
however, that must be considered in a critical evaluation of their results.
One major problem in singling out the effects of one air pollutant in field
studies of morbidity in populations has been the interference of other environ-
mental variables that are critical. Limitations of epidemiological research
on the health effects of oxidants include: interference by other air pollutants
or interactions between oxidants and other pollutants; meteorological factors
such as temperature and relative humidity; proper exposure assessments, includ-
ing determination of individual activity patterns and adequacy of number and
location of pollutant monitors; difficulty in identifying oxidant species
responsible for observed effects; and characteristics of the populations such
as smoking habits and socioeconomic status.
11-49
-------
The most quantitatively useful information of the effects of acute exposure
to photochemical oxidants presented in this chapter comes from the field studies
of symptoms and pulmonary function. These studies offer the advantage of
studying the effects of naturally-occurring, ambient air on a local subject
population using the methods and better experimental control typical of
control!ed-exposure studies. In addition, the measured responses in ambient
air can be compared to clean, filtered air without pollutants or to filtered
air containing artificially-generated concentrations of 0, that are comparable
to those found in the ambient environment. As shown in Table 11-11, studies
by Linn et al. (1980, 1983) and Avol et al. (1983, 1984, 1985a,b,c) have
demonstrated that respiratory effects in Los Angeles area residents are related
to 0, concentration and level of exercise. Such effects include: pulmonary
3
function decrements seen at 03 concentrations of 282 ug/m (0.144 ppm) in
exercising healthy adolescents; and increased respiratory symptoms and pulmonary
3
function decrements seen at 0~ concentrations of 300 ug/m (0.153 ppm) in
3
heavily exercising athletes and at 0- concentrations of 341 ug/m (0.174 ppm)
in lightly exercising normal and asthmatic subjects. The light exercise level
is probably the type most likely to occur in the exposed population of Los
Angeles. The observed effects are typically mild, and generally no substantial
differences were seen in asthmatics versus persons with normal respiratory
health, although symptoms lasted for a few hours longer in asthmatics. Many
of the normal subjects, however, had a history of allergy and appeared to be
more sensitive to 03 than "non-allergic" normal subjects. Concerns raised
about the relative contribution to untoward effects in these field studies by
pollutants other than 0, have been diminished by direct comparative findings
in exercising athletes (Avol et al., 1984, 1985c) showing no differences in re-
sponse between chamber exposures to oxiriant-polluted ambient air with a mean 0-
3
concentration of 294 ug/m (0.15 ppm) and purified air containing a controlled
3
concentration of generated 0- at 314 ug/m (0.16 ppm). The relative importance
of exercise level, duration of exposure, and individual variations in sensiti-
vity in producing the observed effects remains to be more fully investigated,
although the results from field studies relative to those factors are consistent
with results from controlled human exposure studies (Chapter 10).
Studies of the effects of both acute and chronic exposures have been
reported in the epidemiological literature on photochemical oxidants. Investi-
gative approaches comparing communities with high Og concentrations and communi-
ties with low 03 concentrations have usually been unsuccessful, often because
11-50
-------
TABLE 11-11. TABLE: ACUTE EFFECTS OF OZONE AND OTHEB PHOTOCHEMICAL OXIDANTS IN FIELD STUDIES WITH A MOBILE LABORATORY0
Mean ozone .
concentration Heasurement '
Mg/ttr* ppm method
282 0.144 UV,
UV
300 0.153 UV,
UV
U-t 306 0.156 UV,
^ NBKI
323 0.165 UV,
NBKI
341 0.174 UV,
NBKI
Exposure Activity
duration level (Vc)
1 hr CE(32)
1 hr CE(53)
1 hr CE(38)
1 hr CE(42)
2 hr IE(2 x R)
@ 15-min
intervals
Observed effect(s)
Small significant decreases in FVC (-2.1%), FEV0 75
(-4.0%), FEV1<0 (-4.2%), and PEFR (-4.4%) relative
to control with no recovery during a 1-hr post-
exposure rest; no significant increases in
symptoms.
Mild increases in lower respiratory symptom scores
and significant decreases in FEVt (-5.3%) and
FVC; mean changes in ambient air were not statisti-
cally different from those in purified air contain-
ing 0.16 ppm Q3.
No significant changes for total symptom score or
forced expiratory performance in normals or
asthmatics; however, FEVt remained low or
decreased further (-3%) 3 hr after ambient air
exposure in asthmatics.
Small significant decreases in FEVt (-3.3%) and
FVC with no recovery during a 1-hr postexposure
rest; TLC decreased and AN2 increased slightly.
Increased symptom scores and small significant
decreases in FEVj (-2.4%), FVC, PEFR, and TLC
in both asthmatic and healthy subjects however,
25/34 healthy subjects were allergic and "atypi-
cally" reactive to Oa-
No.
of subjects
59 healthy
adolescents
(12-15 yr)
50 healthy
adults (compe-
titive bicy-
clists)
48 healthy
adults
50 asthmatic
adults
60 "healthy"
adults
(7 were
asthmatic)
34 "healthy"
adults
30 asthmatic
adul ts
Reference
Avol et al., 1985a,b
Avol et al., 1984, 1985c
Linn et al., 1983;
Avol et al . , 1983
Linn et al., 1983;
Avol et al., 1983
Linn et al., 1980, 1983
Ranked by lowest observed effect level for 03 in ambient air.
Measurement method: UV = ultraviolet photometry.
c.
Calibration method: • UV = ultraviolet photometry standard; NBKI = neutral buffered potassium iodide.
Minute ventilation reported in L/min or as a multiple of resting ventilation. CE = continuous exercise, IE = intermittent exercise.
-------
actual pollutant levels have not differed enough during the study, or other
important variables have not been adequately controlled. The terms "oxidant"
and "ozone" and their respective association with health effects are often
unclear. Moreover, information about the measurement and calibration methods
used is often lacking. Also, as epidemiological methods improve, the incorpora-
tion of new key variables into the analyses is desirable, such as the use of
individual exposure data (e.g., from the home and workplace). Analyses employ-
ing these variables are lacking for most of the community studies evaluated.
Studies of effects associated with acute exposure that are considered to
be qualitatively useful for standard-setting purposes include those on irrita-
tive symptoms, pulmonary function, and aggravation of existing respiratory
disease. Reported effects on the incidence of acute respiratory illness and
on physician, emergency room, and hospital visits are not clearly related with
acute exposure to ambient 0- or oxidants and, therefore, are not useful for
deriving health effects criteria for standard-setting purposes. Likewise, no
convincing association has been demonstrated between daily mortality and daily
oxidant concentrations; rather, the effect correlates most closely with elevated
temperature.
Studies on the irritative effects of 0, have been complicated by the
presence of other photochemical pollutants and their precursors in the ambient
environment and by the lack of adequate control for other pollutants, meteoro-
logical variables, and non-environmental factors in the analysis. Although 0,
does not cause the eye irritation normally associated with smog, several
studies in the Los Angeles basin have indicated that eye irritation is likely
to occur in ambient air when oxidant levels are about 0.10 ppm. Qualitative
associations between oxidant levels in the ambient air and symptoms such as
eye and throat irritation, chest discomfort, cough, and headache have been
reported at >0.10 ppm in both children and young adults (Hammer et al., 1974;
Makino and Mizoguchi, 1975). Discomfort caused by irritative symptoms may be
responsible for the impairment of athletic performance reported in high school
students during cross-country track meets in Los Angeles (Wayne et al., 1967;
Herman, 1972) and is consistent with the evidence from field studies (Section
11.2.1) and from controlled human exposure studies (Section 10.4) indicating
that exercise performance may be limited by exposure to 0,. Although several
additional studies have shown respiratory irritation apparently related to
exposure to ambient 03 or oxidants in community populations, none of these
11-52
-------
epidemiological studies provide satisfactory quantitative data on acute
respiratory illnesses.
Epidemiological studies in children and young adults suggest an associ-
ation of decreased peak flow and increased airway resistance with acute ambient
air exposures to daily maximum 1-hr 0~ concentrations ranging from 20 to 274
3
|jg/m (0.01 to 0.14 ppm) over the entire study period (Lippmann et a!., 1983;
Lebowitz et a!., 1982a, 1983, 1985; Lebowitz, 1984; Bock et al., 1985; Lioy et
a!., 1985). None of these studies by themselves can provide satisfactory
quantitative data on acute effects of 0, because of methodological problems
along with the confounding influence of other pollutants and environmental
conditions in the ambient air. The aggregation of individual studies, however,
provides reasonably good evidence for an association between ambient 0, exposure
• ' O
and acute pulmonary function effects. This association is strengthened by the
consistency between the findings from the epidemiological studies and the
results from the field studies in exercising adolescents (Avol et al., 1985a,b)
which have shown small decreases in forced expiratory volume and flow at 282
o
(jg/m (0.144 ppm) of 0., in the ambient air; and with the results from the
controlled human exposure studies in exercising children which have shown
3
small decrements in forced expiratory volume at 235 ug/m (0.12 ppm) of 03
(Section 10.2.9.2).
In studies of exacerbation of asthma and chronic lung diseases, the major
problems have been the lack of information on the possible effects of medica-
tions, the absence of records for all days on which symptoms could have occurred,
and the possible concurrence of symptomatic attacks resulting from the presence
of other environmental conditions in ambient air. For example, Whittemore and
Korn (1980) and Holguin et al. (1985) found small increases in the probability
of asthma attacks associated with previous attacks, decreased temperature, and
with incremental increases in oxidant and 03 concentrations, respectively.
Lebowitz et al, (1982a, 1983, 1985) and Lebowitz (1984) showed effects in
asthmatics, such as decreased peak expiratory flow and increased respiratory
symptoms, that were related to the interaction of 0, and temperature. All of
these studies have questionable effects from other pollutants, particularly
inhalable particles. There have been no consistent findings of symptom
aggravation or changes in lung function in patients with chronic lung diseases
other than asthma.
Only a few prospective studies have been reported on morbidity, mortality,
and chromosomal effects from chronic exposure to Q~ or other photochemical
11-53
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oxidants. The lack of quantitative measures of oxidant exposures seriously
limits the usefulness of many population studies of morbidity and mortality
for standards-setting purposes. Most of these long-term studies have employed
average annual levels of photochemical oxidants or have involved broad ranges
of pollutants; others have used a simple high-oxidant/low-oxidant dichotomy.
In addition, these population studies are also limited by their inability to
control for the effects of other factors that can potentially contribute to
the development and progression of respiratory disease over long periods of
time- Thus, insufficient information is available in the epidemiological
literature on possible exposure-response relationships between ambient Q~ or
other photochemical oxidants and the prevalence of chronic lung disease or the
rates of chronic disease mortality. None of the epidemiological studies
investigating chromosomal changes have found any evidence that ambient 03 or
oxidants affect the peripheral lymphocytes of the exposed population.
11-54
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Ulrich, L.; Malik, E.; Hurbankova, M.; Kemka, R. (1980) The effect of low-level
ozone concentrations on the serum levels of immunoglobulins, alpha-v-
antitrypsin and transferrin and on the activation of peripheral lympno-
cytes. J, Hyg. Epidemiol. Microbiol. Immunol. 24: 303-308.
U.S. Environmental Protection Agency. (1978) Air quality criteria for ozone
and other photochemical oxidants. Research Triangle Park, NC: U.S.
Environmental Protection Agency, Environmental Criteria and Assessment
Office; EPA report no. EPA-600/8-78-004. Available from: NTIS, Spring-
field, VA; PB80-124753.
11-63
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late matter and sulfur oxides: v. I-III. Research Triangle Park, NC: U.S.
Environmental Protection Agency, Environmental Criteria and Assessment
Office; EPA report nos. EPA-60Q/8-82-029a,b, and c. Available from: NTIS,
Springfield, VA; PB84-156777.
U.S. House of Representatives. (1980) Adverse health effects on inflight
exposure to atmospheric ozone: hearing. July 18, 1979. Washington, DC:
Committee on Interstate and Foreign Commerce, Subcommittee on Oversight
and Investigations; serial no. 96-84.
Ury, H. K. (1968) Photochemical air pollution and automobile accidents in Los
Angeles. An investigation of oxidant and accidents, 1963 and 1965. Arch.
Environ. Health 17: 334-342.
Urys H. K.; Hexter, A. C. (1969) Relating photochemical pollution to human
physiological reactions under controlled conditions. Arch. Environ.
Health 18: 473-479.
Ury, H. K.; Perkins, N. M.; Goldsmith, J. R. (1972) Motor vehicle accidents
and vehicular pollution in Los Angeles. Arch. Environ. Health 25: 314-322.
van As, A. (1982) The accuracy of peak expiratory flow meters. Chest 82: 263.
von Nieding, G.; Wagner, H. M. (1980) Epidemiological studies of the relation-
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Environmental Protection Agency, Health Effects Research Laboratory; EPA
report no. EPA-600/1-78-030. Available from: NTIS, Springfield, VA;
PB-282894.
Wayne, W. S.; Wehrle, P. F. (1969) Oxidant air pollution and school absenteeism.
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Wayne, W. S.; Wehrle, P. F.; Carroll, R. E. (1967) Oxidant air pollution and
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Whittemore, A. S.; Korn, E. L. (1980) Asthma and air pollution in the Los
Angeles area. Am. J. Public Health 70: 687-696.
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World Health Organization. (1983) Guidelines on studies in environmental
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1627-1628.
Young, W.A.; Shaw, D. B.; Bates, D. V. (1963) Pulmonary function in welders
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12. EVALUATION OF HEALTH EFFECTS DATA
FOR OZONE AND OTHER PHOTOCHEMICAL OXIDANTS
12.1 INTRODUCTION
The preceding chapters (Chapters 9, 10, and 11) have documented a wide
array of toxicological responses elicited by jm vivo and j_n vitro exposures to
ozone at concentrations of 1 ppm and below and to other photochemical oxidants
at various concentrations. The extensive body of data on the health effects
of ozone was reported and discussed in particular detail in those chapters.
The present chapter examines, in the light of the findings presented in the
earlier chapters, specific issues and questions that are important for standard-
setting.
Paramount among the issues considered in standard-setting is the identi-
fication of one or more groups of people who need to be protected by the
regulation; that is, one or more groups of individuals who are at potential
risk from exposure to ozone and other photochemical oxidants. The identifi-
cation of such groups presupposes the identification of one or more effects in
man or animals that are in and of themselves adverse, or that are indicators
of other effects that are adverse but are not measurable in man because of
ethical constraints.
The existing health effects data indicate that ozone can affect structure,
function, metabolism, and defense against bacterial infection in the pulmonary
system and can produce extrapulmonary effects, as well. These data are drawn
from human clinical, field, and epidemiological studies, and from animal
toxicological studies. Each of these research approaches, however, has inherent
strengths and weaknesses relative to the assessment of risk. No single approach
provides an adequate basis for an informed judgment, but together these
approaches provide a reasonable estimate of the human health effects of ozone.
IB vitro studies on isolated cells and tissues and _1ji vivo studies on
laboratory animals permit the measurement of effects under circumstances that
are not permissible in clinical research. Such studies can, therefore, be
useful for defining concentration-response relationships over a wide range of
experimental conditions; for studying responses that can only be examined with
invasive procedures; for sorting out and testing hypotheses as a prelude to
clinical investigations; and as an aid in the design of epidemiological studies.
12-1
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This information can be used to examine possible linkages between acute and
chronic effects and to correlate biochemical, functional, and structural
changes with growth, development, and aging of the lung as the result of exposure
to ozone. The chief weakness of laboratory animal studies lies in the diffi-
culties and associated uncertainties of quantitatively extrapolating their
results to the healthy human population, and the even greater problems of
extrapolating such results to diseased human populations.
Controlled studies on human subjects provide information about sensitive
populations, concentration-response relationships, and responses to a limited
number of repeated exposures. Subjects can be carefully selected and exposure
conditions controlled. Such studies, however, are necessarily restricted to
ethically and legally acceptable pollutant concentrations and exposure regimens,
as well as to noninvasive techniques for measuring effects. Furthermore, only
reversible effects can ethically be studied. The emphasis in studies of human
responses to ozone inhalation found in the literature is, therefore, on pulmonary
function. The chief weaknesses of controlled human exposure studies are found
in the need to (1) restrict studies to short-term exposures; (2) limit the range
of pollutant concentrations and type of subjects studied; and (3) use synthetic,
simplified atmospheres. Some of these weaknesses are, of course, the very
features that constitute the strengths of controlled studies since they permit
the determination of concentration-response functions relative to a specific
pollutant and specific endpoint.
Field and epidemiological studies are designed to associate various
characteristics of human health and function with ambient air concentrations
of photochemical oxidants. For the purposes of this document, field studies
are defined as laboratory experiments in which the postulated cause of an
effect in the population is tested under conditions similar to those found in
controlled human studies. Subjects can be carefully selected and exposure
conditions closely monitored. Exposure-effect relationships, however, are
measured during exposure to existing ambient conditions rather than to artifi-
cially generated pollutants. These studies thus form a bridge between the
controlled human studies and the more traditional epidemiological studies in
which human populations are studied in their normal setting. The effects of
communities acutely and chronically exposed to photochemical oxidants are
generally assessed by comparing the functional or clinical status of the
residents during periods of high or low oxidant concentrations. Occasionally,
12-2
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two or more populations residing in high or low oxidant areas are compared.
Investigations within the normal setting are not, or course, without their
drawbacks. Accurate and reliable air exposure data are extremely difficult to
obtain and often do not include indoor exposure conditions. The information
gathered on exposure-effect relationships and results may be confounded by
factors such as variations in the time spend out of doors and indoors, varia-
tions in activity levels, cigarette smoking, disease status, socioeconomic
status, and the coexistence of other pollutants and other environmental condi-
tions. No single epidemiological study can, therefore, provide definitive
evidence for effects that can be attributed solely to ozone, but can only
indicate whether ambient air levels of ozone and other photochemical oxidants
are associated with some measurable outcome of exposure. Although the strength
of this evidence may vary from study to study, the aggregation of epidemiological
data and their convergence potentially provide stronger evidence for human
health effects of ozone.
The responses to ozone and other photochemical oxidants that can be
linked most directly to the potential impairment of public health, i.e.,
without extrapolation, are those changes in pulmonary function that have been
observed in controlled human studies of ozone exposure and in certain field
studies of human exposure to ambient air containing ozone. Additional, sup-
portive data on related respiratory system effects have been obtained from
epidemiological studies of acute exposure to ozone and other photochemical
oxidants in ambient air and from toxicological studies in laboratory animals
exposed to ozone.
As discussed in the 1978 criteria document for ozone and other photochem-
ical oxidants (U.S. Environmental Protection Agency, 1978), changes in lung
function associated with exposure to ozone and other photochemical oxidants
are viewed as signalling potential impairment of public health for several
reasons. Alterations in lung function potentially interfere with normal
activity in the general population and in population groups, depending upon
the activity and the population. In the general population, for example,
ozone exposure during moderate to heavy exercise can produce significant
decrements in lung function (Chapter 10). In certain individuals in the
general population, not yet characterized medically except by their response .
to ozone, significant decrements, larger than those seen in the rest of the
general population, are elicited by exposure to ozone during either continuous
12-3"
-------
or intermittent exercise. In individuals who have respiratory diseases such
as asthma or chronic obstructive lung disease, even small decrements in lung
function could potentially interfere with normal activity and might be of
clinical significance. Symptoms usually accompany the observed decrements in
lung function and impairments in other respiratory indicators, especially
during exercise.
Thus, at least when associated with ozone exposure, changes in lung
function often represent a level of discomfort that, even among
healthy people, may restrict normal activity or impair the perfor-
mance of tasks.
(U.S. Environmental Protection Agency, 1978)
To evaluate the health effects documented and described in the preceding
chapters, relevant effects and the identification of potentially-at-risk
individuals and groups are discussed at length in this chapter. In addition,
inherent biological characteristics or personal habits and activities that may
attenuate or potentiate typical responses to ozone and other oxidants are dis-
cussed. The environmental factors that determine potential or real exposures
of populations or groups are presented, as well, including known ambient air
concentrations of ozone, of other related photochemical oxidants, and of these
combined oxidants.
The issues discussed in subsequent sections are enumerated below:
1. Concentrations and patterns of ozone and other photochemical oxidants,
including indoor-outdoor gradients, relevant for exposure assessment.
2. Symptomatic effects of ozone and other photochemical oxidants.
3. Effects of ozone on pulmonary function in the general population, at
rest and with exercise and other stresses.
4. Influence on the effects of ozone of age, sex, smoking status,
nutritional status, and red-blood-cell enzyme deficiencies.
5. Effects of repeated exposure to ozone.
6. Effects of ozone on lung structure and the relationship between
acute and chronic effects from ozone exposure.
7. Effects of ozone related to resistance to infections, i.e., host
defense mechanisms.
8. Effects of ozone on extrapulmonary tissues, organs, and systems.
9. Effects of ozone in individuals with preexisting disease.
12-4
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10, Extrapolation to human populations of ozone/oxfdant effects observed
in animals.
11. Effects of other photochemical oxidants and the interactions of
ozone and other pollutants.
12. Identification of potentially-at-risk groups.
13. Demographic information on potentially at-risk groups.
12.2 EXPOSURE ASPECTS
Certain information about the occurrence of ozone and other photochemical
oxidants is important for assessing both the potential and the actual exposures
of individuals and of populations. In this section, air monitoring data are
summarized as background information for relating the concentrations at which
effects have been observed in health studies to the occurrence of ozone and
other oxidants in ambient air; and as background for estimating exposures.
12.2.1 Potential Exposures to Ozone
Ozone concentrations exhibit fairly strong diurnal and seasonal cycles.
In most urban areas, single or multiple peaks of ozone occur during daylight
hours, usually during midday (e.g., about noon until 3:00 or 4:00 p.m.). The
formation of ozone and other photochemical oxidants from precursor emissions
is limited to daylight hours since the chemical reactions in the atmosphere
are driven by sunlight. Because of the intensity of sunlight necessary and
the other meteorological and climatic conditions required, the highest concen-
trations of ozone and' other photochemical oxidants usually occur during the
second and third quarters of the year, i.e., April through September. The
months of highest ozone concentrations depend, however, upon local or regional
weather patterns to a considerable degree, so that the temporal patterns of
ozone concentrations are location-dependent. In California, for example,
October is usually a month of higher ozone concentrations than April, and
therefore the 6-month period of highest average ozone concentrations appears
typically to be May through October in many California cities and conurbations.
Although most peak ozone concentrations occur during daylight hours in
nonurban areas, peak concentrations in the early evening and at night are not
uncommon. The occurrence of nighttime peaks appears to be the result of
combined induction time and transport time for urban plumes, coupled with the
12-5
-------
lack of nitric oxide (NO) sources to provide NO for chemical scavenging of
ozone in the evening and early morning hours. Average ozone concentrations
are generally lower in nonurban than in urban areas, but peak concentrations
higher than those found in urban and suburban areas can sometimes occur.
In urban areas, early morning ozone concentrations (around 2:00 or
3:00 a.m. until about 6:00 a.m.) are near zero (<0.02 ppm), largely because of
scavenging by NO. In nonurban areas, early morning ozone concentrations are
higher and are near background levels (e.g., about 0.025 to 0.045 ppm), since
surface scavenging rather than chemical scavenging by NO is the principal
removal mechanism in nonurban areas.
Quantitative data on ozone concentrations are briefly summarized here.
Figure 12-1 shows the frequency distribution of the three highest 1-hour ozone
concentrations in each year aggregated for 3 years (1979 through 1981) (U.S.
Environmental Protection Agency, 1980, 1981, 1982). These three curves are
based on data obtained from predominantly urban monitoring stations. The
frequency distribution of the highest 1-hour concentrations measured at eight
rural or remote sites (Evans, 1985) is presented separately in Figure 12-1.
These 1-hour concentrations, recorded at sites of the National Air Pollution
Background Network (NAPBN) located in national forests across the country,
have been aggregated for the same 3-year period, 1979 through 1981. The
present primary and secondary national ambient air quality standards for ozone
are expressed as a concentration not to be exceeded on more than one day per
year. Thus, the second-highest value among daily maximum 1-hour ozone concen-
trations, rather than the highest, is regarded as a concentration indicative
of the degree of protection of public health and welfare. As demonstrated by
Figure 12-1, 50 percent of these values reported at the urban monitoring stations,
aggregated for 3 years, were ~ 0-12 ppm; 25 percent were ~ 0.15 ppm; and
10 percent were ~ 0.20 ppm. The frequency distribution of the daily maximum
(i.e., the highest) 1-hour concentrations measured at NAPBN sites shows that
50 percent of the concentrations were < 0.09 ppm; 25 percent were < 0.08 ppm;
and 10 percent were 5 0.07 ppm.
As data in Chapter 10 and in Section 12.3.4 show, human control!ed-exposure
studies have demonstrated that attenuation of responses to ozone during re-
peated, consecutive-day exposures of at least 3 to 4 days occurs in many,
though not all, of the individuals studied. Thus, the potential for repeated,
consecutive-day exposures of that duration to ambient air concentrations of
12-6
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CC
z
IU
o
z
o
o
LU
99.99
0.45
0.40
0.35
0.30
0.25
0.20
99.9 99,8
99 98 95 90
80 70 60 50 40 30 20
10
2 1 0.5 0.2 0.1 0.05 0.01
O 0.15
O
0.10
0.05
0
HIGHEST
2nd HIGHEST
3rd-HIGHEST
HIGHEST, NAPBN SITES
I I I I i I I I I I I I III II II
I I
0.01 0.05 0.1 0.2 0.5 1 2 5 10 20 30 40 50 60 70 80 90 95 98 99 99.8 99.9 99.99
STATIONS WITH PEAK 1-hour CONCENTRATIONS < SELECTED VALUE, percent
Figure 12-1. Distributions of the three highest 1 -hour ozone concentrations at valid sites (906
station-years) aggregated for 3 years (1979,1980, and 1981) and the highest ozone
concentrations at NAPBN sites aggregateed for those years (24 station-years).
Source: U.S. Environmental Protection Agency (1980,1981,1982).
-------
ozone is of interest. Data records from four cities were.examined in Chapter 5
for exposures to four different 1-hour concentrations to determine their
recurrence on 2 or more consecutive days in a 3-year period (see Tables 5-6
through 5-9). Those data are summarized for three cities in Table 12-1. The
data given in Table 12-1 are descriptive statistics based on aerometric data
from the respective localities for 1979, 1980, and 1981, and cannot be used to
predict the number of recurrences of high 1-hour concentrations of ozone for
any other period or locality. The 1-hour ozone concentration at the Pasadena,
CA, site reached a 1-hour concentration > 0.18 ppm for 4 consecutive days six
times and for 8 or more consecutive days seven times in the 3-year period
examined. A 1-hour concentration ^> 0.24 ppm was reached on 4 consecutive days
two times and 8 or more consecutive days one time in the 3 years. Data for
sites in Dallas, TX, and Washington, DC, show no consecutive-day recurrences
of high 1-hour concentrations such as those sustained in Pasadena. Data
presented in Chapter 5 for a Pomona, CA, site, also in the South Coast Air
Basin, show a pattern similar to that in Pasadena of consecutive-day recur-
rences of high 1-hour ozone concentrations.
Potential exposures of nonurban populations, while not easily ascertained
in the absence of a suitable aerometric data base, can be estimated from
measurements made at selected sites known to represent agricultural areas and
at sites of special-purpose monitoring networks. Data from the eight NAPBN
national forest (NF) monitoring stations show that arithmetic mean 1-hour
ozone concentrations at these sites, for the second and third quarters of the
year, ranged from a 5-year average of 25.8 ppb at Kisatchie NF, LA (1977-1980,
1982) to a 4-year average of 49.4 ppb at Apache NF, AZ (1980-1983) (Evans,
1985). (Data are weighted for the number of 1-hour concentrations measured.)
Data from Sulfate Regional Experiment (SURE) sites showed mean concentrations
of ozone for August through December 1977 at four "rural" sites of 0.021,
0.029, 0.026, and 0.035 ppm at Montague, MA, Duncan Falls, OH, Giles County,
TN, and Lewisburg, WV, respectively. At five "suburban" SURE sites (Scranton,
PA; Indian River, DE; Rockport, IN; Ft. Wayne, IN; and Research Triangle Park,
NC), mean concentrations for the "study period were 0.023, 0.030, 0.025, 0.020,
and 0.025 ppm, respectively. Maximum 1-hour ozone concentrations for the nine
stations ranged from 0.077 ppm at Scranton, PA, to 0.153 ppm at Montague, MA
(Martinez and Singh, 1979).
12-8
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TABLE 12-1. NUMBER OF TIMES THE DAILY MAXIMUM 1-hr OZONE
CONCENTRATION WAS > 0.08, > 0.12, > 0.18, and > 0.24 ppm
FOR SPECIFIED CONSECUTIVE DAYS IN PASADENA, DALLAS, AND
WASHINGTON, APRIL THROUGH SEPTEMBER, 1979 THROUGH 1981
of No. of occurrences of daily max. 1-hr 03concns of:
consecutive days >0.06 ppm >_ 0.12 ppm > 0.18 ppm > 0.24 ppm
Pasadena
2
3
4
5
6
7
>8
Dal 1 as
2
3
4
5
6
7
>8
Washington
2
3
4
5
6
7
>8
5a
0
2
2
0
2
10
10
6
5
8
3
5
11
10
6
2
2
0
2
5
10
8
4
7
2
0
14
4
2
0
1 -
0
0
0
1
0
0
0
0
0
0
9
10
6
3
4
1
7
0
0
0
0
0
0
0
0
0
0
0
0
0
0
13
5
2
2
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
aNote: Data are not cumulative by row or by column. This is because an epi-
sode in which, for example, a 1-hour concentration of 0.18 ppm is exceeded
on each of 2 consecutive days is almost always part of a longer episode in
which a lower 1-hour concentration (e.g., 0.12 or 0.06 ppm) has been exceeded
on each day of an even longer consecutive-day period. Thus, the occurrences
of a 2-day episode at a higher concentration, for example, are a subset of
the occurrences of an ji-day episode (e.g., > 3 days) tabulated under one or
more lower concentrations.
Source: SAROAD (1985a,b,c).
12-9
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Concentrations of ozone indoors, since most people spend most of their
time indoors, are of value in estimating total exposures. The estimation of
total exposures, in turn, is of value for optimal interpretation and use of
epidemiological studies. Data on concentrations of ozone indoors are few. It
is known, however, that ozone decays fairly rapidly indoors through reactions
with surfaces of such materials as wall board, carpeting, and draperies (Chap-
ter 5). Ozone concentrations indoors depend also on those factors that affect
both reactive and nonreactive pollutants: concentrations outdoors, temperature,
humidity, air exchange rates, presence or absence of air conditioning, and
mode of air conditioning (e.g., 100 percent fresh-air intake versus recircula-
tion of air). Estimates in the literature on indoor-outdoor ratios (I/O,
expressed as percentage) of ozone concentrations range from just over 0 percent
to 100 percent for residences (Stock et al., 1983), and from 29 percent
(Moschandreas et al., 1978) to 80 ± 10 percent (Sabersky et al., 1973) for
office buildings. Variations in estimated I/O for buildings are attributable
to the diversity of structures monitored, their locations, and their heating,
ventilating, and air-conditioning systems. Measurements made inside automobiles
show inside ozone concentrations ranging from about 30 percent (Peterson and
Sabersky, 1975) to about 56 percent (Contant et al., 1985) of outside concen-
trations. Again, outside concentrations and mode of air conditioning or
ventilation are among the factors determining the inside concentrations. It
should be noted that outside concentrations of ozone on well-traveled roadways
are lower than other outdoor concentrations because nitric oxide emissions
from automobiles scavenge ozone.
Along with small-scale spatial variations in ozone concentrations, such
as indoor-outdoor gradients, large-scale variations exist, such as those that
occur with latitude and altitude. Latitudinal variations have little effect
on potential exposures within the contiguous United States, since the conti-
guous states all fall within latitudes where photochemical oxidant formation
is favored (Logan et al., 1981; U.S. Environmental Protection Agency, 1978).
The increases in concentrations of background ozone with increase with altitude
(Viezee et al., 1979; Seller and Fishman, 1981) are significant only in the
free troposphere. When ozone is carried in layers aloft in long-distance
transport (i.e., mesoscale and synoptic-scale transport), it is conserved
overnight because of the occurrence of temperature inversions (nocturnal
inversions) that prevent downward vertical mixing and thus prevent scavenging
12-10
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at the surface by the nitric oxide present in ground-level emissions. Where
nocturnal inversion layers contact mountainsides, ozone concentrations will be
greater at night at higher elevations than at lower. Daytime concentrations
may vary slightly but not appreciably with elevation. Daytime peak concentrations
may occur later in the day at higher elevations because of transport time from
urban sources, most of which are at lower elevations. There appear to be
fewer implications for human populations than for mountain forests and other
vegetation, however, since high elevations are usually sparsely populated and
since the higher concentrations observed at higher elevations occur overnight.
The altitudinal gradients in the free troposphere could be of possible conse-
quence for certain high-altitude flights, as reported in the field studies
documented in Chapter 11, except that the air filtration and ventilation
systems commonly employed on airplanes reduce the on-board concentrations.
It should be pointed out that the mass of ozone per unit volume decreases
with elevation (altitude), for given concentrations expressed as volume/volume
ratios. In addition, data presented in Chapter 5 for Denver, CO, for example,
show that ozone concentrations are lower there than at many lower-elevation
metropolitan areas of comparable size.
Even though ozone is considered to be a regional pollutant, intermediate-
scale spatial variations in concentrations occur that are of potential conse-
quence for designing and interpreting epidemic!ogical studies. For example,
data from a study of ozone formation and transport in the northeast corridor
(Smith, 1981) showed that in New York City an appreciable gradient existed, at
least for the study period (summer, 1980), between ozone concentrations in
Brooklyn and those in the Bronx. The maximum 1-hour ozone concentration
measured at the Brooklyn monitoring site was 0.174 ppm, while that measured at
the Bronx monitoring site was 0.080 ppm.
12.2.2 Potential Exposures to Other Photochemical Oxidants
12.2.2.1 Concentrations. Concentrations in ambient air of four photochemical
oxidants other than ozone have been presented in Chapter 5. Those data are
drawn upon here to examine the concentrations of these pollutants that might
be encountered in the United States, including "worst-case" situations, in
order to determine both the minimum and maximum additive concentrations of
these pollutants with ozone that could occur in ambient air. The four photo-
chemical oxidants for which concentration data were given in Chapter 5 are
12-11
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peroxyacetyl nitrate (PAN), peroxypropionyl nitrate (PPN), hydrogen peroxide
(H202), and formic acid (HCOOH).
Although they co-occur to varying degrees with ozone, aldehydes are not
photochemical oxidants. Since they are not oxidants and are not measured by
methods that measure oxidants, their role relative to public health and welfare
is not reported in this document. The reader is referred to a recent compre-
hensive review by Altshuller (1983) for a treatment of the relationships in
ambient air between ozone and aldehyde concentrations.
Few health effects data or aerometric data on formic acid exist. Those
ambient air concentrations that are given in the literature, however, indicate
that formic acid occurs at trace concentrations, i.e., <0.015 ppm, even in
high-oxidant areas such as the South Coast Air Basin of California (Tuazon et
al., 1981). No data are available for other urban areas or for nonurban
areas. Given the known atmospheric chemistry of formic acid, concentrations
in the South Coast Air Basin are expected to be higher than in other urban
areas of the country (Chapter 3).
The measurement methods (IR and GC-ECD) for PAN and PPN are specific and
highly sensitive, and have been in use in air pollution research for nearly
two decades. Thus, the more recent literature on the concentrations of PAN
and PPN confirm and extend, but do not contradict, earlier findings reported
in the two previous criteria documents for ozone and other photochemical
oxidants (U.S. Department of Health, Education, and Welfare, 1970; U.S. Environ-
mental Protection Agency, 1978).
Concentrations of PAN are reported in the literature from 1960 through
the present. The highest concentrations reported over this extended period
were those found in the 1960s in the Los Angeles area: 70 ppb (1960), 214 ppb
(1965), and 68 ppb (1968) (Renzetti and Bryan, 1961; Mayrsohn and Brooks,
1965; Lonneman et al., 1976, respectively).
The highest concentrations of PAN measured and reported in the past
5 years were 42 ppb at Riverside, CA, in 1980 (Temple and Taylor, 1983), and
47 ppb at Claremont, CA, also in 1980 (Grosjean, 1983). These are clearly the
maximum concentrations of PAN reported for California and for the entire country
in this period. Other recently measured PAN concentrations in the Los Angeles
Basin were in the range of 10 to 20 ppb. Average concentrations of PAN in the
Los Angeles Basin in the past 5 years ranged from 4 to 13 ppb (Tuazon et al.,
1981; Grosjean, 1983). The only published report covering PAN concentrations
12-12
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outside California in the past 5 years is that of Lewis et al. (1983) for New
Brunswick, NJ. The average PAN concentration there was 0.5 ppb and the maximum
was 11 ppb during a study done from September 1978 through May 1980. Studies
outside California from the early 1970s through 1978 showed average PAN concen-
trations ranging from 0.4 ppb in Houston, TX, in 1976 (Westberg et al., 1978)
to 6.3 ppb in St. Louis, MO, in 1973 (Lonneman et al., 1976). Maximum PAN
concentrations outside California for the same period ranged from 10 ppb in
Dayton, OH, in 1974 (Spicer et al., 1976) to 25 ppb in St. Louis (Lonneman
et al., 1976).
The highest PPN concentration reported in studies from 1963 through the
present was 6 ppb in Riverside, CA, in the early 1960s (Darley et al., 1963).
The next highest reported PPN concentration was 5 ppb at St. Louis, MO, in
1973 (Lonneman et al. , 1976). Among more recent data, maximum PPN concentra-
tions at respective sites ranged from 0.07 ppb in Pittsburgh, PA (Singh et al.,
1982) to 3.1 ppb at Staten Island, NY, in 1981 (Singh et al., 1982). California
concentrations fell within this range. Average PPN concentrations at the
respective sites for the more recent data ranged from 0.05 ppb at Denver and
Pittsburgh to 0.7 ppb at Los Angeles in 1979 (Singh et al., 1981).
Altshuller (1983) has succinctly summarized the nonurban concentrations
of PAN and PPN by pointing out that they overlap the lower end of the range of
urban concentrations at sites outside California. At remote locations, PAN
and PPN concentrations are lower than even the lowest of the urban concentra-
tions (by a factor of three to four).
Concentrations of H^Op reported in the published literature must be
regarded as inaccurate, since all wet-chemical methods used to date are now
thought to be subject to positive interference from ozone. Evidence that
reported HpOp concentrations have been in error is provided not only by recent
investigations of wet-chemical methods, but by the fact that FTIR measurements
of ambient air have not demonstrated the presence of H^Op even in the high-
oxidant atmosphere of the Los Angeles area. The limit of detection for a .
,1-km-pathlength FTIR system, which can measure HpOp with specificity, is
around 0.04 ppm (Chapter 4). In urban areas, hydrogen peroxide ^02) concen-
trations have been reported to range from < 0.5 ppb in Boulder, CO (Heikes
et al., 1982) to < 180 ppb in Riverside, CA (Bufalini et al. , 1972). In
nonurban areas, reported concentrations ranged from 0.2 ppb near Boulder, CO,
in 1978 (Kelly et al., 1979) to < 7 ppb 54 km southeast of Tucson, AZ (Farmer
12-13
-------
and Dawson, 1982). These nonurban data were obtained by the luminol chemilumi-
nescence technique (see Chapter 4). The urban data were obtained by a variety
of methods, including the luminol chemiluminescence, the titanium (IV) sulfate
8-quinolinol, and other wet chemical methods (see Chapter 4). Thus, these
reported concentrations have all been measured by methods in which ozone is a
positive interference.
12.2.2.2 Patterns. The patterns of formic acid (HCOOH), PAN, PPN, and H202
can be summarized fairly succinctly. They bear qualitative but not quantita-
tive resemblance to the patterns already summarized for ozone concentrations.
Qualitatively, diurnal patterns are similar, with peak concentrations of each
of these occurring in close proximity to the time of the ozone peak. The
correspondence in time of day is not exact, but is close. As the work of
Tuazon et al. (1981) at Claremont, CA, demonstrates (see Chapter 5) ozone
concentrations return to baseline levels faster than the concentrations of
PAN, HCOOH, or H202 (PPN was not measured).
Seasonally, winter concentrations (first and fourth quarters) of PAN are
lower than summer concentrations (second and third quarters). The winter
concentrations of PAN are proportionally higher relative to ozone in winter
than in summer. Data are not available on the seasonal patterns of the other
non-ozone oxidants.
Indoor-outdoor data on PAN are limited to one report (Thompson et al.,
1973), which confirms the pattern to be expected from the known chemistry of
PAN; that is, it persists longer indoors than ozone. Data are lacking for
indoor concentrations of the other non-ozone oxidants.
12.2.3 Potential Combined Exposures and Relationship of Ozone and Other
Photochemical Oxidants
Data on concentrations of PAN, PPN, and H202 indicate that in "worst-case"
situations these non-ozone oxidants together could add as much as about 0.15
ppm of oxidant to the ozone burden in ambient air. The highest of the "second-
highest" ozone concentration measured in the United States in 1983 was 0.37
ppm, in the Los Angeles area. (For the definition of the "second-highest"
1-hour value see Chapter 5). In the presence of that concentration of ozone,
the addition of "worst-case" concentrations of non-ozone oxidants (0.15 ppm
total) would bring the total oxidant concentration to around 0.52 ppm, provided
12-14
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peak concentrations of ozone and non-ozone oxidants were reached at the same
time. It should be noted that such "worst-case" concentrations are not viewed
as typical. Data from recent years for the Los Angeles Basin indicate that
average concentrations of PAN and PPN together would add 0.014 ppm (14 ppb) to
the average oxidant burden there (4 to 13 ppb average PAN: Tuazon et a!.,
1981; Grosjean, 1983, respectively; and 0.7 ppb PPN: Singh et al., 1981).
The significance for public health of the imposition of an additional
oxidant burden from non-ozone oxidants rests not only on average or "worst-case"
concentrations, however, but on the answers to at least several other questions,
e.g.:
1. Do PAN, PPN, or hLQ^, singly or in combination, elicit adverse or
potentially adverse responses in human populations?
2. Do any or all of these non-ozone oxidants act additively or syner-
gistically in combination with ozone to elicit adverse or poten-
tially adverse responses in human populations? Do any or all act
antagonistically with ozone?
3. What is the relationship between the occurrence of ozone and these
non-ozone oxidants? Can ozone serve as a surrogate for these other
oxidants?
The first two questions are addressed by health effects data presented in
Chapters 9 through 11 and in Section 12.6 of the present chapter. The third
question has been addressed in detail by Altshuller (1983). His conclusion is
that "the ambient air measurements indicate that 03 may serve directionally,
but cannot be expected to serve quantitatively as a Surrogate for the other
products" (Altshuller, 1983). It must be emphasized here that Altshuller
examined the issue of whether Oq could serve as an abatement surrogate for all
o ~~~*~~~
photochemical products, including those not relevant to effects data examined
in this document. For example, the products he reviewed relative to ozone
included aldehydes, aerosols, and nitric acid. Nevertheless, his conclusions
appear to apply to the subset of photochemical products of concern here: PAN,
PPN, and H^.
The most straightforward evidence of the lack of a quantitative, monotonic
relationship between ozone and the other photochemical oxidants is the range
of PAN-to-03 ratios and, indirectly, of PAN-to-PPN ratios presented in the
review by Altshuller (1983) and summarized in Table 12-2 and in Chapter 5.
12-15
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TABLE 12-2. RELATIONSHIP OF OZONE AND PEROXYACETYL NITRATE AT URBAN AND;
SUBURBAN SITES IN THE UNITED STATES IN REPORTS PUBLISHED 1978 OR LATER
Site/year of study
West Los Angeles, CA, 1978
Claremont, CA,
Claremont, CA,
Riverside, CA,
Riverside, CA,
Riverside, CA,
Riverside, CA,
1978
1979
1975-1976
1976
1977
1977
Houston, TX, 1976
New Brunswick,
NJ, 1978-1980
PAN/03, %
Avg.
9
7
4
9
5
4
4
3
4
At 03 peak Reference
6
6
4
5
4
4
NAa
3
2
Hanst et al. (1982)
Tuazon et al. (1981a,
1981b)
Tuazon et al . (1981a)
Pitts and Grosjean (1979)
Tuazon et al . (1978)
Tuazon et al. (1980)
Singh et al. (1979)
Westberg et al . (1978)
Brennan (1980)
aNot available.
Source: Derived from Altshuller (1983).
Chapter 5.
For primary references, see
Certain other information presented in Chapter 5 bears out the lack of a
strictly quantitative relationship between ozone and PAN and its homologues.
Not only are ozone-PAN relationships not consistent between different urban
areas (e.g., Singh et al., 1982), but they are not consistent in urban versus
nonurban areas (e.g., Lonneman et al., 1976), in summer versus winter (e.g.,
Temple and Taylor, 1983), in indoor versus outdoor environments (Thompson et
al., 1973), or even, as the ratio data show, in location, timing, or magnitude
of diurnal peak concentrations within the same city (e.g., Jorgen et al.,
1978). In addition, Tuazon et al. (1981) demonstrated that PAN persists in
ambient air longer than ozone, its persistence paralleling that of HN03, at
least in some localities. Reactivity data presented in the 1978 criteria
document for ozone and other photochemical oxidants indicate that all precur-
sors that give rise to PAN also give rise to ozone. Not all are equally
12-16
-------
reactive toward both products, however, and therefore some precursors prefer-
entially give rise, on the basis of units of product per unit of reactant, to
more of one product than the other (U.S. Environmental Protection Agency,
1978).
It must be emphasized that information presented in Chapter 4 clearly
shows that no one method can quantitatively and reliably measure all four
oxidants of potential concern (ozone, PAN, PPN, and hydrogen peroxide), either
one at a time or in ambient air mixtures. This point was not clearly presented
in the 1978 criteria document but is given substantial discussion in Chapter 4
of this document.
12.3 HEALTH EFFECTS IN THE GENERAL HUMAN POPULATION
12.3,1 Clinical Symptoms
A close association has been observed between the occurrence of respira-
tory symptoms and changes in pulmonary function in adults acutely exposed in
environmental chambers to 0, (Chapter 10) or to ambient air containing 0- as
the predominant pollutant (Chapter 11). This association holds for both the
time-course and magnitude of effects. Insofar as cough and chest pain or
irritation may interfere with the maximal inspiratory or expiratory efforts
(see Section 12.3.5), such associations between symptoms and function might be
expected. In a comparison of adults exposed to both oxidarit-polluted ambient
air and purified air containing only 0- (Avol et a!,, 1984, 1985c), no evidence
was found to suggest that any pollutant other than Og contributed to the symptom
increases associated with decrements in lung function. Studies on children and
adolescents exposed to 03 or ambient air containing 03 under similar conditions
have found no significant increases in symptoms despite significant changes in
pulmonary function (Avol et al., 1985a,b; McDonnell et a!., 1985b,c).
Epidemiological studies have been conducted to compare the incidence of
acute, irritative symptoms associated with exposure of communities to varying
concentrations of photochemical oxidants, but to date no studies have been
designed specifically to test the comparative frequency or magnitude of response
of symptoms versus functional changes. In addition, epidemiological studies have
been complicated by (1) the presence of other pollutants, including photochemical
pollutants and their precursors, in the ambient environment and (2) the lack of
12-17
-------
adequate control for other pollutants, meteorological variables, and non-
environmental factors in the analysis. The symptoms most likely to occur
within the polluted community are difficult to associate with a specific
pollutant and are, therefore, of limited use for quantifying exposure-response
relationships.
The symptoms found in association with controlled exposure to 0- and with
exposure to photochemical air pollution are similar but not identical. Eye
irritation, one of the commonest complaints associated with photochemical
pollution, is not characteristic of controlled exposures to 0, alone or to
ambient air containing predominantly 0,, even at concentrations of the gas
several times higher than any likely to be encountered in ambient air. Other
components of photochemical air pollution, such as aldehydes and PAN, are held
to be chiefly responsible for eye irritation (National Air Pollution Control
Administration, 1970; Altshuller, 1977; National Research Council, 1977; U.S.
Environmental Protection Agency, 1978; Okawada et a!., 1979).
There is limited qualitative evidence to suggest that at low concentra-
tions of 0-, symptoms other than eye irritation are more likely to occur in
populations exposed to ambient air pollution than in subjects exposed in
chamber studies, especially if Og is the sole pollutant administered in the
chamber studies. The symptoms may be indicative of either upper or lower
respiratory tract irritation. For example, in two epidemiological studies,
qualitative associations between oxidant levels and symptoms such as throat
irritation, chest discomfort, cough, and headache have been reported at > 0.10
ppm in both children and young adults (Hammer et al., 1974; Makino and Mizoguchi,
1975). While some individual subjects have experienced cough, shortness of
breath, and pain upon deep inspiration at 03 concentrations as low as 0.12 ppm
during controlled exposure with exercise (McDonnell et al., 1983), the group
mean symptom response was significant only for cough. It is not clear, however,
if the symptoms reported in the epidemiological studies cited above could have
been induced by other pollutants in the ambient air. Above 0.12 ppm 03, a
variety of both respiratory and non-respiratory symptoms have been reported in
controlled exposures. They include throat dryness, difficulty or pain when
inspiring deeply, chest tightness, substernal soreness or pain, cough, wheeze,
lassitude, malaise, headache, and nausea (DeLucia and Adams, 1977; Kagawa and
Tsuru, 1979b; McDonnell et al., 1983; Adams and Schelegle, 1983; Avol et al.,
1984, 1985c; Gibbons and Adams, 1984; Folinsbee et al., 1984; Kulle et al.,
12-18
-------
1985). Most "symptom scores" have been positive at concentrations of 0.2 ppm
0- and above. Symptoms tend to remit within hours after exposure is ended.
Relatively few subjects have reported persistence of symptoms beyond 24 hours.
Many variables could possibly explain differences in symptomatic effects
reported in epidemiological and controlled human studies. They include dif-
ferent subject populations, pollutant mixtures, and exposure patterns utilized
in each study, factors affecting the perception of symptoms in one type of
study compared to the other, or differences in the methods used to assess
symptoms. Alternatively, the presence of reactive chemical species other than
DO in polluted ambient air might be chiefly responsible for the symptoms
observed in epidemiological studies or might interact synergistically with 0~
to initiate the symptoms, although recently published data show no excess
response to oxidant-polluted air containing predominantly 0., and particles
(Avol et a!., 1984, 1985c).
Symptoms have commonly been assessed by the use of recording sheets
combined with reliance on the subject's recall, usually right after exposure
but sometimes several hours or days after exposure (e.g., community studies).
While it is difficult to score the intensity of symptoms with confidence, the
types of symptoms obtained immediately after exposure have been noteworthy for
their general consistency across studies. Moreover, as noted earlier, a good
association has been observed between changes in symptoms and objective
functional tests at 0, concentrations > 0.15 ppm. Symptoms are therefore con-
sidered to be useful adjuncts for assessing the effects of 03 and photochemical
pollution, particularly if combined with objective measurements of pulmonary
function.
12.3.2 Pulmonary Function at Rest and withExercise and Other Stresses
12.3.2.1 At-Rest Exposures. The great majority of short-term ozone exposure
studies on resting subjects were published almost a decade ago and were reviewed
extensively in the previous ozone-oxidants criteria document (U.S. Environmen-
tal Protection Agency, 1978). Briefly, resting subjects inhaling ozone at
concentrations up to 0.75 ppm for 2 hr showed no decrements or only very small
(< 10 percent) decrements in FVC (Silverman et al., 1976; Folinsbee et a!.,
1975; Bates eta!., 1972), VC (Silverman et al. , 1976; Folinsbee eta!.,
1975), FEVp and FRC (Silverman et al., 1976). Other flow-derived variables,
such as the maximal expiratory flow at 50 percent VC (FEF 50%) and the maximal
12-19
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expiratory flow at 25 percent VC (FEF25I), were affected to a greater degree,
showing decreases of up to 30 percent from control in certain individuals at
0.75 ppm 03 (Bates et al., 1972; Silverman et a!., 1976), Small increases in
airway resistance (R < 17 percent) were reported at concentrations greater
than 0.5 ppm (Bates et al., 1972; Golden et al., 1978). Specific tests of
lung mechanical properties generally exhibited a lack of significant effects.
Static compliance (C .) remained virtually unchanged, whereas dynamic compliance
(Cj ) and the maximum static elastic recoil pressure of the lung (P. max)
showed some borderline effects at 0.75 ppm 0., (Bates et al., 1972). Ventila-
tory (Vj, fp, VV) and metabolic (V02> VV/02) responses to ozone, even at 0.75
ppm level, were not significantly altered (Folinsbee et al., 1975). The only
non-spirometric test reported to be significantly affected by ozone inhalation
was a bronchial response. Post-ozone (0.6 ppm for 2 hr) challenge with histamine
showed significant enhancement of airway responsiveness in every subject
tested. Premedication with atropine blocked only transiently the ozone-induced
hyperreactivity of airways (SR ) to histamine (Golden et al., 1978). Breathing
0.6 to 0.8 ppm 03 for 2 hr markedly reduced diffusion capacity (D-ico) across
the alveolar-capillary membrane (Young et al., 1964); however, the mean frac-
tional CO uptake, also an index of diffusion, decreased only marginally under
similar exposure conditions (Bates et al., 1972). The slope of phase III of
the single-breath nitrogen closing volume curves, which increases as the
inhoraogeneity in the distribution of ventilation increases, was not signifi-
cantly altered by 03 inhalation (Silverman et al., 1976).
More recent at-rest ozone exposure studies basically confirmed previously
reported findings. Decrements in forced expiratory volume and flows have been
found from exposures to concentrations at and above 0.5 ppm (Folinsbee et al.,
1978; Horvath et al., 1979). Airway resistance was not significantly affected
at these 0, concentrations, and static lung volume changes (increase in RV and
decrease in TLC) were only suggestive (Shephard et al,, 1983). Metabolic and
cardiopulmonary effects were also minimal (Horvath et al., 1979). At concen-
trations below 0.5 ppm ozone, the effects assessed by commonly used pulmonary
function tests were small and inconsistent (Folinsbee et a!., 1978; Horvath et
al,, 1979). Reports, however, of ozone-induced symptoms and functional effects
in some subjects, well exceeding the group mean response, indicate that even
under resting exposure conditions some subjects are more responsive to ozone
(Konig et al, 1980; Lategola et al., 1980a,b; Golden et al., 1978).
12-20
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12.3.2.2 Exposures with Exercise. Minute ventilation (VF) is considered to be
one of the principal modulators of the magnitude of response to 03. The most
convenient physiological procedure for increasing VV is to exercise exposed
individuals either on a treadmill or bicycle ergometer. Consequent increases
in frequency and depth of breathing will increase the overall volume of inhaled
pollutant. Moreover, such a ventilatory pattern also promotes penetration of
ozone into peripheral lung regions. Thus, a larger amount of ozone will reach
tissues most sensitive to injury. These processes are further enhanced at
higher workloads (Vr > 35 L/min), since the mode of breathing will change from
nasal to oronasal or oral only (Niinimaa et al., 1980). As the ventilation
increases, an increasingly greater portion of the total minute volume is
inhaled orally, bypassing the scrubbing capacity of the nose and nasopharynx
(Niinimaa et al., 1981) and further augmenting the ozone dose to the lower
airways and parenchyma.
Even in well-controlled experiments on an apparently homogeneous group of
subjects, physiological responses to the same work and pollutant loads can
vary widely among individuals (Chapter 10). Under strenuous exposure conditions
(VV = 45-51 L/min at 0.4 ppm) the least responsive subjects showed FEV-. decre-
ments of less than 10 percent, while the most responsive yet apparently healthy
individuals had severely impaired lung function (FEV-. = 40 percent of control);
the average decrement was 26 percent (Haak et al., 1984; Silverman et al.,
1976). Some factors, such as the mode of ventilation (oral versus nasal) and
the pattern of breathing (shallow rapid versus slow deep) contribute to but
cannot account totally for the commonly observed heterogeneous responses of an
otherwise homogeneous group of subjects. Implementation of strict subject
selection criteria including restrictions on age and sex in most of the studies
narrowed only slightly the distribution of responses. Attempts to determine
predisposing factors responsible for increased or decreased 03 responsiveness
utilizing nonspecific tests were unsuccessful (Hazucha, 1981). Individual
responsiveness is probably a function of many factors. Previous exposures of
individuals to other pollutants (Hackney et al., 1976, 1977b), and nutritional
deficiencies and/or latent infection(s), known to be relevant in animals
(Chapter 9), might be among contributing factors. Individual responsiveness
appears to be maintained relatively unchanged for as long as 10 months.
Generally, within-individual variability in response is considerably smaller
than the variations reported between subjects (McDonnell et al,, 1985a; Gliner
et al., 1983).
12-21
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In studies that have described the distribution of individual responses
to ozone (McDonnell et al,, 1983; Kulle et a!., 1985), the changes in pulmonary
function resulting from exposure to clean air or near zero ozone concentrations
are small and uniformly distributed. As the ozone concentration increases,
the distribution widens and becomes skewed towards larger decrements in pulmonary
function, the largest changes respresenting the most responsive subjects.
Reported retrospective classification of subjects into "responders/sensitives"
and "nonresponders/nonsensitives" varies from study to study. Some subjects
were classified as "responders" by medical history and previous exposures or
test results, or both (Hackney et al.3 1975); others had to show more than 10
percent post-exposure decrements (Horvath et a!., 1981) or decrements exceeding
two standard deviations of the control (Haak et a!., 1984). The term "hyper-
reactor" or "hyperresponder" has been arbitrarily used to describe the 5 to 20
percent of the population that is most responsive to ozone exposure. There
are no clearly established criteria for defining "reactive" or "nonreactive"
subjects. Nevertheless, it is important to identify criteria to define the
"reactive" portion of the population since they may represent a subgroup of
the population which can be considered "at risk".
Intermittent exercise augments physiological response to 0.,. Moderate
exercise (vV = 24-43 L/min) in 0.4 ppm ozone for 2 hr reduced the FEV-, of
healthy subjects by an average of 11 percent. In contrast, rest under the
same environmental conditions decreased FEV,. by only 3 percent (Haak et a!.,
1984), while very heavy exercise (VV > 64 L/min) reduced FEV., by 17 percent on
the average (5 to 50 percent) (McDonnell et al., 1983). Even low 0, concentra-
tions (0.12 ppm) induced measurable changes in the lung function of more
responsive individuals; the average decrements in FVC, FEV.,, and FEFpe^jg were
3, 4.5, and 7.2 percent from control, respectively (McDonnell et al., 1983).
The maximum changes were observed within 5 to 10 minutes following the end of
each exercise period (Haak et al., 1984). During subsequent rest periods,
however, the response does not persist and partial improvement in lung function
can be observed despite continuous inhalation of ozone (Folinsbee et al.,
1977b). Functional recovery from a single exposure with exercise appears to
progress in two phases: during the initial rapid phase, lasting between 30
min and 3 hr, improvement in lung function exceeds 50 percent; this is followed
by a much slower recovery phase usually completed in most subjects within 24
hr (Bates and Hazucha, 1973). There are some individuals, however, whose lung
12-22
-------
function did not reach the pre-exposure level even after 24 hrs. Despite
apparent functional recovery of most of the subjects, an enhanced responsive-
ness to a second 03 challenge may persist in some subjects for up to 48 hr
(Bedi et al., 1985; Folinsbee and Horvath, 1986). In addition, other regula-
tory systems may still exhibit abnormal responses when stimulated; e.g.,
airway hyperreactivity may persist for days (Golden et al., 1978; Kulle et
al., 1982b).
The magnitude of functional changes assessed by spirometry is positively
associated with 0~ concentration. Exposure of intermittently exercising
subjects (Vr > 63 L/min) for 2 hr to 0.4 ppm reduced significantly (p <0.005)
FVC by 12 percent, FEV-^ by 17 percent, and FEF25-75 by 27 percent on the
average. At lower 03 concentrations (0.18 to 0.24 ppm) the respective decre-
ments (FVC 4 to 11 percent, FEV-, 6 to 14 percent, FEF25_75 12 to 23 percent)
were still statistically significant (McDonnell et al., 1983). The same
ventilation in a 0.12 or 0.15 ppm 03 atmosphere elicited spirometric changes
(1 to 7 percent) of only questionable significance (McDonnell et al., 1983;
Kulle et al., 1985).
Similar positive associations have been reported between lung function
decrements and the level of ventilation. Intermittent exercise (Vr > 68
L/min) in 0.3 ppm 03 decreased .FVC, FEV-., and FEF25_75 by 7, 8, and 10 percent,
respectively. A lower intensity of exercise (V^ ~ 32 L/min) in the same 03
atmosphere induced proportionally smaller changes; the respective mean decre-
ments were 2, 5, and 8 percent (Folinsbee et al., 1978).
More recently, the relationship between ventilation, exposure time, 03
concentration, and functional response has been examined in a more general
way. The response has been evaluated as a function of an "effective rate"
(Colucci, 1983), an "effective dose" (Colucci, 1983; Folinsbee et al., 1978;
Silverman et al., 1976), and 03 concentration (Kulle et al. , 1985). The
concept of defining ozone exposure in terms of an "effective dose" (the product
of concentration, ventilation, and time) is relatively simple from a modeling
point of view. A major weakness of this concept, however, is that the same .
dose/rate may induce quantitatively different responses, which limits the
general applicability of the model for standard-setting (Silverman et al.,
1976; Folinsbee et al., 1978). Moreover, the small data base(s) and the
limited statistical evaluation of almost all of these models further precludes
their quantitative applications and limits their qualitative application(s) to
conditions similar to those for which the models were derived.
12-23
-------
The effects of intermittent exercise and 03 concentration on the magnitude
of average pulmonary function responses (e.g., FEV-.) during 2-hr exposures are
illustrated in Figures 12-2 through 12-5. The data sets on which the predictive
models are based have been limited to studies utilizing intermittent exercise
and 2-hr exposure protocols. The following types of data were included in the
analysis: (1) data from single exposures; (2) data obtained on the first day
of sequential, multiday exposures; and (3) data obtained from repetitive
exposures of the same cohort to a range of concentrations or to the same
concentration but with different levels of exercise, provided the reported
exposures were each separated by at least 7 days. To minimize inhomogeneity
of data further, studies conducted under unique environmental conditions
(e.g., high relative humidity and temperature) or on known hyperreactive
groups of subjects were not included in this analysis. Neither were data from
resting and continuous exercise studies included in the calculations.
The selected set of 25 studies represents data obtained on 320 subjects
studied between 1973 and 1985, in 8 different laboratories (Table 12-3). Since
minute ventilation is one of the most important determinants of response to
ozone, the data have been categorized by reference to exercise level, as
defined by minute ventilation. Based on a distribution pattern of VE during
exercise, four subgroups were identified: light exercise (VV < 23 L/min),
moderate (V£ = 24 to 43 L/min), heavy (V^ = 44 to 63 L/min), and very heavy
exercise group (V£ > 64 L/min). Although basic second-order functions were
considered in modeling the concentration-response relationship, the pure
quadratic function with no intercept was found to be the simplest and most
suitable model since this is the only function that passes through a minimum
(no response) at zero 03 concentration. The relative contribution of each
data point was adjusted by weighing it by the number of subjects. Scatter
plots with superimposed best-fit curves and 95 percent confidence limits for
FEV., at each exercise level show clearly differentiated response curves with
high correlation coefficients (r = 0.89 to 0.97). A strong and statistically
significant (p <0.0001) positive association between decrements in FEV-^ and
ozone concentration for all levels of exercise is apparent. From the curves,
it can be determined with 95 percent confidence that light exercise in a 0.2
ppm 03 atmosphere will decrease FEV., by 1.6 percent, moderate exercise by 2.4
percent, heavy exercise by 2.8 percent, and very heavy exercise by 4.7 percent
on the average, respectively. Inversely, a 5 percent decrement in FEV., can be
12-24
-------
110
INJ
Ol
IU
§
>-
oc
O
x
UJ
Q
ui
O
oc
O
IL,
O
UI
(0
100
80
70
60
LIGHT EXERCISE
K23 L/min)
r = 0.92
I
0.2 0.4
OZONE CONCENTRATION, ppm
0.6
I14
•14
0.8
Figure 12-2. The effects of ozone concentration on 1 -sec forced expiratory volume during 2-hr
exposures with light intermittent exercise. Quadratic fit of group mean data, weighted by
sample size, was used to plot a concentration-response curve with 95 percent confidence
limits. Individual means (+standard error) are given in Table 12-3 along with specific
references.
-------
110
i
INJ
£ 100
O
a
LU
s
3
_i
O
DC
O
x
ui
O
ui
O
DC
O
u.
O
ui
M
8
80
70
60
16
13
MODERATE EXERCISE
(24-43 L/min)
r = 0.94
I
0,2
0,4
0.6
0.8
OZONE CONCENTRATION, ppm
Figure 12-3. The effects of ozone concentration on 1 -sec forced expiratory volume during 2-hr
exposures with moderate intermittent exercise. Quadratic fit of group mean data, weighted by
sample size, was used to plot a concentration-response curve with 95 percent confidence
limits. Individual means (± standard error) are given in Table 12-3 along with specific
references.
-------
rsi
ro
110
6,8,19,25
100
• 24
80
70
60
19
HEAVY EXERCISE
(44*63 L/min)
r = 0.97
I i
0.2
0.4
0.6
0.8
OZONE CONCENTRATION, ppm
Figure 12-4. The effects of ozone concentration on 1 -sec forced expiratory volume during 2-hr
exposures with heavy intermittent exercise. Quadratic fit of group mean data, weighted by
sample size, was used to plot a concentration-response curve with 95 percent confidence
limits, individual means (± standard error) are given in Table 12-3 along with specific
references.
-------
110
I
l\>
00
o
ui
(0
70
60
VERY HEAVY EXERCISE
(>64 L/min)
r = 0.89
0
0.2 0.4
OZONE CONCENTRATION, ppm
0.6
0.8
Figure 12-5. The effects of ozone concentration on 1 -sec forced expiratory volume during 2-hr
exposures with heavy intermittent exercise. Quadratic fit of group mean data, weighted by
sample size, was used to plot a concentration-response curve with 95 percent confidence
limits. Individual means (± standard error) are given in Table 12-3 along with specific
references.
-------
TABLE 12-3. EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC
FORCED EXPIRATORY VOLUME DURING 2-hr EXPOSURES
Ozone3 b
concentration Measurement '
jjg/m3
LIGHT
1470
1470
0
1470
1470
0
510
1156
490
725
980
784
784
490
1098
0
0
725
725
1470
1470
ppm method
EXERCISE (V£ < 23 L/min)
0.75 MAST, NBKI
0.75
0.00 MAST, NBKI
0.75
0.75 CHEM, NBKI
0.00 CHEM, NBKI
0.26
0.59s
0.25 CHEM, NBKI
0.37
0.50
0.4 CHEM, NBKI
0.4
0.25 MAST, NBKI
0.56
0.00 MAST, NBKI
0.00
0.37
0.37
0.75
0.75
Exposure
duration,
min
120
120
120
120
120
125
125
125
120
120
120
135
135
120
120
120
120
120
120
120
120
Number of
subjects
10
10
3
3
11
21
21
21
6
5
7
6
9
3
3
6
6
6
6
6
6
Minute
ventilation
L/min
22.5
22.5
23.0
23.0
20.0
22.6
22.6
22.6
20.0
20.0
20.0
20.0
20.0
22.0
22.0
22.0
22.0
22.0
22.0
22.0
22.0
• «v-d
79.3 ± 2.7
76.6 ± 2.7
104.9
69.7
77.2 ± 4.4
100.3 ±0.8
96.9 ±1.3
81.6 ±2.7
100.3
97.7
95.3
99.5
95.5
95.7 ± 4.1
82.1 ± 13.2
101.4 ±1.7
100.5 ±3.3
92.6 ±2.3
96.1 ± 0.7
73.3 ± 6.8
72.4 ± 4.7
(1)
(2)
(3)
(7)
(9)
(10)
(12)
(14)
Reference3
Bates and Hazucha, 1973
Bates et al . , 1972
Folinsbee et al., 1977a
Gliner et al., 1983
Hackney et al . , 1975
Hackney et al . , 1976
Hazucha, 1973
Hazucha et al . , 1973
-------
TABLE 12-3 (continued). EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC
FORCED EXPIRATORY VOLUME DURING 2-hr EXPOSURES
Ozone3 ,
concentration Measurement '
iO
1
to
o
ug/m3
431
451
470
784
784
784
1215
1235
0
294
588
0
294
0
0
980
1470
725
941
1509
pptn method
0.
0.
0.
0.
0.
0.
0.
0.
0.
22 MAST, NBKI
23
24
40
40
40
62
63
00
0.15
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
30
00
15
00
00
50
75
37
48
77
Exposure
duration,
min
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
Number of
subjects
4
4
4
4
4
4
4
4
15
15
10
6
6
8
8
8
8
5
5
5
Minute
ventilation, F
L/min
22.
22.
22.
22.
22.
22.
22.
22.
22.
22.
22.
20.
20.
22.
22.
22.
22.
22.
22.
22.
5
5
5
5
5
5
5
5
0
0
0
0
0
5
5
5
5
5
5
5
101.
93.
96.
93.
91.
89.
88.
86.
100.
100.
100.
93.
94.
102.
101.
98.
86.
94.
95.
79.
EVi-o,'1
%
5
7 ± 1.4
0 + 3.1
9 ± 2.5
9 ± 5.9
5
0
0
9
3
1
3
3
8
9
2
0
6 ± 3.5
1 ± 1.9
8 ± 6.4
Reference
(15) Hazucha et al., 1977
(17) Kagawa, 1984
(18) Kagawa and Tsuru, 1979b
(23) Shephard et al., 1983
(24) Silver-man et al., 1976
-------
TABLE 12-3 (continued). EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC
FORCED EXPIRATORY VOLUME DURING 2-hr EXPOSURES
Ozone3
concentration
jjg/ra^
MODERATE
0
0
980
980
0
-. 216
7s 588
% 960
0
0
0
392
666
921
0
0
784
666
666
0
0
1176
1176
ppm
EXERCISE
0.0
0.0
0.5
0.5
0.00
0.11
0.30
0.49
0.00
0.00
0.00
0.20
0.34
0.47
0.0
0.0
0.4
0.34
0.34
0.0
0.0
0.6
0.6
, Exposure
Measurement ' duration,
method min
(VE = 24-43 L/min)
CHEM, NBKI 118
118
118
118
CHEM, NBKI 120
120
120
120
CHEM, NBKI 135
135
135
135
-135
135
CHEM, GPT 120
120
120
CHEM, NBKI 120
120
CHEM, NBKI 120
120
120
120
Number of
subjects
8
6
8
6
10
10
10
10
10
10
10
10
10
10
29
15
15
4
4
14
14
14
14
Minute j
ventilation, FEVj.Q,
L/min %
36.0
35.0
33.3
39.2
32.6
32.3
31.0
32.1
32.0
30.0
31.0
31.0
32.0
30.0
35.0
35.0
35.0
24.0
24.0
35.0
35.0
35.0
35.0
99.4 ± 2.7
96.4 ± 5.5
87.8 ± 6.4
81.9 ± 5.6
99.4 ± 13.1
101.9 ± 13.8
95.4 ± 16.0
87.3 ± 16.6
99.6 ± 4.3
100,. 6 ±4.7
100.2 ±5.1
101.3 ± 4.8
95.5 ± 4.3
91.3 ±5.0
101.5 ±2.6
99.7 ±4.3
96.9 ±5.5
91.7 ± 27.4
99.7 ± 18.1
97.9 ± 5.1
96.0 ±6.7
78.8 ± 6.1
73.1 ± 6.5
Reference3
(4) Folinsbee et a!., 1977b
(5) Folinsbee et al., 1978
(6) Folinsbee et al., 1980
(8) Haak et al . , 1984
(11) Hackney et al., 1977b
(13) Hazucha, 1981
-------
TABLE 12-3 (continued), EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC
FORCED EXPIRATORY VOLUME DURING 2-hr EXPOSURES
Ozone
concentration
ng/m3
0
1058
0
921
_, HEAVY
i> 0
1X3 196
588
980
0
0
0
784
0
1176
725
941
0
784
ppm
0.00
0.54
0.00
0.47
EXERCISE
0.00
0.11
0.30
0.49
0.0
0.0
0.0
0.4
0.0
0.6
0.37
0.48
0.0
0.4
. Exposure
Measurement ' duration,
method
UV, UV
UV, NBKI
(V£ = 44-63 L/min)
CHEM, NBKI
CHEM, GPT
CHEM, NBKI
MAST, NBKI
CHEM, NBKI
min
125
' 125
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
Number of
subjects
24
24
11
11
10
10
10
10
15
15
15
15
20
20
5
5
10
12
Mi nute
ventilation
, rc\
d
0.
L/mi n %
30.
30.
24.
24.
50.
49.
56.
51.
57.
57.
57.
57.
45.
45.
46.
44.
55.
55.
0
0
0
0
4
8
3
4
0
0
0
0
0
0
5
7
3
3
99.7
78.9
100.8
88.7
100.8
100.5
93.7
85.8
99.4
98.7
101.9
90.6
102.5
71.6
94.3
84.4
98.8
92.3
±
±
±
+
±
±
±
±
±
±
±
±
1.0
3.0
16.3
16.2
17.5
19.5
5.0
4.1
4.3
4.9
5.6
4.8
(16)
(21)
(5)
(8)
(19)
(24)
(25)
3
Reference
Horvath et al . , 1981
Linn et al.', 1982b
Folinsbee et al., 1978
Haak et al . , 1984
Ketcham et al . , 1977
Silverman et al.. 1976
Stacy et al . , 1983
-------
TABLE 12-3 (continued). EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC
FORCED EXPIRATORY VOLUME DURING 2-hr EXPOSURES,
Ozone3 .
Exposure
concentration Measurement ' duration,
Ijg/m1
VERY
0
216
588
960
_. o
~ 235
oo 353
w 470
588
784
0
196
294
392
490
! ppm method
HEAVY EXERCISE (V£ > 64 L/min)
0.00 CHEM, NBKI
0.11
0.30
0.49
0.00 CHEM, UV
0.12
0.18
0.24
0.30
0.40
0.0 UV, UV
0.10
0.15
0.20
0.25
min
120
120
120
120
125
125
125
125
125
125
113
113
113
113
113
Number of
subjects
10
10
10
10
22
22
20
21
21
29
20
20
20
20
20
Mi nute
A
ventilation, FEV^o,"
L/mi n
66.8
71.2
68.4
67.3
66.2
68.0
64.6
64.9
65.4
64.3
70
70
70
70
70
% Reference
99.7 ± 13.7 (5) Folinsbee et al., 1978
97.4 ± 17.6
92.3 ± 12.7
76.1 ± 11.9
98.9 ±2.4 (22) McDonnell et al., 1983
95.7 ± 3.2
93.6 ± 3.4
85.6 ± 3.4
83.2 ± 3.8
83.0 ±3.7
101.3 (20) Kulle et al., 1985
101.0
99.4
96.7
93.3
References are listed alphabetically within each exercise category; reference number refers to data points on
Figures 12-2 through 12-5.
Measurement method: MAST = Kl-coulometric (Mast meter); CHEM = gas-phase chemiluminescence; UV = ultraviolet photometry.
Calibration method: NBKI = neutral buffered potassium iodide; GPT = gas phase titration; UV = ultraviolet photometry.
Data reported as mean ± standard error of the mean; not all references provided standard errors.
^Subjects exposed to 0.55 and 0.65 ppm ozone were reported as one group (Gliner et al., 1983).
-------
expected with light exercise in 0.36 ppm 03, moderate exercise in 0.29 ppm 03,
heavy exercise in 0.27 ppm 03, and very heavy exercise in a 0.21-ppm 03 atmos-
phere. Since the models are based on a large number of .data and show highly
statistically significant differences of slope with narrow confidence bands,
they are acceptable for quantitative estimates of response. It is important
to note, however, that any predictions of average pulmonary function responses
to Oo only apply under the specific set of exposure conditions at which these
data were derived. Other pulmonary function variables analyzed in the same
manner, although not illustrated here, showed the same trend as the FEV-., but
as expected, changes differed in magnitude. For example, the decrements in
FVC were smaller, while decrements in FEF?5-75 were greater, for a given 03
concentration, than decrements in FEV... The R showed a similar concentration-
J. o.W
dependent, positively correlated response (r = 0.73).
Continuous exercise equivalent in duration to the sum of intermittent
exercise periods at comparable ozone concentrations and minute ventilation (VV
>60 L/min) elicited greater changes in pulmonary function. The enhancement
ranged from several percent to more than a twofold augmentation of the effects
(Folinsbee et al., 1984; Avol et al., 1984, 1985c). Others, on the other hand,
have reported group mean responses in continuous exercise exposures that were
similar to those previously observed with comparable levels of intermittent
exercise (Adams et al., 1981; Adams and Schelegle, 1984). The lack of suffi-
cient data, however, on comparable levels of exercise in the same subjects
prevents any quantitative comparison of the effects induced by continuous
versus intermittent exercise.
Exercise not only stresses the respiratory system but other physiological
systems, as well, particularly the cardiovascular and musculoskeletal systems.
Various compensatory mechanisms activated within these systems during physical
activity might facilitate, suppress, or otherwise modify the magnitude and
persistence of the reaction to ozone. Unfortunately, to date only a few of
the studies were specifically designed to examine nonpulmonary effects of
exercise in ozone atmospheres (Gliner et al., 1975, 1979). In one study,
light intermittent exercise (Vr = 20-25 L/min) at a high ozone concentration
(0.75 ppm) reduced post-exposure maximal exercise capacity by limiting maximal
oxygen consumption (Folinsbee et al., 1977a); submaximal oxygen consumption
changes were not significant (Folinsbee et al., 1975). The extent of ventila-
tory (v"T, fR) and respiratory metabolic changes (V02) observed during or
12-34
-------
following the exposure appears to have been related to the magnitude of pul-
monary function impairment. Whether such (metabolic) changes are consequent
to respiratory discomfort or are the result of changes in lung mechanics, or
both, is still unclear and needs to be elucidated.
12.3.2.3 Environmental Stresses. Environmental conditions such as heat and
relative humidity (rh) may contribute to symptoms and physiological impairment
during and following 03 exposure. A hot (31 to 40°C) and/or humid (85 percent
rh) environment, combined with exercise in the 0» atmosphere, has been shown
to reduce forced expiratory volume more than similar exposures at normal room
temperature and humidity (25°C, 50 percent rh) (Folinsbee et a!., 1977b;
Gibbons and Adams, 1984). Modification of the effects of 0- by heat or humidity
stress may be attributed to increased ventilation associated with elevated
body temperature but there may also be an independent effect of elevated body
temperature on pulmonary function (e.g., VC).
12.3.3 Other Factors AffectingPulmonary Response to Ozone
12.3.3.1 Age. Although age has been postulated as a factor capable of modi-
fying responsiveness to 0,, studies have not been designed to test specifically
for the effects of age on responsiveness to Og. Epidemic!ogical studies in
both children and young adults have suggested an association between decreased
lung function and exposure to oxiriant-polluted ambient air but no comparisons
were made in these studies between different age groups (Lippmann et al.,
1983; Lebowitz et al., 1982, 1983, 1985; Lebowitz, 1984; Bock et al. , 1985;
Lioy et al., 1985). In addition, it is not clear if the observed effects are
attributable to 03 alone since these studies have considerable methodological
problems, including the inability to adjust adequately for the confounding
influence of other pollutants and environmental conditions in ambient air (see
Chapter 11). Control!ed-exposure studies, however, on children and adolescents
exposed to 0_ or ambient air containing predominantly 0, (Avol et al., 1985asb;
McDonnell et al., 1985b,c) have indicated that the effects of 0- on lung
spirometry were very similar to those found in adults exposed under similar
conditions, except that no significant increases in symptoms were found in
children. Therefore, based on the limited pulmonary function data available,
young children and adolescents do not appear to respond any differently to 0^
than adults. Further research is needed to confirm these preliminary findings
in the young and also to determine if older subjects have altered responsiveness
to 03.
12-35
-------
As with human studies to date, the influence of age on responsiveness to
ozone is also difficult to assess from animal studies. Very few age compari-
sons have been made within a single study. Raub et al. (1983), Barry et al.
(1983), and Crapo et al. (1984) studied pulmonary function and morphometry of
the proximal alveolar region in neonatal (1-day-old) and young adult (6-week-
old) rats exposed to 0.08, 0.12, or 0.25 ppm ozone for 12 hr/day, 7 days/week
for 6 weeks. A few different responses were observed in the neonates and
adults, but they were not major. Generally, neonates and young adults were
about equally responsive, which is consistent with the human studies summarized
above.
Animal studies of lung antioxidant metabolism and oxygen consumption
(Lunan et al., 1977; Tyson et al., 1982; Elsayed et al., 1982) indicate that
the stage of development at initiation of short-term exposure determines the
response to 0». Generally, the direction of the effect differs before and
after weaning. Suckling neonates (5 to 20 days old) exhibited a decrease in
antioxidant enzyme activities; as the animals grew older (up to 180 days old),
enzyme activities increased progressively, reached a plateau at 35 days of
age, and persisted after cessation of exposure. This biochemical response may
be attributed to morphological changes in the lung that have a similar age-
related pattern in the progression of centriacinar lesions in rats exposed to
03 before and after weaning (Stephens et al.; 1978). Thus, further research
is needed to determine if the young differ markedly from adults in their
response to 0-.
O ,
12.3.3.2 Sex. Sex differences in responsiveness to ozone have not been
adequately studied. A small number of female subjects have been exposed to'' 03
in mixed cohorts in many human controlled studies, but only three reports gave
enough information for a limited comparative evaluation (Horvath et al., 1979;
Gliner et al., 1983; DeLucia et al., 1983). Two additional studies (Gibbons
and Adams, 1984; Lauritzen and Adams, 1985) compared 0- effects in women with
the results from male subjects previously studied in the same laboratory. The
studies reported above suggest that lung function of women, as assessed by
changes in FEV-, ~, may have been affected more than that of men under similar
exercise and exposure conditions, but the results are not conclusive. Field
and epidemiological studies of children and adolescents exposed to ambient air
have also tended to show greater effects in girls, but the differences either
were not tested statistically (Bock et al., 1985) or were not significant
12-36
-------
(Avol et a!., 1985a,b). Further research is needed to determine whether
systematic differences exist between the sexes in their responses to ozone and
what factors might be responsible for those differences.
The majority of animal studies have been conducted with male animals.
Generally, when females have been used they have not been compared to males in
the same study. This makes comparisons from animal data of sex-related differ-
ences in sensitivity to ozone virtually impossible. The only exception is a
study of effects of ozone in increasing pentobarbital-induced sleeping time
(Graham et al., 1981). Since waking from pentobarbital anesthesia is brought
about by xenobiotic metabolism in the liver, this effect is considered to be
extrapulmonary. Both sexes of mice, rats, and hamsters were exposed to 1 ppm
ozone for 5 hr. Increased sleeping time was observed in all females, but not
in male mice or male rats. Male hamsters were affected, but significantly
less than the females. The reasons for this sex difference are unknown. Rats
have major sex differences in xenobiotic metabolism, but the other species do
not. .
12.3.3.3 Smoking Status. Differences between smokers and nonsmokers have
been studied often, but the smoking histories of subjects are not documented
well. Hazucha et al. (1973) and Bates and Hazucha (1973) appear to have
demonstrated greater responses (FVC, MMFR) in nonsmokers at 0.37 ppm O.,, but
the responsiveness was reversed at 0.75 ppm (RV, FEV-,, V ,-„, and MMFR).
Kerr et al. (1975) observed greater responses. (FVC, SG_,,, R, , FEV,, and symptoms)
ctW L *5
in nonsmokers at 0.5 ppm 03 for 6 hr. DeLucia et al. (1983) also observed
greater responses in nonsmokers for VC, FEV-,, MMFR, fg, and Vy at 0.3 ppm 0,
(1 hr). Kagawa and Tsuru (1979a) found greater effects of ozone among non-
smokers at 0.5 ppm than at 0.3 ppm 0~ (2 hr); a later study (Kagawa, 1983)
showed that nonsmokers also had a greater response (SG ) than smokers to
0.15 ppm (2 hr). Shephard et al. (1983) found a slower and smaller change in
spirometric variables in smokers at 0.5 and 0.75 ppm (2 hr). While none of
these controlled studies examined the effects of different degrees of smoking,
the general trend suggests that smokers are less responsive than nonsmokers.
The reasons for these differences are not known; however, smokers have altered
lung function and an increase in mucus, both of which could influence the
dosimetry of 0™ in respective regions of the lung.
12.3,3.4 Nutritional Status. Posin et al. (1979) found that human volunteers
receiving 800 (about four times the recommended daily units) or 1600 IU of
12-37
-------
vitamin E for 9 weeks as a supplement showed no differences in blood biochem-
istry from unsupplemented volunteers when exposed to 0.5 ppm ozone for 2 hr.
The biochemical parameters studied included red cell fragility, hematocrit,
hemoglobin, glutathione concentration, and activities of acetylene!inesterase,
glucose-6-phosphate dehydrogenase, and lactic acid dehydrogenase. No differ-
ences in pulmonary function and symptoms were found between the vitamin
E-supplemented and placebo groups (Hackney et al., 1981).
Hamburger et al. (1979) studied the effects of ozone exposure on the
agglutination of human erythrocytes by the lectin concanavalin A. Pre-incuba-
tion with malonaldehyde, an oxidation product of polyunsaturated fatty acids,
decreased concanavalin A agglutination of red cells exposed in vitro to ozone.
Red cells obtained from 29 subjects receiving 800 ID of vitamin E or a placebo
were exposed to 0.5 ppm ozone for 2 'hr. Following ozone exposure, a slight
decrease in agglutination occurred in cells from subjects who did not receive
vitamin E supplementation, but the results were not statistically significant.
Increased activity of the glutathione peroxidase system may be one of the
most sensitive, biochemically measured indices of exposure to < 1 ppm of 0~
because it is involved in antioxidant metabolism. Increases in the activity
of the glutathione peroxidase system have been reported after exposure of rats
on a vitamin E-deficient diet to levels as low as 0.1 ppm 0,, for 7 days (Chow
et al., 1981; Mustafa, 1975; Mustafa and Lee, 1976). The amount of dietary
vitamin E fed to the rats influenced the ozone-induced increase in this system.
For example, when the diet of rats contained 66 ppm of vitamin E, increased
glutathione peroxidase activity was observed at 0.2 ppm of 03; with .11 ppm of
vitamin E, increases occurred at 0.1 ppm (Mustafa and Lee, 1976). Several
other investigators have shown that vitamin E deficiency in rats makes them
more susceptible to these ozone-induced enzymatic changes (Chow et al., 1981;
Plopper et al., 1979; Chow and Tappel, 1972).
Studies of ozone-exposed vitamin E-deficient or supplemented rats have
been undertaken to correlate biochemical findings with morphological altera-
tions. Rats maintained on a basal vitamin E diet had the typical centriacinar
lesions found as a result of 0, exposure (Stephens et al., 1974; Schwartz et
al., 1976). Lesions were generally worse, however, in vitamin E-deficient or
marginally supplemented rats compared to highly supplemented rats (Plopper et
al., 1979; Chow et al., 1981), supporting the finding from mortality (Donovan
et al., 1977) and biochemical studies that vitamin E is protective in rats.
12-38
-------
The difference in response between animals and man with regard to the
protective effects of vitamin E against ozone toxicity may lie in the pharma-
cokinetics of vitamin E distribution in the body. Redistribution of vitamin E
from extrapulmonary stores to the lung is slow. Short exposures to ozone may
not allow adequate time for redistribution and for a protective effect to be
observed. Animal exposures in which the striking effects of vitamin E on
ozone toxicity were observed were generally conducted over longer exposure
periods (often 1 to 2 weeks). Human subjects were exposed for shorter times
and lower concentrations because of ethical considerations. Thus, vitamin E
may have protective effects in man, but if they occur their demonstration
might require longer exposure times and higher ozone concentrations. In
animal studies, vitamin E-deficient rats are subject to increased toxicity
from 0~ compared to supplemented groups, while animals on basal vitamin E
diets are afforded little if any protection from CU, In human studies, subjects
were not likely to have had a deficiency substantial enough to show any effect.
Thus, no evidence indicates that man would benefit from increased vitamin E
intake relative to ambient ozone exposures, even though the antioxidant role
of vitamin E in preventing ozone-initiated peroxidation in vitro is well
demonstrated and the protective effects jjn vivo are clearly demonstrated in
rats and mice. Further, vitamin E protection is not absolute and can be
overcome by continued ozone exposure. The effects of vitamin E do support the
general idea, however, that lipid peroxidation is involved in ozone toxicity.
12.3.3.5 Red Blood Cell EnzymeDeficiencies. The enzyme glucose-6-phosphate
dehydrogenase (G-6-PD) is essential for the functioning of the glutathione
peroxidase system in the red blood cell (RBC), which is the enzyme system
proposed as having an integral part in the decomposition of fatty acid peroxides
or hydrogen peroxide formed by 0~-initiated polyunsaturated fatty acid peroxi-
dation (see Section 12.5.1). Therefore, Calabrese et al. (1977) have postulated
that individuals with a hereditary deficiency of G-6-PD could possibly experience
significant hematological effects from 0, exposure. There have been too few
studies performed, however, to reliably document this possibility. Most ozone
studies have been with red blood cells from rodents, even though differences
may exist between rodent and human RBCs. Calabrese and Moore (1980) and Moore
et al. (1981) have pointed out the lack of ascorbic acid synthesis and the
relatively low level of glucose-6-phosphate dehydrogenase (G-6-PD) in man
compared to active ascorbic acid synthesis and high levels of G-6-PD in mice
12-39
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and rats. Although their species comparisons are based on a very limited data
base, the authors point out the importance of developing animal models that
can accurately predict the response of G-6-PD-deficient humans to oxidants
such as 0,. This group has suggested the use of the C57L/J strain of mice and
the Dorset sheep as better animal models for hematological studies since these
species have levels of G-6-PD closer to those in man, especially those levels
found in G-6-PD-defieient patients. The RBCs of Dorset sheep, however, appear
to be no more sensitive to ozone than normal human RBCs, even though the
Q-6-PD levels in Dorset sheep are very low. Additional jji vitro studies
(Calabrese et a!., 1982, 1983; Williams et al., 1983a,b,c) have demonstrated
that the responses of sheep and normal human RBCs responded quite similarly
when separately incubated with potentially toxic 0~ intermediates, but that
G-6-PD-deficient human RBCs were considerably more susceptible. Even if 0~ or
a reactive product of 03-tissue interaction were to penetrate the RBC after jji
vivo exposure, it is unlikely that decrements in reduced glutathione activity
would be large enough to lead to chronic hemolytic anemia in the affected
individual.
12.3.4 Effectsof Repeated Exposure to Ozone
12.3.4.1 Introduction. The attenuation of response associated with repeated
exposure to CL is generally referred to as "adaptation." Earlier work in
animals that focused primarily on reductions in pulmonary edema and mortality
rate to assess this process employed the term "tolerance"; other terms have
also been used to describe this phenomenon (Chapter 9, Section 9.3.5). The
distinction, if any, among these terms with respect to 0~ and its effects has
never been established in a clear, consistent manner.
The following sections describe the nature of observed alterations in
responsiveness to 03 and discuss possible interrelationships for those observed
changes in responsiveness.
12.3.4.2 Development of Altered Responsiveness to Ozone. Successive daily
brief exposures of human subjects to Q3 (< 0.7 ppm for ~ 2 hrs) induce a
typical temporal pattern of response (Chapter 10, Section 10.3). Maximum
functional changes that occur on the first exposure day, as assessed by plethys-
mographic and bronchial reactivity tests (Parrel! et al., 1979; Dimeo et al.,
1981), or on the second exposure day, as assessed by spirometry, become progres-
sively attenuated on each of the subsequent days (Horvath et al., 1981; Kulle
12-40
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et al., 1982b; Linn et al., 1982b). By the fourth day of exposure, the average
effects are not different from those observed following control (air) exposure.
Individuals need between 3 and 7 days of exposure to develop full attenuation,
with more sensitive subjects requiring more time (Horvath et al., 1981; Kulle
et al., 1982b; Linn et al., 1982b; Haak et al., 1984). The magnitude of a
peak response appears to be directly related to 0., concentration (Folinsbee
et al., 1980; Haak et al., 1984). Whether varying the length or the frequency
of exposure will modify the time course of this altered responsiveness has not
been explored. Full attenuation, even in ozone-sensitive subjects, does not
persist for more than 3 to 7 days after exposure in most individuals (Horvath
et al., 1981; Kulle et al., 1982b; Linn et al., 1982b), while partial attenua-
tion might persist for up to 2 weeks (Horvath et al., 1981). Although the
severity of symptoms generally correlates with the magnitude of the functional
response, partial attenuation of symptoms appears to persist longer, for up to
4 weeks after exposure (Linn et al., 1982b). Ozone concentrations inducing
few or no functional effects (< 0.2 ppm) elicited no significant changes in
pulmonary function with consecutive exposures (Folinsbee et al., 1980). The
latter findings are consistent with the proposition that functional attenuation
may not occur in the airways of individuals living in communities where the
ambient ozone levels do not exceed 0.2 ppm. The difficulty, however, of
drawing such inferences on the basis of narrowly defined laboratory studies is
that under ambient conditions a number of uncontrollable factors might modify
the response. Most notably, other pollutants may interact with ozone during
more protracted ambient exposures to induce changes at concentrations lower
than those reported from control!ed-laboratory studies. The evidence sug-
gesting that Los Angeles residents exhibit functional attenuation of the
response to 03 is sparse (Hackney et al., 1976, 1977a,b; Linn et al., 1983a)
and requires confirmation.
12.3.4.3 Conclusions Relative to Attenuation with Repeated Exposures. The
attenuation of acute effects of 03 after repeated exposure, such as changes in
lung function, have been well documented in controlled human exposure studies.
There are no practical means at present, however, of assessing the role of
altered responsiveness to 0- in human populations chronically exposed to
ozone. No epidemiological studies have been designed to test whether attenua-
tion of symptoms, pulmonary function, or morbidity occurs in association with
photochemical air pollution. It might be added that the proposition would be
12-41
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difficult to test epidemiologically. Thus, scientists must rely mainly on
inferences and qualitative extrapolations from animal experimentation.
Attenuation of response to 0, may be viewed as a process exhibiting some
concentration-response characteristics. Concentrations of 0~ that have little
or no effect do not appear to influence measurably the response invoked by
subsequent exposures to higher 0, concentrations. Over some higher range (0.2
to 0.8 ppm) of exposure, functional recovery after repeated exposure is virtu-
ally complete within several days. Insofar as this generalization is valid,
it suggests that photochemical air pollution may induce altered responses only
in individuals who previously responded to exposure. Above this range, per-
sistent or progressive damage is most likely to accompany repeated exposure.
The attenuation, however, of the functional changes (and the time course of
attenuation) following repeated exposure to 0- does not necessarily follow the
morphological or biochemical pattern of responses nor does it necessarily
imply that there is attenuation of the morphological or biochemical responses
to 03.
Responses to 0,, whether functional, biochemical, or morphological, have
the potential for undergoing changes during repeated or continuous exposure.
There is an interplay between tissue inflammation, hyperresponsiveness, ensuing
injury (damage), repair processes, and changes in response. The initial
response followed by its attenuation may be viewed either as sequential states
in a continuing process of lung injury and repair or as a physiological adapta-
tion to the irritative stimulus.
12.3.5 Mechanisms of Responsiveness to Ozone
The time course, type, and consistency of changes of such indices as
symptoms, lung volumes, flows, resistances, and bronchial reactivity strongly
implicate vagal sensory receptors as substantial modulators of responsiveness
to03.
A growing body of evidence from both animal (Roum and Murlas, 1984; Lee
et al., 1979; Gertner et a!., 1983a,b) and human studies (Golden et a!., 1978;
DiMeo et al., 1981; Beckett et al., 1985) indicates that a post-ozone exposure
increase in bronchial smooth muscle tone is mediated, at least in part, by
increased tonic vagal activity consequent to stimulation of muscarinic recep-
tors. Beckett et al. (1985) demonstrated that pretreatment of subjects with
atropine (a bronchodilator and muscarinic, cholinergie blocker) prevented an
12-42
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increase in SR , and partially blocked a decrease in FEV1; both tests are used
3W JL
clinically as indirect indices of bronchoconstriction. Atropine did not,
however, prevent the reduction in FVC, increase in frequency of breathing
(fg). or decrease .in tidal volume (Vy). Inhalation of other types of broncho-
dilators (e.g. , isoproterenol, metaproterenol; adrenergic receptor agonists)
immediately post-exposure relaxed constricted airways, while elevated R and
SR returned rapidly to baseline values (Golden et a!., 1978; Beckett et al.,
QW
1985). Such a pattern of response strongly suggests the involvement of vagal
sensory receptors (irritant, stretch and J-receptors), since stimulation of
these receptors will generally elevate bronchomotor tone, increase fB, and
decrease Vy. These findings show that ozone-induced increases in airway
resistance are caused primarily by a reflex constriction of airway smooth
muscle. The afferent pathways of this reflex originate at different receptor
sites, but the (increased) efferent activity seems to be vagally mediated.
Besides direct excitation of afferent end-organs (receptors, nerve endings),
other factors may influence this (afferent) discharge. Enhanced sensitivity
of receptors (Lee et al., 1977) and mucosal inflammation (Holtzman et al.,
1983a,b), leading to increased epithelial permeability of bronchodilators
(Davis et al., 1980), are some of the proposed mechanisms. Relative to effec-
tors, sensitization of muscarinic receptors (Roum and Murlas, 1984) and mucosal
hypersecretion may be contributing factors. . . , ,
Under most circumstances, increased R • may be expected to reduce FVC and
clW
increase RV. The lack, however, of a significant association between individual
changes in R and FVC (McDonnell et al., 1983), and the disparate effects of
3W
bronchodilator agents on airway diameter, indicate the presence of more than
one mechanism for CL-induced changes in pulmonary function. At 0, concentra-
tions of 0.5 ppm and less, decrements in FVC have been related to decreases in
TLC without changes in RV or TGV (Hackney et al., 1975; Folinsbee et al.,
1977b, 1978; Kulle et al., 1985). The consequent decrease in TLC most likely
results from inhibition of maximal inspiration, as indicated by the reduced 1C
reported at higher (0.75 ppm) 03 concentrations (Bates et al., 1972). Whether
such an inhibition of maximal inspiration is voluntary (due to discomfort) or
involuntary (due to reflex pathways or altered lung mechanics) is unclear and
awaits further experimentation. It is highly probable, however, that most of
the decrements in lung volume reported to result from exposure to 0, at concen-
trations of greatest relevance to standard-setting (< 0.3 ppm) are caused by
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the inhibition of full inspiration rather than by changes in airway diameter.
The lack of any reported changes in the FEV-./FVC ratio also supports the
restrictive nature of this mechanism (Farrell et al., 1979; Kagawa, 1984).
Among the non-vagal components of the functional response, the release of
mediators is one of more plausible mechanisms suggested (Lee et al., 1979).
None of the experimental evidence, however, is definitive. Additional investi-
gation is needed to elucidate, assess the relative importance of, and determine
the overall contribution of the mechanisms associated with ozone exposure.
Recent experiments by Gertner et al. (1983a,b,c) may provide additional
information on possible mechanisms. They demonstrated that even a brief
exposure of the peripheral airways of dogs to ozone triggered a functional
response that, depending on 03 concentration, could be mediated through reflex
or humoral pathways, or both. The reflex-mediated response was subject to
attenuation after repeated exposure, whereas the response mediated humorally
was not.
Experimental evidence in laboratory animals also suggests a close rela-
tionship between the cellular response to 03-induced injury, as measured by
the appearance of neutrophils in the airway epithelium of dogs exposed to 03,
and airway hyperresponsiv.eness, as determined with a provocative aerosol
(Holtzman et al., 1983a,b; Fabbri et al., 1984; Sielczak et al., 1983). When
mobilization of the neutrophils was prevented by prior treatment with hydroxy-
urea (O'Byrne etal., 1983), the (neutrophilic) infiltration after ozone
exposure was depressed (Fabbri et al., 1983), and no increase was seen in
airway responsiveness.
Ozone toxicity, in both humans and laboratory animals, may be mitigated
through altered responses at the cellular or subcellular level, or both. At
present, the mechanisms underlying altered responses are unclear and the
effectiveness of such mitigating factors in protecting the long-term health of
the individual against 03 is still uncertain (Bromberg and Hazucha, 1982).
Since cellular mechanisms are difficult if not impossible to investigate in
humans, animal studies become essential for identifying potential mechanisms
of effects. Numerous basic metabolic processes in humans and animals appear
to be similar; mechanisms underlying these processes may indeed provide some
clues on possible mechanisms in humans (Mustafa and Tierney, 1978; Boushey et
al., 1980). It has been shown that human and animal leukocytes, alveolar
macrophages, and neutrophils produce superoxide radicals not only as a product
12-44
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of a vital biological reduction of molecular oxygen but also as a result of
stressful stimuli (Pick and Keisari, 1981). Excessive production of radicals
without adequate scavenging will injure the supporting tissues, while the
attenuation of response to successive stimuli suppresses the release of free
oxygen radicals and depresses the chemotactic responsiveness of the cells
(Mustafa and Tierney, 1978; Bhatnagar et al., 1983). Accumulation of inflamma-
tory cells at the site of injury and subsequent release of proteases capable
of degrading connective tissue may upset the protease-antiprotease balance
critical for controlling the extent of inflammation and injury. Perturbation
of lung collagen metabolism, seen in vivo in animals exposed to 0, (see
___ ' O
Section 9.3.3.6), could be involved in the inflammatory response. Furthermore,
the attenuation of prolyl hydroxylase (a key enzyme in collagen synthesis)
activity (Hussain et al. , 1976a,b), and concurrent changes in the activity of
superoxide dismutase, the enzyme that catalyzes the dismutation of the super-
oxide free radical (Bhatnagar et al., 1983), could be another important pathway
to the development of changes in responsiveness to 0-. (However, even though
the prolyl hydroxylase activity returns to control levels, the collagen produced
through the original increase in metabolism remains). The glutathione peroxi-
dase system also increases after 0, exposure, thereby providing another line
of defense against oxidant toxicity (Chow, 1976; Chow et al., 1976).
With time, there is a reduction in the intensity and a change in the
composition of the inflammatory response. Partial remission occurs with
continuous or intermittent exposure. There are no data, however, showing how
important the timing and duration of the 03 pulsations may be in influencing
the induction and remission of the inflammatory reaction. The latter issue
has potential significance for public health, since exposure to ambient air
pollution is essentially intermittent. The timing and intensity of exposure
to ozone within the community, and consequently the potential of such exposures
for inducing altered responses, are likely to be highly variable. Differences
within the population in patterns of activity and biological status may be
expected to contribute to this variability.
12.3.6 Relationship Between Acute and Chronic Ozone Effects
Understanding the relationship between acute effects that follow 03
exposure of man or animals and the effects that follow long-term exposures of
man or animals is crucial to the evaluation of the full array of possible
12-45
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human health effects of oxidant pollutants. Most of the acute responses to 03
described in animals and man tend to return toward control (filtered air)
values with time after the exposure ends. While effects of longer periods of
exposure have been documented in laboratory animals (Chapter 9), human beings
have not undergone long-term exposures in laboratory studies because of ethical
and logistical considerations. In fact, little is known about the long-term
implications of acute damage or about the chronic effects in man of prolonged
exposure to 03.
With newer techniques, the pulmonary function of experimental animals can
be more completely evaluated and correlated with biochemical and morphological
parameters. Long-term exposure of rats to less than 1.0 ppm 03 results in
increased lung volume, especially at high transpulmonary pressures (Bartlett
et al., 1974; Moore and Schwartz, 1981; Raub et a!., 1983; Costa et a!.,
1983). Costa et al. (1983) also observed increased pulmonary resistance and,
at low lung volumes, decreased maximum expiratory flows in rats exposed to 0.2
or 0.8 ppm 03 6 hr/day, 5 days/week for 62 exposures. The latter change was
related to decreased airway stiffness or to narrowing of the airway lumen.
Raub et al. (1983), in neonatal rats exposed to 0.12 or 0,25 ppm 03 12 hr/day
for 42 days, observed significantly lower peak inspiratory flows during spon-
taneous respiration, in addition to the increased lung volumes noted above.
While Yokoyama and Ichikawa (1974) did not find changes in lung static pressure-
volume curves of rats exposed to 0.45 ppm 03 6 hr/day, 6 days/week for 6 to 7
weeks, Martin et al. (1983) reported increased maximum extensibility of alveolar
walls and increased fixed lung volumes following exposure of rabbits to 0.4 ppm
03 1 hr/day, 5 days/week for 6 weeks.
Wegner (1982) studied pulmonary function in bonnet monkeys exposed to
0.64 ppm 0- 8 hr/day, 7 days/week for up to 1 year. After 6 months of exposure,
significant increases in pulmonary resistance and in the frequency dependence
of pulmonary compliance were reported. In the monkeys exposed for 1 year,
Wegner (1982) reported significantly increased pulmonary resistance and inertance;
and decreased flows during forced expiratory maneuvers at low lung volumes and
decreased volume expired in 1 second (FEV.,). These findings were interpreted
as indicating narrowing of the peripheral airways. This observation was
confirmed, using morphometric techniques, by Fujinaka et al. (1985), who
reported that respiratory bronchioles of the bonnet monkeys exposed for 1 year
12-46
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had smaller internal diameters and thicker walls. Following a 3-month postex-
posure period, static lung compliance tended to decrease in both exposed and
control monkeys, but the decrease in exposed monkeys was significantly greater
than that in control monkeys. No other significant differences were measured
following the 3-month recovery period, although values for CL-exposed animals
remained substantially different from those for control animals. Wegner
(1982) interpreted these differences as an indication that full recovery was
not complete.
Morphological alterations in both rats and monkeys tend to decrease in
magnitude with increasing duration of exposure to CL, but significant altera-
tions in the centriacinar region have still been reported at the end of long-
term exposures of rats (Boorman et al., 1980; Moore and Schwartz, 1981; Barry
et a!., 1983; Crapo et al., 1984), monkeys (Eustis et al., 1981; Fujinaka et
al.s 1985), and dogs (Freeman et al., 1973). While repair, as indicated by
DNA synthesis by repair cells, starts as early as 18 hours of exposure (Castleman
et al., 1980; Evans et al., 1976a,b,c; Lum et al., 1978), damage continues
throughout long-term exposures, but at a lower rate.
Morphological damage reported in the centriacinar region of rats and
monkeys exposed to less than 1.0 ppm CL for 42 to 180 days includes damage to
ciliated cells and centriacinar alveolar type 1 cells; hyperplasia of noncili-
ated bronchiolar and alveolar type 2 cells, with extension of nonciliated
bronchiolar cells into more distal structures than in unexposed controls;
accumulation of intraluminal and intramural inflammatory cells; and in rats,
but not reported in monkeys, thickening of interalveolar septa (Boorman et al.,
1980; Moore and Schwartz, 1981; Eustis et al., 1981; Barry et al., 1983; Crapo
et al., 1984). Lungs from the bonnet monkeys studied by Wegner (1982) were
evaluated morphologically and morphometrically by Fujinaka et al. (1985). At
the end of the 1-year exposure to 0.64 ppm 0~ for 8 hr/day, a significant
increase was found in the total volume of respiratory bronchioles in the lung,
but their lumens were smaller in diameter because of thickened epithelium and
other wall components. The reduction in .diameter of the first generation
respiratory bronchioles correlates with the results of the pulmonary function
tests performed by Wegner (1982). Cuboidal bronchiolar epithelial cells in
respiratory bronchioles were hyperplastic. Walls of respiratory bronchioles
contained significantly more macrophages, lymphocytes, plasma cells, and
neutrophils. Neither the numbers of fibroblasts nor amount of stainable
12-47
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collagen was increased significantly, but there was more amorphous intercellu-
lar material. There was also a significant increase in arteriolar media and
intima.
Lung collagen content was increased after short-term exposures to 0-
concentrations ranging from 0.5 to 1.0 ppm 03 (Last et al., 1979). This
change continued during long-term exposure (Last and Greenberg, 1980; Last
et al., 1984b). Exposure to 0.96 ppm 0- resulted in increased Tung collagen
content in both weanling and adult rats exposed for 6 and 13 weeks, respective-
ly, and in young monkeys exposed to 0.64 ppm 03 for 1 year (Last et al.,
1984b). Some of the weanling rats and their controls were examined after a
6-week post-exposure period in clean air following the 6-week exposure to 0-.
During this post-exposure period, the differences in lung collagen content be-
tween exposed and pair-fed controls increased rather than decreased. Thus,
with respect to this biochemical alteration, the post-exposure period was one
of continued damage rather than recovery.
Continuation of the centriacinar inflammatory process during long-term 03
exposures is especially important, as it appears to be correlated with remodel-
ing of the centriacinar airways (Boorman et al., 1980; Moore and Schwartz,
1981; Fujinaka et al., 1985). There is morphometric (Fujinaka et al., 1985),
morphologic (Freeman et al., 1973), and functional evidence (Costa et al.,
1983; Wegner, 1982) of distal airway narrowing. Continuation of the inflamma-
tion also appears to be correlated with the increased lung collagen content
(Last et al., 1979; Boorman et al., 1980; Moore and Schwartz, 1981; Last
et al., 1984b) that morphologically appears predominantly in centriacinar
regions of the lung.
The distal airway changes described in the above studies of ozone-exposed
animals have many similarities to those reported in lungs from cigarette
smokers (Niewoehner etal., 1974; Cosio etal., 1980; Hale etal., 1980;
Wright et al., 1983). Even though cigarette smoking has been linked with
emphysema in humans, however, there is no evidence of emphysema in the lungs
of animals exposed to 03. The previous criteria document for 03 (U.S. Environ-
mental Protection Agency, 1978) cited three studies reporting emphysema in
laboratory animals after exposure to 03 concentrations ranging from 0.4 to 0.88
ppm for prolonged periods (P'an et al., 1972; Freeman et al., 1974; Stephens
et al., 1976); but a reevaluation of these findings based on the currently
accepted definition of emphysema does not find any evidence for such claims
12-48
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(see Chapter 9; Section 3.1.4.2). Since then, no similar exposures (i.e.,
same species, 0- concentration, and times) have been documented to confirm
observations of emphysematous changes in the lungs of animals exposed to 03.
12.3.7 Resistance to Infection
Normally the mammalian respiratory system is protected from bacterial and
viral infections by the integrated activity of the mucociliary, phagocytic,
and immunological defense systems. Animal models and isolated cells have been
used to assess the effects of oxidants on the various components of these lung
defenses and to measure the ability of these systems to function as an inte-
grated unit in resistance against pulmonary infections. In these studies,
short-term (3 hr) exposure to 03 at concentrations of 0.08 to 0.10 ppm can in-
crease the incidence of mortality from bacterial pneumonia (Coffin et al.,
1967; Ehrlich et al., 1977; Miller et al., 1978a). Subchronic exposure to 0.1
ppm caused similar effects (Aranyi et al., 1983). Following short-term expo-
sures to 03, a number of alterations in lung defenses have been shown, such as
(1) impairment in the ability of the lung to inactivate bacteria and viruses
(Coffin et al., 1968; Coffin and Gardner, 1972; Goldstein et al., 1977; Ehrlich
et al., 1979); (2) reduced effectiveness of mucociliary clearance (Phalen et
al., 1980; Frager et al., 1979; Kenoyer et al., 1981; Abraham et al., 1980);
(3) immunosuppression (Campbell and Hilsenroth, 1976; Aranyi et al., 1983;
Thomas et al., 1981b; Fujimaki et al., 1984); (4) significant reduction in
number of pulmonary defense cells (Coffin et al., 1968; Alpert et al., 1971);
and (5) impaired macrophage phagocytic activity, less mobility, more fragility
and membrane alterations, and reduced lysosomal enzymatic activity (Dowel 1 et
al., 1970; Hurst et al. , 1970; Hurst and Coffin, 1971; Goldstein et al. ,
1971a,b, 1977; Hadley et al., 1977; McAllen et al., 1981; Witz et al., 1983;
Amoruso et al., 1981). Such effects on pulmonary host defense have been
reported in a variety of species of animals following either short-term or
subchronic exposure to 03 in combination with other airborne chemicals (Gardner
et al., 1977; Aranyi et al., 1983; Ehrlich, 1980, 1983; Grose et al. , 1980,
1982; Phalen et al., 1980; Goldstein et al., 1974). Studies have also indicated
that the activity level of the test subject is an important variable that can
influence the determination of the lowest effective concentration of the
pollutant (Illing-et al., 1980).
12-49
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The major problem remaining is the assessment of the relevance of these
animal data to humans. If animal models are to be used to reflect the toxicol-
ogical response occurring in humans, then the end point for comparison of such
studies should be morbidity rather than mortality. A better comparison in
humans would be the increased prevalence of respiratory illness in the com-
munity. Such a comparison is proper since both mortality (animals) and mor-
bidity (humans) result from an impairment in pulmonary defenses. Ideally,
studies of pulmonary host defenses should be performed in.man using epidemio-
logical or volunteer methods of study. Unfortunately, such studies have not
yet been reported. Therefore, attention must be paid to experiments conducted
with animals.
Present knowledge of the physiology, metabolism, and function of host
defense systems has come primarily from various animal systems, but it is
generally accepted that the basic host defence mechanisms are similar in
animals and man. Green (1984) recently delineated the many similarities that
exist between the rodent and human antibacterial defenses. Both defenses
consist of the same defense components, which together act to maintain the
lung free of bacteria. The effects seen in animals represent alterations in
basic biological systems. An equivalent response (e.g., mortality) may not be
expected in man, but similar alterations in basic defense mechanisms could
occur in humans because they possess pulmonary defense systems equivalent to
those in laboratory animals. It is understood that different exposure levels
may be required to produce similar responses in humans. The concentrations of
DO at which effects become evident can be influenced by a number of factors,
such as preexisting disease, dietary factors, combinations with other pollutants,
and the presence of other environmental stresses. Although not confirmed by
experimental data, it is possible that humans exposed to 0, could experience
decrements in host defenses; but at the present time, the exact concentration
at which effects might occur in man cannot be predicted, nor can the severity
of the effect.
12.3.8 Extrapulmonary Effects of Ozone
Because of the high degree of reactivity of 0- with biological tissue, it
is not clear whether 03 reaches the circulation. Results from mathematical
modeling (Miller et a!., 1985) suggest that only a small fraction of Oj can
penetrate the air-blood barrier. Several studies discussed in Chapters 9 and
12-50
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10 are indicative, however, of either direct or indirect extrapulmonary effects
of ozone exposure. For example, alterations in red blood cell morphology and
enzymatic activity, as well as cytogenetic effects in circulating lymphocytes,
have been reported in man and laboratory animals. Other organ systems of the
body may also be involved. Exposure to 0~ may have central nervous system
effects, since subjective limitations in performance of vigilance tasks have
been observed in man and laboratory animals. Cardiovascular, reproductive,
and teratological effects of CU have also been reported in laboratory animals,
along with changes in endocrine function; but the implications of these findings
for human health are difficult to judge. More recent studies in laboratory
animals have shown that hepatic metabolism of xenobiotic compounds may be
impaired by 0, inhalation. While some of these systemic effects, such as
decrements in exercise and vigilance performance, may be attributed to odor
perception or respiratory irritation, the reasons for the others are more
difficult to conceptualize. These effects may result from direct contact with
0, or, more likely, from contact with a reactive product of 03 that penetrates
to the blood and is transported to the other organs.
Cytogenetic and mutational effects of ozone are controversial. In human
cells in culture, a significant increase in the frequency of sister chromatid
exchanges has been reported to occur after exposure to concentrations of ozone
as low as 0.25 ppm for 1 hr (Guerrero et a!., 1979). Lymphocytes isolated
from animals were found to have significant increases in the numbers of chromo-
some ^Zelac et a!., 1971a,b) and chromatid (Tice et al., 1978) aberrations,
after 4- to 5-hr exposures to 0.2 and 0.43 ppm ozone, respectively. Single-
strand breaks in DNA of mouse peritoneal exudate cells were measurable after a
24-hr exposure to 1 ppm ozone (Chaney, 1981). Gooch et al. (1976) analyzed
the bone marrow samples from Chinese hamsters exposed to 0.23 ppm of 0., for
5 hr and the leukocytes and spermatocytes from mice exposed for up to 2 weeks'
to 0.21 ppm of 0,. No effect was found on either the frequency of chromatid
or chromosome aberrations, nor were there any reciprocal translocations in the
primary spermatocytes. Small increases observed in chromatid lesions in
peripheral blood lymphocytes from humans exposed to 0.5 ppm ozone for 6 or 10
hr were not significant because of the small number (n=6) of subjects studied
(Merz et al., 1975). Subsequent investigations, however, with more human
subjects exposed to ozone at various concentrations and for various times have
failed to show any cytogenetic effect considered to be the result of ozone
12-51
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exposure (McKenzie et al., 1977; McKenzie, 1982; Guerrero et al., 1979). In
addition, epidemiological studies have not shown any evidence of chromosome
changes in peripheral lymphocytes of humans exposed to ozone in the ambient
environment (Scott and Burkart, 1978; Magie et al., 1982). Clearly, additional
evaluation of potential chromosomal effects in humans exposed to On is needed.
Evidence now available, however, fails to demonstrate any cytogenetic or
mutagenic effects of ozone in humans when exposure schedules are used that are
representative of exposures that the population at large might actually experi-
ence.
With the exception of peripheral blood lymphocytes, the potential genotoxic
effects of ozone for all of the other body tissues are unknown. No cytogenetic
investigations have been conducted on the respiratory tissues of animals
exposed to ozone, even though these tissues are exposed to the highest concen-
trations and are also the target of most of the toxic manifestations of ozone.
Clearly, ozone-induced genotoxicity data from peripheral blood lymphocytes
cannot be extrapolated to other organs, such as the lungs or reproductive
organs.
Ozone exposure produces a number of hematological and serum chemistry
changes both in rodents and man, but the physiological significance of these
effects is unknown. Most of the hematological changes appeared to be linked
to a decrease in RBC GSH content (Menzel et al., 1975; Buckley et al., 1975;
Posin et al., 1979; Linn et al., 1978) at concentrations of 0.2 ppm for 30 to
60 min in man, or 0.5 ppm for 2.75 hr in sheep, or 0.5 ppm continuously for
5 days in mice and rats. Heinz bodies, disulfide cross-linked methemoglobin
complexes attached to the inner RBC membrane, were detected in mice exposed to
ozone (Menzel et al., 1975). Inhibition of RBC acetylcholinesterase was found
in mouse (Goldstein et al., 1968), human (Buckley et al., 1975), and squirrel
monkey RBCs (Clark et al., 1978) at concentrations of 0.4 to 0.75 ppm and
times as short as 2.75 hr in man or 4 hr/day for 4 days in monkeys. Loss of
RBC acetylcholinesterase could either be mediated by membrane peroxidation or
by loss of acetylcholinesterase thiol groups at the active site. Dorsey
et al. (1983) observed that the deformability of CD-I mouse RBCs decreased on
exposure to 0.7 and 1 ppm for 4 hr. Deformability also decreased at 0.3 ppm,
but was not statistically significant. These data support the concept of
membrane damage to circulating RBCs, which appears to be similar in most
species of animals studied and in normal human RBCs exposed to 0,.
12-52
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12.4 HEALTH EFFECTS IN INDIVIDUALS WITH PREEXISTING DISEASE
12.4.1 Patients with Chronic Obstructive Lung Disease (COLD)
Patients with mild COLD have not shown increased responsiveness to 0, in
controlled human exposure studies. For example, Linn et al. (1982a, 1983b)
and Hackney et al. (1983) showed no changes in symptoms or lung function at
0.12, 0.18, or 0.25 ppm 03 (1 hr with intermittent light exercise). Likewise,
Solic et al. (1982) and Kehrl et al. (1983, 1985) found no significant changes
in symptoms or function at 0.2 or 0.3 ppm 03 (2 hr with intermittent moderate
exercise). At higher concentrations, however, Kulle et al. (JLB84) found
decreased lung function in a group of 20 smoking chronic bronchitics at 0.4 ppm
(3 hr with intermittent moderate exercise) on day 1 of exposure and upon
reexposure at day 9 (fourth day following cessation of repeated daily expo-
sures); these subjects were less responsive to Q3 than healthy nonsmokers.
There is suggestive evidence that bronchial reactivity is increased in
some subjects with COLD (two of three) following exposure to 0.1 ppm 03 (Konig
et al., 1980). Small decreases in arterial Og saturation (SO.) have also
been observed in COLD subjects exercising at 0.12 ppm Q3 for 1 hr (Linn et
al,, 1982a; Hackney et al., 1983) and at 0.2 ppm 03 for 2 hr (Solic et al.,
1982). Decreased Sa02 was also seen at higher 03 concentrations but was not
significant (Linn et al., 1983b; Kehrl et al., 1985). Interpretation of small
differences in S_0« or their physiological and clinical significance is there-
O, C.
fore uncertain. In addition, since many of the COLD subjects were smokers,
the interpretation of small changes in S_00 is complicated. Further studies
3. £.
are needed to resolve this issue, particularly on COLD subjects exposed to 03
at higher exercise levels.
One difficulty in attempting to characterize the responsiveness of patients
with COLD is that they exhibit a wide diversity of clinical and functional
states. These range from a history of smoking, cough, and minimal functional
impairment to chronic disability that is usually combined with severe changes
in blood gases or respiratory mechanical behavior. The chief locus of damage
may also vary: either the bronchi (chronic bronchitis) or parenchyma (emphy-
sema) may dominate the clinical picture. Finally, the mixture of acute and
chronic inflammatory processes may vary considerably among patients. Even
with strict selection criteria, however, it may be very difficult to sort out
many of these manifestations of COLD in the design of pollutant-exposure
studies.
12-53
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12.4.2 Asthmatics .
There is as yet no definitive laboratory evidence demonstrating that mild
asthmatics are functionally more responsive than healthy individuals to 03.
Linn et al. (1978) found no significant changes in lung function, as indicated
by forced expiratory spirometry or the nitrogen washout test, when a hetero-
geneous group of adult asthmatics with mild to moderate bronchial obstruction
was exposed to 0.20 ppm 0- for 2 hr with intermittent light exercise; increased
symptom scores were noted, however. Silverman (1979) found minimal changes in
forced expiratory spirometry following 2-hr exposures of adult asthmatics to
0.25 ppm 0~ while at rest. Although group mean changes were not statistically
significant, one third of the subjects who rested for 2 hr while inhaling
0.25 ppm Og demonstrated a greater than 10 percent decrement in lung function.
Changes of this magnitude have not been reported in normal subjects under
these conditions. In laboratory field studies with ambient air containing an
average concentration of 0.17 ppm 03, Linn et al. (1980) found small but
statistically significant decrements in forced expiratory measures in both
healthy and asthmatic adults, following 2-hr exposures with intermittent light
exercise. The magnitude of functional responses did not differ statistically
between the two groups. Finally, Koenig et al. (1985) found no significant
changes in pulmonary function or symptoms when a group of adolescent subjects
with atopic, extrinsic asthma were exposed at rest to 0.12 ppm 03 for 1 hr.
The studies reported above are not considered definitive since major
limitations leave open the question of whether the pulmonary function of
asthmatics is more affected by 0~ than that of healthy subjects. Intake of
medication was not controlled in several of the studies, and some subjects
continued to use oral medication during testing. Adequate characterization of
subjects is lacking in most studies and, as a result, group mean changes could
not be detected because of the large variability in responses from such
heterogeneous groups. For example, some of the subjects in one study (Linn
et al.j 1978) showed evidence of chronic obstructive lung disease in addition
to asthma. Most of the normal subjects (70 percent) in the Linn et al. (1980)
study, in which asthmatics were compared to normals, had a history of allergy
and appeared atypically reactive to the 03 exposure. In addition, the subjects
in these studies either performed light exercise or rested while exposed. In
view of the recognized importance of minute ventilation, which increases
proportionately with the intensity of exercise, in determining the response to
03, additional testing at higher levels of exercise should be undertaken.
12-54
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The specific measurements of pulmonary function and the exposure protocols
employed in the above studies may be inappropriate for ascertaining pulmonary
effects in asthmatic subjects. Asthma is essentially characterized by broncho-
constriction. Compared to airway resistance, some measures of forced expiratory
spirometry are less sensitive to bronchoconstriction, since fairly severe
bronchoconstriction must occur in order to affect decrements in these measures.
McDonnell et al. (1983), reporting on healthy subjects exposed to levels of 0.,
as low as 0.12 ppm with heavy intermittent exercise, attributed small (<5
percent) decrements in forced expiratory spirometry to a reduced inspiratory
capacity resulting from stimulation or sensitization of airway receptors by 0,
(see Section 12.3.5). They also observed that there was no correlation between
changes in airway resistance and forced expiratory spirometry for individual
subjects, which prompted them to postulate two different mechanisms of action.
It may be that the sensitivity of the mechanism affecting inspiratory capacity
is the same in asthmatics and normals, while the mechanism affecting airway
resistance is different.
Epidemiological findings provide only qualitative evidence of exacerbation
of asthma at ambient concentrations of 0~ below those generally associated
with symptoms or functional, changes in healthy adults. Whittemore and Korn
(1980) and Holguin et al. (1985) found small increases in the probability of
asthma attacks associated with previous attacks, decreased temperature, and
incremental increases in oxidant and 0~ concentrations, respectively. Lebowitz
et al. (1982, 1983, 1985) and Lebowitz (1984) also showed effects in asthma-
tics, such as decreased peak expiratory flow and increased respiratory symptoms,
that were related to the interaction of 0 and temperature. All of these
studies have questionable effects from other pollutants, particularly inhalable
particles. The major problem in epidemiological studies, therefore, has been
the lack of definitive information on the effects of 0-, alone, since there is
confounding by the presence of other environmental conditions in ambient air.
Other factors leading to inconsistencies between epidemiological and control!ed-
laboratory studies include (1) differences in the pulmonary function tests
employed, (2) differences in study subjects, since the general population
contains individuals with more severe disease than can be studied in controlled
human exposures, (3) insufficient clinical information in most of these studies,
or (4) the lack of data on other, unmeasured pollutants and environmental
conditions in ambient air.
12-55
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12.4.3 Subjects with Allergy, Atopy, and Ozone-Induced .Hyperreac.tlv.lty
Allergic or hypersensitivity disorders may be recognized by generalized
systemic reactions as well as localized reactions in various sites of the
body. The reactions can be acute, subacute, or chronic; immediate or delayed;
and may be caused by a variety of physical and chemical stimuli (antigens).
Although many hypersensitive individuals in the population have a family
history of allergy, a true allergic reaction is one that is classically elicited
through an immunological mechanism (i.e., antigen-antibody response), thereby
distinguishing allergic responses from simple chemical or pharmacologic reac-
tions. There are also some individuals with family histories who develop
natural or spontaneous allergies, defined generally as atopy. Determination
of the specific allergens (antigens) responsible for these disorders is often
difficult, but clinical history, physical examination, skin tests, and selective
diets are very useful. A more definitive evaluation can be provided by pulmo-
nary function tests (e.g., airway reactivity), serum IgE levels, and nasal
cytology. The information available on the responsiveness of these individuals
to ozone, i.e., whether they differ from normal non-allergic, non-atopic
individuals, is sparse.
Hackney et al. (1977a) found decreases in spirometric function among
atopic individuals exposed to 0.5 ppm 03 with light intermittent exercise.
Neither Folinsbee et al. (1978), in a controlled laboratory exposure, nor Linn
et al. (1980), in a field study in the Los Angeles area, distinguished between
the responses of normal subjects and allergic non-asthmatic subjects. In the
latter study, spirometric function was reduced and symptoms were increased in
association with an average ambient 0« concentration of 0.17 ppm. Similarly,
Lebowitz et al. (1982, 1983) reported, after adjusting for other covariables,
that Og and TSP were independently associated with peak flow in adults with
airway obstructive disease.
Some healthy subjects with no prior history of respiratory symptoms or
allergy demonstrate increased nonspecific airway sensitivity resulting from 03
exposure (Golden eta!., 1978; Holtzman etal., 1979; Konig eta!., 1980;
Dimeo et al., 1981; Kulle et al., 1982b). Airway responsiveness is typically
defined by changes in specific airway resistance produced by a provocative
bronchial challenge to drugs like acetylcholine, methacholine, or histamine,
administered after 03 exposure. In one study (Holtzman et al., 1979), in
which subjects were classified as atopic or nonatopic based on medical history
12-56
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and allergen skin testing, the induction and time course of increased bronchial
reactivity after exposure to 0_ were unrelated to the presence of atopy. An
association of O^-induced increases in airway responsiveness with airway
inflammation has been reported in dogs at high 03 concentrations (1 to 3 ppm)
(Holtzman et al.» 1983a,b; Fabbri et a!., 1984); and in sheep at 0.5 ppm 0~
(Sielczak et a!., 1983). Little is known, however, about this relationship in
animals at lower 0., concentrations (<0.5 ppm), and the possible association
between 0~-induced inflammation and airway hyperresponsiveness in human subjects
has not been explored systematically.
12.5 EXTRAPOLATION OF EFFECTS OBSERVED IN ANIMALS TO HUMAN POPULATIONS
12.5.1 Species Compa r i s ons
Comparisons of the effects of ozone on different animal species are of
value in attempting to understand whether man might experience similar effects.
Two criteria are useful for judging whether effects seen in animals may plausi-
bly be expected to occur in man: (1) the same effects occur in multiple
animal species; and (2) the mechanisms of toxicity underlying the observed
effects are common across animal species and between animals and man. Thus,
if only one of several tested species experienced a given effect of ozone,
this effect might be species-specific and might not occur in man. Conversely,
if several animal species, with all their inherent differences, shared a given
effect of ozone, it would be reasonable to infer that all mammalian species,
including man, would be susceptible to that effect from ozone. A commonality
of effects across species would be expected, provided the effects were related
to mechanisms that are shared across species. In the case of ozone, the
proposed major molecular mechanisms of action are the oxidation of polyun-
saturated fatty acids and the oxidation of thiols or ami no acids in tissue
proteins or lower-molecular-weight peptides. Since the affected molecules are
identical across all species, then any differences in the observed responses
between species would be a function of species differences in other factors,
such as delivered doses or subsequent processes of injury and repair. For
example, a likely target site for 03 toxicity is the cellular membrane, such
as the membrane of cells like the Type 1 and ciliated cells that cover a large
surface area of the respiratory tract. Since there are no major interspecies
differences in cell membranes, and membranes are composed of proteins and
12-57
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lipids, then both proposed molecular mechanisms of CL toxicity could occur at
the cellular membrane. In fact, the two proposed mechanisms most likely occur
simultaneously. Although the mechanisms of toxicity would be common across
species, the consequent toxic impact on the membrane, the cell, and surrounding
tissue would be influenced by species-specific differences, such as antioxidant
defenses or repair mechanisms. Even if both criteria cited above are met, it
does not imply that the concentrations at which man might experience the
observed effects are the same as those eliciting the effects in experimental
animals.
The health data base for ozone includes hundreds of studies in about
eight species, and even more strains, of laboratory animals. , Generally, for a
given effect, whether it be on lung morphology, physiology, biochemistry, or
host defenses, all species tested have been responsive to ozone, albeit some-
times at different concentrations. The few studies of several species having
at least two points of identity for comparison will be discussed.
Morphological examinations of the lungs of several species have been
conducted after ozone exposure. In the groups studied, there are significant
differences in lung structure. Man, nonhuman primates, and dogs have both
nonrespiratory and respiratory bronchioles, while respiratory bronchioles are
either absent or poorly developed in mice, rats, and guinea pigs. Additional
differences exist. Nonetheless, a characteristic ozone lesion occurs at the
junction of the conducting airways and the gaseous exchange tissues, regardless
of species differences in structure. The typical effect in all the species
examined is damage to ciliated and Type 1 cells and hyperplasia of nonciliated
bronchiolar cells and Type 2 cells. An increase in inflammatory cells is also
observed. Such changes have been observed after a 7-day intermittent exposure
of monkeys to 0.2 ppm (Dungworth et al., 1975; Castleman et a!., 1977) and, of
rats to 0.2 ppm (Schwartz et al,, 1976). With different exposure regimens,
similar effects occur in cats (0.26 ppm, endotracheal tube, about 6 hr, Boatman
et al., 1974), mice (0.5 ppm, 35 days, Zitnik et al., 1978), and guinea pigs
(0.5 ppm, 6 mo, Cavender et al., 1978). For these studies, lower concentrations
of ozone were not tested. Unfortunately, quantitative comparisons between
monkey and rat studies is not possible because of inadequate data. Nonetheless,
responses were roughly equivalent under similar exposure conditions in these
two species, even though major structural differences exist between them.
12-58
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Pulmonary function of eight species of animals has been studied after
exposure to ozone. Short-term exposure for 2 hr to 0 concentrations as low
as 0.22 ppm produces rapid, shallow breathing. Similar changes in respiration
have been observed in man during exposure to comparable ozone concentrations,
as shown in Table 12-4. The onset of these effects is rapid and appears to be
related to the ozone concentration. In a literature review, Mauderly (1984) ;
compared changes in breathing patterns of humans and guinea pigs during and
after a 2-hr exposure to 0.7 ppm 0~. The respiratory frequency increased and •"'
tidal volume decreased, with similar patterns in these two species during
exposure, and returned toward normal in the first 3 hr after exposure.
Enhanced airway reactivity to inhaled bronchoconstrictive agents has also
been observed in animals and man after 03 exposure (Table 12-5). Short-term
exposure to 0, concentrations as low as 0.32 ppm increases airway responsive-
ness to provocative aerosols such as acetylcholine, carbachol, methacholine,
i •
or histamine in sheep, dogs, and humans. However, the time course of this -
response may be species-specific. A maximum response is obtained immediately
after exposure in man but appears to be delayed by 24 hr in sheep and dogs.
Mauderly (1984) has also compared the effect of 2-hr 0~ exposures on
airway constriction in humans, guinea pigs, and cats. Although measured
indices of airflow limitation are similarly depressed in both animals and man,
there are too many differences in the experimental methods and too few species
studied to provide an adequate comparison.
Qualitative comparisons of changes in breathing patterns and airway
reactivity indicate that many similarities occur during exposure of animals
and humans to ozone. However, quantitative extrapolation of these effects may '"'
be limited by the small number of studies having similar experimental procedures
and similar exposure levels. Other effects of short- and long-term ozone
exposure on lung function have been observed (Chapter 9), but there are insuf-
ficient points of identity in the experiments to permit direct comparisons
among animal species or between animals and man.
Species comparisons of host defense against infection are theoretically
possible, given the abundance of information describing the effect of exposure
to photochemical oxidants in mice and other rodents (see Section 12.3.7).
Therefore, examination of the similarities between host antibacterial defense
systems in rodents and man are in order. Green (1984) has delineated the
similarities as follows. Both defense systems consist of an aerodynamic
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TABLE 12-4, COMPARISON OF THE ACUTi EFFECTS OF OZONE ON BREATHIHG PATTERNS IN ANIHALS AHD HAN
Ozone3
concentration
yg/m3 ppm
392
686
431
804
1588
470
588
784
588
588
— t
I"O
i 588
en
° 588
980
666
1333
2117
2646
725
980
1470
980
1100
1470
0.20
0.35
0.22
0.41
0.8
0.24
0.30
0.40
0.3
0.3
0.3
0.3
0.5
0.34
0.68
1.08
1.35
0.37
0.50
0.75
0.5
0.56
0.75
Measurement
method
UV
CHEM
CHEH
HAST
UV
UV
CHEM
NBKI
MAST
NBKI
CHEM
MAST
Exposure
duration
1 hr
(Mouthpiece)
2 hr
2,5 hr
1 hr
(mouthpiece)
1 hr
(mouthpiece)
1 hr
2 hr
2 hr
2 hr
2 hr
2 hr
2 hr
Activity0
level (V£)
CE(77,5)
R
IE(65)
CE(34.7, 51)
CE(66)
CE(55)
IE(31,50,67)
R
IE(29)
R
R
IE
Observed effects(s)
Increased fn and decreased V,.
Concentration-dependent increase in fn for
all exposure levels.
Increased fR and decreased Vj.
Increased fn and decreased V_.
Increased fn and decreased V_.
Increased fn and decreased V_.
K I
Increased fR and decreased V,
with tine or exposure; signi-
ficant linear correlations with
03.
Increased fR and decreased Vj during
exposure to all 03 concentrations.
Dose-dependent increase in fD and decrease
in VT. K
Increased f^.
Abnormal, rapid, shallow breathing while
exercising on a treadmill after exposure.
Increased fR and decreased VT at maximum
workloads only.
Species Reference
Human Adams and Schelegle, 1983
Guinea pig Andur et al., 1978
Human McDonnell et al.,
1983
Hunan OeLucia et al., 1983
Human OeLucia and Adams,
Human Gibbons and Adams,
Human Folinsbee et al,,
1977
1984
1978
Guinea pig Murphy et al. , 1964
Human Folinsbee et al.,
Guinea pig Yokoyaoia, 1969
Dog Lee et al . , 1979
Human Folinsbee et al.,
1975
1977a
Ranked by lowest observed effect level.
Measurement method: MAST = Kl-Coulometric (Mast meter); CHEM = gas phase chemiluminescence; UV = ultraviolet photometry; NBKI = neutral buffered
potassium iodide.
Minute ventilation reported in L/nin or as a multiple of resting ventilation. R = rest; IE = intermittent exercise; CE = continuous exercise.
-------
TABLE 12-5. COMPARISON OF THE ACUTE EFFECTS OF OZONE ON AIRWAY REACTIVITY IN ANIMALS AND MAN
Ozone
concentration
ug/m3
627
784
784
en 980
1176
1176
1372
1960
ppm
0.32
0.4
0.4
0.5
0.6
0.6
0.7
1.0
Measurement
method
MAST
CHEM
UV
CHEM
UV
CHEM
CHEM
UV
Exposure
duration
2 hr
3 hr
2 hr
2 hr
2 hr
2 hr
2 hr
2 hr
Activity*"
level (V£)
R
IE(4-5xR)
IE(2xR)
R
IE(2xR)
R
R
R
Observed effects(s)
SR increased with ACh challenge.
3W
SG decreased with methacholine;
attenuation develops with repeated
exposures.
SR increased with histamine challenge;
attenuation develops with repeated expo-
sure. No effect on bronchial reactivity
at 0.2 ppm.
R, increased with carbachol 24 hr but not
immediately after exposure.
SR increased with histamine and
metnacholine in atopic and non-atopic
subjects.
Bronchoreactivity to histamine; may persist
for up to 3 weeks.
R, increased with histamine 24 hr but not
1 hr after 03 exposure.
R, increased with ACh and histamine 1 hr
and 24 hr after exposure.
Species Reference
Human Kb'nig et al., 1980
Human Kulle et al., 1982b
Hu«an Dimeo et al , , 1981
Sheep Abraham et al . , 1980
Human Holtzman et al., 1979
Human Golden et al., 1978
Dog Lee et al . , 1977
Dog Holtzman et al., 1983a,b
Ranked by lowest observed effect level.
Measurement method: MAST = Kl-Coulometrie (Mast meter); CHEM = gas phase chemiluminescence; UV = ultraviolet photometry.
€Minute ventilation reported in L/min or as a multiple of resting ventilation. R = rest; IE = intermittent exercise.
-------
filtration system; a fluid lining layer covering the respiratory membranes; an
active transport mechanism for removal and inactivation of viable microorganisms;
pulmonary cells (alveolar macrophages, polymorphonuclear leukocytes); and
immune secretions of lymphocytes and plasma cells. These similarities provide
an ideal basis for qualitative extrapolation, since in man and rodents these
components act in concert to maintain the lung free of bacteria. On the basis
of 03 exposure data and the similarities in host antibacterial defense systems,
Goldstein (1984) has drawn the following conclusions. First, sufficient
similarity exists between the major defense mechanisms in rodents and humans
to permit the use of the rat as a human surrogate. Second, the pulmonary
antibacterial system is a sensitive means of assessing potential toxicity of
oxidants. Third, pollutant-induced abnormalities in the individual components
of the host defense system permit bacterial proliferation and disease. Fourth,
results can be qualitatively extrapolated from rodents to humans. Although
quantitative relationships may also exist, the detailed information is not yet
available for such extrapolation. Too few studies of antiviral host defenses
after CU exposure exist to form any accurate conclusions regarding viral
infections.
Rats and monkeys have been examined for changes in lung biochemistry
following ozone exposure. In these animals exposed for 7 days (8 hr/day) to
0.8 ppm ozone (DeLucia et a!., 1975), glucose-6-phosphate dehydrogenase acti-
vity was elevated to a roughly equivalent degree. Glutathione reductase
activity was increased in rats, but not monkeys. Chow et al. (1975) also
compared these species after exposure to 0.5 ppm ozone for 8 hr/day for 7
days. Antioxidant enzymes were increased in the rats, but not in the monkeys.
The authors referred to "relatively large variations" in the monkey data.
Oxygen consumption was measured in rats and monkeys after a 7-day (8 hr/day)
exposure to several levels of ozone (Mustafa and Lee, 1976). Rhesus monkeys
may have been slightly less responsive than rats. However, at 0.5 ppm ozone,
bonnet monkeys and rats had roughly equivalent increases. In all of these'
reports, there was no mention of statistical comparisons between species or of
power calculations that would indicate whether, under the experimental condi-
tions of data variability, there was equivalent power for statistically de-
tecting effects in both species. In a few of the reports, the number of
animals was not given. Mustafa et al. (1982) compared mice to three strains
of rats exposed to 0.45 ppm ozone continuously for 5 days. Antioxidant
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metabolism and oxygen consumption were measured. Generally, increases in
enzyme activities were observed in both species; in several cases the increase
in the mice was statistically greater than the increase in the rats.
For extrapulmonary effects, the only species comparison was made by
Graham et al. (1981). Female mice, rats, and hamsters had an increase in
pentobarbital-induced sleeping time after a 5-hour exposure to 1 ppm ozone.
Under the experimental conditions used, relative species responsivity cannot
be assessed.
An analysis of the animal toxicological data for ozone indicates that the
rat is the species most often tested. Other species often used include mice,
rabbits, guinea pigs, and monkeys. A few dog, cat, sheep, and hamster studies
exist. As has been noted above, very few species comparisons can be made
because of differences in exposure regimens and measurement techniques. Even
when direct comparisons are possible, interpretation is difficult. Statements
regarding responsiveness can be made, but statements about sensitivity (e.g.,
responses to an equivalent delivered dose) cannot be made until more dosimetry
and other types of data are available. Nonetheless, even with the wide varia-
tion in techniques and experimental designs, acute and subchronic exposures to
levels of ozone less than 0.5 ppm produce remarkably similar types of responses
in many species of animals. Thus, it may be hypothesized that man experiences
more types of effects from exposure to ozone than can be deduced from human
studies. Types of effects for which substantial animal data bases exist
include changes in lung structure, biochemistry, and host defenses. However,
the risks to man from breathing ambient .levels of ozone cannot fully be deter-
mined until quantitative extrapolations of animal results can be made.
12.5.2 Dosimetry Modeling
Dosimetry refers to determination of the amount of ozone that reaches
specific sites in animals and man, while sensitivity relates to the likelihood
of equivalency of biological response given the delivery of the same dose of
ozone to a target site in different species. A coupling of these two elements
is required to permit quantitative interspecies comparisons of toxicological
results from different experiments.
Although additional research is needed on dosimetry and on species sensi-
tivity before quantitative extrapolations can confidently be made between
species, only dosimetry is sufficiently advanced for discussion here. Because
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the factors affecting the transport and absorption of 03 are general to animals
and man, dosimetry models can be formulated that use appropriate species
anatomical and ventilatory parameters to describe 03 absorption. Thus far,
theoretical modeling efforts (McJilton et a!., 1972; Miller et a!., 1978b,
1985) have focused on the lower respiratory tract.
Largely because of the technical ease of measuring ozone uptake in the
head, nasopharyngeal removal of ozone has been experimentally studied in the
dog (Vaughan et al., 1969; Yokoyama and Frank, 1972; Moorman et a!., 1973),
rabbit (Miller et al., 1979), and guinea pig (Miller et al., 1979). To date,
information on nasopharyngeal removal of 03 in man is not available. Since
nasopharyngeal removal of 0., serves to lessen the insult to lower respiratory
tract tissue, an assessment of species differences in this area is critical to
interspecies comparisons of dosimetry.
Damage to all respiratory tract regions occurs in animals exposed to 0-,
with location and intensity dependent upon concentration and exposure duration.
When comparisons are made at the analogous anatomical sites, the morphological
effects of Do on the lungs of a number of animal species are remarkably similar.
Despite inherent differences in the anatomy of the respiratory tract between
various experimental animals and man, the junction between the conducting
airways and the gas exchange region is the site most severely damaged by 0^
exposure in animals (see Section 9.3.1), This finding is consistent with the
inference that this region is also most likely the principal site affected in
man. Dosimetry model simulations (Miller et al., 1978b) predict that the
maximal tissue dose occurs at the region of predominant morphological damage
in animals. The overall similarity of the predicted 03 dose patterns in
animal lungs studied thus far (rabbits and guinea pigs) extends to the simula-
tion of 03 uptake in humans (Miller et al., 1985) (see Section 9.2.3.1).
The consistency and similarity of the human and animal lower respiratory
tract dose curves lend strong support to the feasibility of extrapolating to
man the results obtained from animals exposed to 0,. In the past, extrapola-
tions have usually been qualitative in nature. With additional research in
areas that are basic to the formulation of dosimetry models, quantitative
dosimetric differences among species can be determined. If, in addition, more
information is obtained on species sensitivity to a given dose, significant
advances can be made in quantitative extrapolations of effects from exposure
to 03> Since animal studies are the only available approach for investigating
12-64
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the full array of potential effects induced by exposure to 03, quantitative
use of animal data is in the interest of better establishing the CU levels to
which man can safely be exposed.
12.6 HEALTH EFFECTS OF OTHER PHOTOCHEMICAL OXIDANTS AND POLLUTANT MIXTURES
Ozone is considered to be chiefly responsible for the adverse effects of
photochemical air pollutants, largely because of its relative abundance compared
with other photochemical oxidants. Still, the coexistence of other reactive
oxidants (Section 12.2.2) suggests that the potential effects of other ambient
oxidants should be examined. Animal and clinical research, however, has
centered largely on 0~; very limited effort has been devoted to studies of
peroxyacetyl nitrate (PAN) and hydrogen peroxide (H^O^). Field and epidemio-
logical studies evaluate health effects associated with exposure to the ambient
environment, making it difficult to single out the oxidant species responsible
for the observed effects.
12.6.1 Effects of Peroxyacetyl Nitrate
There have been too few controlled toxicological studies with the other
oxidants to permit a sound scientific evaluation of their contribution to the
toxic action of photochemical oxidant mixtures. The few animal toxicology
studies on PAN indicate that it is less acutely toxic than 03> When the
effects seen after exposure to Q~ and PAN are examined and compared, it is
obvious that the test animals must be exposed to concentrations of PAN much
greater than those needed with 0~ to produce a similar effect on lethality,
behavior modification, morphology, or significant alterations in host pulmonary
defense system (Campbell et a!., 1967; Dungworth et al., 1969; Thomas et a!.,
1979, 1981a).
All of the available controlled human studies with other photochemical
oxidants have been limited to a series of reports on the effects of PAN on
healthy young and middle-aged males during intermittent moderate exercise
(Smith, 1965; Drinkwater et al., 1974; Raven et al., 1974a,b, 1976; Gliner
et al., 1975). No significant effects were observed at PAN concentrations of
0.25 to 0.30 ppm, which are higher than the daily maximum concentrations of
PAN reported for relatively high oxidant areas (0.047 ppm). One study
(Drechsler-Parks et al., 1984) suggested a possible simultaneous effect of PAN
12-65
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and 0~; however, there are not enough data to evaluate the significance of
this effect.
Field and epidemic!ogical studies have found few specific relationships
between reported health effects and PAN concentrations. The increased preva-
lence of eye irritation reported during ambient air exposures has been asso-
ciated with PAN as well as other photochemical reaction products (National Air
Pollution Control Administration, 1970; Altshuller, 1977; National Research
Council, 1977; U.S. Environmental Protection Agency, 1978; Okawada et a!.,
1979). In one of these studies (Okawada et al., 1979), eye irritation was
produced experimentally in high school students at concentrations of PAN
>0.05 ppm. An increased incidence of other health Symptoms such as chest
discomfort was reported along with eye irritation as PAN concentrations in the
ambient air increased from 0 to 0.012 ppm (Javitz et al., 1983). However, the
significance of these symptomatic responses is questionable since functional
changes reported in this study for the subjects exposed to total oxidants (0,
and PAN) were similar to those found for 03 alone.
12.6.2 Effects of Hydrogen Peroxide
lexicological studies on HpOp have been performed at concentrations much
higher than those reported to occur in the ambient air (see Section 12.2). The
majority have been mechanistic studies using various iji vitro techniques for
exposure. Very limited information is available on the health significance of
inhalation exposure to gaseous hLQp in laboratory animals. No significant
effects" were observed in rats exposed for 7 days to >95 percent FLOp gas with
a concentration of 0.5 ppm in the presence of inhalable ammonium sulfate
particles (Last et al., 1982). Because HpQ2 is highly soluble, it is generally
assumed that it does not penetrate into the alveolar regions of the lung but
is instead deposited on the surface of the upper airways (Last et al., 1982).
Unfortunately, no studies have been designed to look for possible effects in
this region of the respiratory tract.
A few J_n vitro studies have reported cytotoxic, genotoxic, and biochemical
effects of H202 when using isolated cells or organs (Stewart et al., 1981;
Bradley et al., 1979; Bradley and Erickson, 1981; Spelt et al., 1982; MacRae
and Stich, 1979). Although these studies can provide useful data for studying
possible mechanisms of action, it is not yet possible to extrapolate these
responses to those that might occur in the mammalian system.
12-66
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12.6.3 Interactions with Other Pollutants
Controlled human exposures have not consistently demonstrated any enhance-
ment of respiratory effects for combined exposures of 03 with SO,,, NQ2, CO,
and HpS04 or other particulate aerosols. Ozone alone is considered to be
responsible for the observed effects of those combinations or with multiple
mixtures of these pollutants. Studies reviewed in the previous 0, criteria
document (U.S. Environmental Protection Agency, 1978) suggested that mixtures
of S02 and 03 at a concentration of 0.37 ppm are potentially more active than
would be expected from the behavior of the gases acting separately (Bates and
Hazucha, 1973; Hazucha and Bates, 1975). High concentrations of inhalable
aerosols, particularly H2S04 or ammonium sulfate, could have been responsible
for the results (Bell et al.s 1977). Subsequent studies, however, of 0,
mixtures with S02, H^SO,, or ammonium sulfate have not conclusively demonstrated
any interactive effects (Bedi et al., 1979, 1982; Kagawa and Tsuru, 1979c;
Kleinman et al., 1981; Kulle et al., 1982a; Stacy et al.s 1983).
Combined exposure studies in laboratory animals have produced varied
results, depending upon the pollutant combination evaluated, the exposure
design, and the measured variables. Additive or possibly synergistic effects,
or both, of Og exposure in combination with NQ2 have been described for increased
susceptibility to bacterial infection (Ehrlich et al., 1977, 1979; Ehrlich,
1980, 1983), morphological lesions (Freeman et al., 1974), and increased
antioxidant metabolism (Mustafa et al., 1984). Additive or possibly synergistic
effects from exposure to 03 and H2S04 have also been reported for host defense
mechanisms (Gardner et al.s 1977; Last and Cross, 1978; Grose et al., 1982),
pulmonary sensitivity (Osebold et al., 1980), and collagen synthesis (Last et
al., 1983), but not for morphology (Cavender et al., 1977; Moore and Schwartz,
1981). Mixtures of 03 and (NH.)2SO» had synergistic effects on collagen
synthesis and morphometry, including percentage of fibroblasts (Last et al.,
1983, 1984a).
Combining 03 with other particulate pollutants produces a variety of
responses in laboratory animals, depending on the endpoint measured. Mixtures
of 03, Fe2(S04)3, H2S04, and (NH4)2S04 produced the same effect on clearance
rate of particles from the lung as exposure to 0., alone (Phalen et al., 1980).
However, in studies measuring changes in host defenses, the combination of 03
with N02 and ZnS04 (Ehrlich, 1983) or 03 with S02 and (NH4)2S04 (Aranyi et al.,
1983) produced enhanced effects that can not be attributed to 03 only.
12-67
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Early studies in animals exposed to complex mixtures of UV-irradiated
auto exhaust containing oxidant concentrations of 0.2 to 1.0 ppm demonstrated
a greater number of effects compared to those reported for nonirradiated
exhaust (Chapter 9, Section 5.3). No significant differences were found in
the magnitude of the response either with or without the presence of sulfur
oxides in the mixture. Although the effects described in these studies would
be difficult to associate with any particular oxidant species, they are quali-
tatively similar to the general effects described for exposure to 03 alone.
One of the major limitations of field and epidemiological studies includes
the interference of other pollutants or potential interactions between 0- and
other pollutants in the environment, therefore limiting the usefulness of
these studies for standard-setting. Concerns raised about the relative contri-
bution to .untoward effects by pollutants other than 0, have been diminished
somewhat by direct comparative findings in exercising athletes showing no
differences in response between chamber exposures to oxidant-polluted ambient
air or to purified air containing an equivalent concentration of generated 03
(Avol et al., 1984). Nevertheless, there is still concern that combinations
of oxidant pollutants, including precursors of oxidants, may contribute to the
decreased function and exacerbation of symptoms reported in asthmatics
(Whittemore and Korn, 1980; Linn et al., 1980, 1983a; Lebowitz et al., 1982,
1983, 1985; Lebowitz, 1984; Holguin et al., 1985) and in children and young
adults (Lippmann et al., 1983; Lebowitz et al., 1982, 1983, 1985; Bock et al.,
1985; Lioy et al., 1985). Possible interactions between 0~ and total suspended
particulate matter have been reported with decreased expiratory flow in children
(Lebowitz et al., 1982, 1983, 1985; Lebowitz, 1984) and adults with symptoms
of airway obstructive disease (Lebowitz et al., 1982, 1983).
The effects of interactions between inhaled oxidant gases and other
environmental pollutants on the lung have not been systematically studied. In
fact, one of the major problems with the available literature on interaction
concerns the exposure design. Most of the controlled studies have not used
concentrations of combined pollutants that are found in the ambient environment.
In addition, no studies have been reported that used exposure regimens for
combined pollutants that are more representative of ambient ratios of peak
concentrations, frequency, duration, and time intervals between events, or that
examined sequential exposures to individual pollutants.
12-68
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12.7 IDENTIFICATION OF POTENTIALLY AT-RISK GROUPS
12.7.1 Introduction
The identification of the population or group to be protected by a national
ambient air quality standard depends upon a number of factors, including
(1) the identification of one or more specific biological endpoints (effects)
that individuals within the population should be protected from; and (2) the
identification of those individuals in whom those specific pollutant-induced
endpoints are (a) observed (b) observed at lower concentrations than in other
individuals, (c) observed with greater frequency than in other individuals,
(d) have greater consequences than in other individuals, or (e) observed with
various combinations of "effects levels," frequency, or consequences. In
addition to identification of effects and of groups susceptible to those
effects, other factors such as activity patterns and personal habits, as well
as actual and potential exposures to the pollutant in question, must be taken
into account when identifying one or more groups potentially at risk from
exposure to that pollutant.
In the following sections, biological and other factors that have been
\
found to predispose one or more groups to particular risk from exposure to
photochemical oxidants are discussed. It should be noted that these factors
are discussed in relation to ozone exposure only. There are too few controlled
studies with the other oxidants to permit a sound scientific evaluation of
their contribution to the toxic action of photochemical oxidant mixtures.
Furthermore, all of the controlled studies to date, both in humans and in experi-
mental animals, have utilized non-ozone oxidants at levels one order of magnitude
and more above the concentrations measured in ambient air. The health effects
of most concern, therefore, are those resulting from exposure to ozone. The
following sections also include estimates of the number of individuals in the
United States that fall into certain categories of potentially at-risk groups.
It must be emphasized that the final identification of those effects that
are considered "adverse" and the final identification of "at-risk" groups are
both the domain of the Administrator of the U.S. Environmental Protection Agency.
12.7.2 Potentially At-Risk Individuals
All studies have shown that there is a wide variation in sensitivity to
ozone among healthy subjects. The factors suspected of altering sensitivity
to ozone are numerous, but those actually known to alter sensitivity are few,
12-69
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largely because few have been examined adequately to determine definitively
their effects on sensitivity. The discussion below presents information on the
factors that are thought to have the potential for affecting sensitivity to
ozone, along with what is actually known from the data regarding the importance
of these factors. The terms "sensitivity" and "susceptibility" have been used
interchangeably in the Clean Air Act and are also used interchangeably in this
discussion.
Sensitivity to a specified dose of an air pollutant may be greater or
less than normal. Changes in sensitivity may arise from some prior exposure
or may result from cross-reactivity to chemicals. Individual differences in
sensitivity or an unusual response upon exposure cannot be explained at the
present time. Statistical analysis is generally relied upon to establish the
range of normal responses for a particular biological endpoint, and to distin-
guish between normal responses and those that are indicative of either increased
or decreased sensitivity.
Susceptibility may be conferred by some predisposing host factor, such as
immunological or biochemical factors; or by some condition, such as preexisting
disease. Susceptibility may also result from some aspect of the growth or
decline of lung development (e.g., greater bronchomotor tone in childhood,
loss of lung function in the elderly), or some previous infectious or immunolog-
ical process (e.g., childhood respiratory trouble, prior bronchiolitis or
other lower respiratory tract infections, and prior asthma). In most human
studies, the complex diagnostic procedures needed to classify study subjects
properly are not performed, nor is the mechanism of response usually determined
or even examined (i.e., underlying immunological, biochemical, or structural
character). In epidemiclogical studies, often not even baseline pulmonary
function pulmonary is determined. Furthermore, even diagnostic labels, such
as COLD, asthma, allergy, and atopy, are not usually based on sufficient
clinical evaluation nor standardized inclusion/exclusion criteria, so that
differences in such classifications within and between studies are bound to
occur. For example, there are few studies in which bronchoconstrictor
challenges, skin or blood antibody testing, or similar procedures were per-
formed, let alone radiograph!c studies, to characterize disease status.
Airway reactivity is affected by a variety of pharmacologic and non-phar-
macologic stimuli. The degree to which different stimuli act in a given
individual is determined by a complex set of mechanisms that may vary from
subject to subject and from time to time. Unfortunately, little information
12-70
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on these aspects of the study population is available so that reliance must be
placed on limited work-ups, non-standardized clinical evaluations and defini-
tions, and theoretical considerations. Thus, estimates of susceptible groups
are difficult to assess with any precision with presently available data.
Anthropomorphic and demographic characteristics that have been used to
attempt to characterize susceptible individuals in the general population
include gender, age, race, ethnic group, nutritional status, baseline lung
function, and immunological status. Many of these factors have implications
for the acquisition or progress of infectious and chronic diseases. For
example, the very young and very old members of the population, individuals
with inadequate nutrition, or individuals with depressed baseline lung function
may all be predisposed to susceptibility or sensitivity to ozone. None of
these factors, however, has been sufficiently studied in relation to CU exposure
to give definitive answers.
The most prominent modifier of response to 03 in the general population
is minute ventilation, which increases proportionately with increases in
exercise workload. Higher levels of exercise enhance the likelihood of in-
creased frequency of irritative symptoms and decrements in forced expiratory
volume and flow. However, even in well-controlled experiments on apparently
homogeneous groups of healthy subjects, physiological responses to the same
exercise levels and the same 0~ concentrations have been found to vary widely
among individuals.
Exposure history may determine susceptibility or sensitivity. Smokers,
for example, are more susceptible to impaired defense against infection, have
some chronic inflammation in the airways, have cellular damage, and may have
altered biochemical/cellular responses (e.g., reduced trypsin inhibitory
capacity, neutrophilia, impaired macrophage activity). Likewise, those with
"significant" occupational exposures to irritants, sensitizers or allergens
may have similar predispositions. Furthermore, both groups show differential
immunological status, atopy, and, in some cases, bronchomotor tone. Despite
these inferences, there is some evidence to suggest that smokers may be less
sensitive to Q~, although the available data are not conclusive.
Social, cultural, and economic factors, especially as they affect nutri-
tional status (e.g., vitamin E intake, anemia), may be important. While
animal studies with vitamin E indicate that differential responses may be
related to nutrition, no evidence exists to indicate that man would benefit
from increased vitamin E intake in relation to ambient ozone exposures.
12-71
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Another determinant of sensitivity is preexisting disease. Asthmatics,
who have variable airflow obstruction or reversible airway reactivity, or
both, and who may have altered immunological states (e.g., atopy, increased
immunoglobulin-E, possibly altered prostaglandin function and/or T-cell func-
tion) or cellular function (e.g., eosinophilia), may be expected to be poten-
tially more sensitive to Og. Asthma, however, is not a specific homogeneous
disease and efforts to define asthma precisely have been unsuccessful. Like-
wise, allergic individuals, with a predisposing atopy, have altered immunolog-
ical responses, similar to those in asthmatics, and may have labile bronchomotor
tone, such that they may also be expected to be potentially more sensitive to
Og. Patients with COLD may be expected to have a variable sensitivity to 03,
since they exhibit a wide diversity of clinical and functional states (see
Section 12.4.1). Although currently available evidence indicates that individ-
uals with preexisting disease respond to 0, exposure to a similar degree as
normal subjects, appropriate inclusion and exclusion criteria for selection of
these subjects, especially better clinical diagnoses validated by pulmonary
function, must be considered before their sensitivity to 03 can be adequately
determined. Furthermore, it should be noted that ethical constraints have
precluded the testing in controlled studies of individuals with severe pre-
existing disease. It is also prudent to consider carefully whether small
functional changes in individuals with COLD, asthma, or allergy represent
equivalent or more severe physiological significance compared to the normal
subject.
12.7.3 Potentially At-Risk Groups
As the preceding discussion and discussions in Sections 12.3 and 12.4
indicate, only small samples of the population, either of healthy individuals
or those with preexisting disease, have been tested. Definitive data on the
relative susceptibilities to ozone of various kinds of individual subjects are
therefore lacking, both in epidemiological and control!ed-exposure studies.
Notwithstanding the uncertainties that exist in the data, it is possible to
identify the groups that might be at potential risk from ozone-induced effects
if exposed under certain conditions. The following discussion deals with
potential risk only, not actual risk. Actual risk must be estimated (1) in
conjunction with actual exposure to ozone, as opposed to potential exposure; »
(2) in conjunction with any factors known to modify the effects of ozone, such
12-72
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as exercise; and (3) in conjunction with the existing uncertainties in the
data on the effects of ozone from controlled, field, or epidemiologic studies.
In the legislative history of Section 109 of the Clean Air Act (U.S.
Senate, 1970), the definition of a "sensitive population" excludes "individuals
who are otherwise dependent on a controlled internal environment" but includes
"particularly sensitive citizens . . . who in the normal course of daily
activity are exposed to the ambient environment." Early research demonstrated
that the respiratory system is affected by exposure to certain air pollutants,
including ozone, nitrogen dioxide, and other oxidants. As a consequence,
Congress took note of pollutant effects on the respiratory system and gave
bronchial asthmatics and emphysematics as examples of "particularly sensitive"
individuals. With regard to research on health effects, Congress has noted
that attention should go beyond "normal segments of the population to effects
on the very young, the aged, the infirm, and other susceptible individuals."
Concern should be given to the "contribution of age, ethnic, social, occupa-
tional, smoking, and other factors to susceptibility to air pollution agents."
Consonant with the provisions of the Clean Air Act and with its legisla-
tive history, the first group that appears to be at potential risk from exposure
to ozone is that group of the general population characterized as having
preexisting respiratory disease. In the case of asthmatics, in particular,
emerging data from controlled studies indicate no greater responsiveness to
ozone in mild asthmatics than in the normal, healthy population. Data from
epidemiological studies continue to introduce an element of uncertainty
regarding the potential risk from exposure to ambient air in asthmatics. The
epidemiological studies, however, lack definitive information on the effects
of ozone alone, since there is confounding by the presence of other pollutants
(e.g., inhalable particles) and environmental conditions (e.g., temperature)
in ambient air (see Section 12.4.2). Furthermore, it must be emphasized that
neither controlled nor epidemiological or field studies give any indication
that asthmatics are less responsive to ozone exposure than healthy individuals.
In the case of individuals with COLD, clinical and functional states vary
widely, and responsiveness to ozone exposure may also vary accordingly (see
Section 12.4.1).
Nevertheless, several important considerations place individuals with
preexisting respiratory disease among groups at potential risk from exposure
to ozone. First, it must be noted that concern with triggering untoward
reactions has necessitated the use of low concentrations and low exercise
12-73
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levels in most studies on subjects with preexisting disease as well as the
involvement only of subjects clinically diagnosed as having mi Id-to-moderate,
but not severe, disease. As a result, few or no data on responses at higher
concentrations, at higher exercise levels, or in subjects with more severe
disease states are available for comparison with responses in normal subjects.
Second, subjects in controlled studies may not have been adequately characterized
in all instances regarding disease state. Thus, definitive data on the modifi-
cation by preexisting disease of responses to ozone are not available. Third,
the effects that ozone may have on groups with preexisting disease may not be
measured by traditional tests of lung function and the identification of such
effects may require the use of different tests or may have to await new
technological developments. Finally, it must be emphasized that in individuals
with already compromised pulmonary function, the decrements in function produced
by exposure to ozone, while similar to or even the same as those experienced
by normal subjects, represent a further decline in volumes and flows that are
already diminished. It is possible that such declines may impair further the
ability to perform normal activities involving exercise. Although many individ-
uals with preexisting disease would not be expected to exercise at the levels
at which healthy individuals exercise, any increase in activity level would
bring about a commensurate increase in minute ventilation, which is a potentiator
of ozone-induced effects. In individuals with preexisting diseases such as
asthma or allergies, increases in symptoms upon exposure to ozone, above and
beyond symptoms seen in the general population, may also impair or further
curtail the ability to function normally.
The second group at potential risk from exposure to ozone consists of the
general population of normal, healthy individuals (i.e., not diagnosed as
having preexisting respiratory disease). Data presented in Chapter 10 and
discussed in preceding sections of this chapter indicate that two factors
place members of the general population at potential risk from exposure to
ozone: (1) unusual responsiveness to ozone in some members of the general
population; and (2) potentiation by exercise of the effects induced by ozone
at any given concentration.
Unusual responsiveness to ozone has been observed in isome individuals
("responders"), not yet characterized medically except by their response to
ozone, who experience greater decrements in lung function from exposure to
ozone than the average response of the groups studied. It is not known if
12-74
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"responders" are a specific population subgroup or simply represent the upper
5 to 20 percent of the ozone response distribution. As yet no means of deter-
mining in advance those members of the general population who are "responders"
has been devised. It is important to note here what has been discussed previ-
ously in this chapter and in Chapter 10; that is, the group means presented in
Chapter 10 (and the references therein) and in Figures 12-2 through 12-5 (and
Table 12-3) include values for the "responders" in the respective study cohorts
of otherwise healthy, normal subjects; and reflect the sometimes dramatic
decrements seen in those individuals.
Data presented in Chapter 10 and in this chapter underscore the importance
of exercise in the potentiation of effects from exposure to ozone. Thus, the
general population potentially at risk from exposure to ozone includes those
individuals whose activities out of doors, whether vocational or avocational,
result in increases in minute ventilation. As stated in section 12.7.2, "the
most prominent modifier of response to 0~ in the general population is minute
ventilation, which increases proportionately with increases in exercise workload."
As pointed out in this chapter, other biological and nonbiological factors
are suspected of influencing responses to ozone. Data remain inconclusive at
the present, however, regarding the importance of age, gender, and other
factors in influencing response to ozone. Thus, at the present time, no
groups are thought to be at potential risk from exposure to ozone in ambient
air through biological predisposition or activity patterns other than those
identified in this section.
12.7,4 Demographic Distribution of the General Population
The U.S. Bureau of the Census periodically provides an updated statistical
summary of the U.S. population by conducting a decennial survey, supplemented
by monthly surveys of representative population samples. The complete census
represents a total count of the population since an attempt is made to account
for the social, economic, and housing characteristics of every residence. In
determining residence, the census counts.the place where eating and sleeping
usually take place rather than counting a person's legal or voting residence.
Each residence is, in turn, grouped according to the official standard
metropolitan statistical areas (SMSA's) and standard consolidated statistical
areas (SCSA's) as defined by the Office of Management and Budget. Briefly,
12-75
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SMSA's represent a large population nucleus together with adjacent communities
which have a high degree of social and economic integration; SCSA's are large
metropolitan complexes consisting of groups of closely related adjacent SMSA's.
Table 12-6 gives the geographical distribution of the resident population of
the United States for 1980 (U.S. Bureau of the Census, 1982). The entire
territory of the United States is classified as metropolitan (inside SMSA's)
or nonmetropolitan (outside SMSA's). According to the 1980 census, the urban
population comprises all persons living in cities, villages, boroughs, and
towns of 2500 or more inhabitants. Additional data on age, sex, and race
obtained from the 1980 census are shown in Table 12-7. Evaluation of previous
census data indicated a total net underenumeration rate of about 2.2 percent
in 1970 and 2.7 percent in 1960. Although estimates for 1980 have not been
published, preliminary results indicated that overall coverage improved in the
1980 census. Census data presented in Tables 12-6 and 12-7 have not been
adjusted for underenumeration.
12.7.5 Demographic Distribution of Individuals with Chronic Respiratory
Conditions
Certain subpopulations have been identified as potentially-at-risk to
ozone or photochemical oxidant exposure by virtue of preexisting respiratory
conditions like chronic obstructive lung disease (COLD) and asthma. Each year
the National Health Interview Survey (HIS) conducted by the National Center
for Health Statistics (NCHS) reports the prevalence of chronic respiratory
conditions in the United States. These conditions are classified by type,
according to the Ninth Revision of the International Classification of Diseases
adopted for use in the United States (World Health Organization, 1977).
According to NCHS, a condition was considered to be chronic if it had been
documented by a physician more than three months before the interview was
conducted. In the HIS for 1979 (U.S. Department of Health and Human Services,
1981) COLD was not listed as a specific medical condition since it is a clinical
term and not generally recognized by the general public. However, this term
has been used with increasing frequency by physicians rather than the more
common terms chronic bronchitis and emphysema in classifying chronic airways
obstruction. As a result, there may be an underestimation by the HIS of the
true prevalence of this disorder.
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TABLE 12-6. GEOGRAPHICAL DISTRIBUTION OF THE RESIDENT POPULATION
OF THE UNITED STATES, 1980a
Residence
Total
Northeast
North Central
South
West
Metropolitan areas
Central cities
Outside central cities
Nonmetropolitan areas
Urban0
Rural
Population,
millions
226.5
49.1
58.9
75.4
43.2
169.4
68.0
101.5
57.1
167.1
59.5
Population,
percent
100.0
21.7
26.0
33.3
19.0
74.8
30.0
44.8
25.2
73.7
26.3
aU.S. Bureau of the Census (1982).
Represented by 318 standard metropolitan statistical areas (SMSA's).
Comprises all persons living in cities, villages, boroughs, and towns of
2500 or more inhabitants but excluding those persons living in the rural
portions of extended cities.
The estimated prevalence of chronic bronchitis, emphysema, and asthma in
the United States is shown in Table 12-8 for the year 1979 (U.S. Department of
Health and Human Services, 1981). All three respiratory conditions combined
accounted for over 16 million individuals in 1979, representing 7.5 percent of
the population. Approximately one-third of the individuals with chronic
bronchitis and asthma were under 17 years of age. An additional 15 to 16
million persons reported having hay fever and other upper respiratory allergies.
Accounting for an underestimation by the HIS, the total number of individuals
with documented and undocumented respiratory conditions in the United States
may be as high as 47 million, which is approximately 20 percent of the popula-
tion.
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TABLE 12-7. TOTAL POPULATION OF THE UNITED STATES
BY AGE, SEX, AND RACE, 1980a
Age, sex, race
Total
Under 5 years
5-17 years
18-44 years
45-64 years
65 years and over
Male
Female
Black^
Other0
Population,
millions
226.5
16.3
47.1
93.3
44.4
25.5
110.0
116.5
194.8
26.6
5.1
Population,
percent
100.0
7.2
20.8
41.2
19.6
11.3
48.6
51.4
86.0
11.7
2.3
aU.S. Bureau of the Census (1982).
Data represent self-classification according to 15 groups listed on the 1980
census questionnaire: White, Black, American, Indian, 'Eskimo, Aleut,
Chinese, Filipino, Japanese, Asian Indian, Korean, Vietnamese, Hawaiian,
Samoan, Guamanian, and Other.
12.8 SUMMARY AND CONCLUSIONS
12.8.1 Health Effects in the General Human Population
Controlled human studies of at-rest exposures to 03 lasting 2 to 4 hr
have demonstrated decrements in forced expiratory volume and flow occurring at
and above 0.5 ppm of 03 (Chapter 10). Airway resistance was not significantly
changed at these 03 concentrations. Breathing 03 at rest at concentrations
< 0.5 ppm did not significantly impair pulmonary function although the occur-
rence of some On-related pulmonary symptoms has been suggested in a number of
studies.
One of the principal modifiers of the magnitude of response to 03 is
minute ventilation (VV), which increases proportionately with increases in
exercise work load. Adjustment by the respiratory system to an increased work
load is characterized by increased frequency and depth of breathing. Consequent
increases in vV not only increase the overall volume of inhaled pollutant, but
the increased tidal volume may lead to a higher concentration of ozone in the
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TABLE 12-8. PREVALENCE OF CHRONIC RESPIRATORY CONDITIONS BY SEX AND AGE FOR 1979C
Number of persons, In thousands
t— »
ro
i
"•4
UD
Condition
Chronic bronchitis
Emphysema
Asthma6
Hay fever and
other upper
respiratory
allergies
Total0
7474
2137
6402
15,620
Male
3289
1364
3113
7027
Femal e
4175
770
3293
8584
<17
years old
2458
12d
2225
3151
17-44
years old
2412
127d
2203
8278
45-64
years old
1547
1008
1482
3012
>65
years old
1060
990
488
1181
% of U.S.
population
3.5
1.0
3.0
7.2
U.S. Department of Health and Human Services, 1981.
Classified by type, according to the Ninth Revision of the International Classific of Diseases (World Health
Organization, 1977).
£
Reported as actual number in thousands; remaining subsets have been calculated from percentages and are rounded off.
Does not meet standards of reliability or precision set by the National Center for Health Statistics (more than 30%
relative standard error).
eWith or without hay fever.
Without asthma.
-------
lung regions most sensitive to ozone. These processes are further enhanced at
high work loads (VE > 35 L/min), since the mode of breathing changes at that
VV from nasal to oronasal.
Statistically significant decrements in forced expiratory volume and flow
are generally observed in healthy adult subjects (18 to 45 yr old) after 1 to
3 hr of exposure as a function of the level of exercise performed and the
ozone concentration inhaled during the exposure. Group mean data pooled from
numerous controlled human exposure (Chapter 10) and field (Chapter 11) studies
Indicate that, on average, pulmonary function decrements occur:
1. At >0.37 ppm 03 with light exercise (V£ < 23 L/min);
2. At >0.30 ppm 07 with moderate exercise (Vc = 24-43 L/min);
***" O El
3. At >0.24 ppm 0~ with heavy exercise (VV = 44-63 L/min); and
4. At >0.18 ppm Og with very heavy exercise (VV > 64 L/min).
Note, however, that data from specific individual studies indicate that pulmonary
function decrements occur with very heavy exercise in healthy adults at 0.15
to 0.16 ppm 03 (Avol et a!., 1984) and suggest that such effects may occur
in healthy adults at levels as low as 0.12 ppm 03 (McDonnell et a!., 1983).
Also, pulmonary function decrements have been observed in children and adoles-
cents at concentrations of 0.12 and 0.14 ppm 0~ with heavy exercise (McDonnell
et a!., 1985b; Avol et a!., 1985a). At the lower 03 concentrations (0.12 to
0.15 ppm), the average changes in lung function are generally small (<5 percent)
and are a matter of controversy in regard to their medical significance.
In the majority of the studies reported, 15-min intermittent exercise
alternated with 15-min rest was employed for the duration of the exposure.
Figure 12-6 uses the pulmonary function measurement FEV-, to illustrate the
effects of intermittent exercise and 0~ concentration during 2-hr exposures.
As noted above, larger decrements in lung function occur at higher exercise
levels and at higher 03 concentrations. The maximum response to 03 exposure
can be observed within 5 to 10 rain following the end of each exercise period.
Other measures of spirometric pulmonary function (e.g., FVC and FEF25_75^) are
consistent with FEV.. and, therefore, are not depicted here. It is important
to note, however, that any predictions of average pulmonary function responses
to 03 only apply under the specific set of exposure conditions at which these
data were derived.
12-80
-------
I\J
I
CD
110
I 100
«
a
*
LU
90
O
>
DC
O
X 80
Q
ui
U
QT
O
g 70
CO
60
*•.. LIGHT EXERCISE
VERY HEAVY
EXERCISE
HEAVY
EXERCISE
MODERATE
EXERCISE
0.2 0.4
OZONE CONCENTRATION, ppm
0.6
0.8
Figure 12-6. Group mean decrements in 1 -sec forced expiratory volume during 2-hr ozone(
exposures with different levels of intermittent exercise: light (v*|= < 23 L/min); moderate (V
24-43L/min); heavy (V"E = 44-63 L/min); and very heavy (v*£ ^ 64 L/min). Concentration-
response curves are taken from Figures 12-2 through 12-5.
-------
Continuous exercise equivalent in duration to the sum of intermittent
exercise periods at comparable ozone concentrations (0.2 to 0.4 ppm) and
minute ventilation (60 to 80 L/min) seems to elicit greater changes in pulmonary
function (Folinsbee et al., 1984; Avol et al., 1984, 1985c) but the differences
between intermittent and continuous exercise are not clearly established.
More experimental data are needed to make any quantitative evaluation of the
differences in effects induced by these two modes of exercise.
Functional recovery, at least from a single exposure with exercise,
appears to progress in two phases: during the initial rapid phase, lasting
between 1 and 3 hr, pulmonary function improves more than 50 percent; this is
followed by a much slower recovery that is usually completed in most subjects
within 24 hr. In some individuals, an enhanced responsiveness to a second 0-
challenge may persist for up to 48 hr (Bedi et al., 1985; Folinsbee and Horvath,
1986). In addition, despite apparent functional recovery, other regulatory
systems may still exhibit abnormal responses when stimulated; e.g., airway
hyperreactivity may persist for days.
Group mean changes may be useful for making statistical inferences about
homogeneous populations, but they are not adequate for describing differences
in-responsiveness to 0, among individuals. Even in well-controlled experiments
on an apparently homogeneous group of healthy subjects, physiological responses
to the same work and pollutant loads will vary widely among individuals (Horvath
et al., 1981; Gliner et al., 1983; McDonnell et al., 1983; Kulle et al., 1985).
Despite large intersubject variability, individual responsiveness to a given
DO concentration is quite reproducible (Gliner et al., 1983; McDonnell et al.,
1985a). Some individuals, therefore, are consistently more responsive to 0,
than are others. The term "responders" has been used to describe the 5 to 20
percent of the studied population that is most responsive to 0,, exposure.
There are no clearly established criteria to define this group of subjects.
Likewise, there are no known specific factors responsible for increased or
decreased responsiveness to 0,. Characterization of individual responses to
0~, however, is pertinent since it permits the assessment of a segment of the
general population that is potentially at-risk to 0, exposure (see Section
12.7.3) although statistical treatment of these data is still rudimentary and
their validity is open to question.
12-82
-------
A close association has been observed between the occurrence of respiratory
symptoms and changes in pulmonary function in adults acutely exposed in environ-
mental chambers to CU (Chapter 10) or to ambient air containing 03 as the
predominant p.ollutant (Chapter 11). This association holds for both the
time-course and magnitude of effects. Studies on children and adolescents
exposed to 0, or ambient air containing CU under similar conditions have found
no significant increases in symptoms despite significant changes in pulmonary
function (Avol et al., 1985a,b; McDonnell et al., 1985b,c). Epidemiological
studies of exposure to ambient photochemical pollution are of limited use for
quantifying exposure-response relationships for 0~ because they have not
adequately controlled for other pollutants, meteorological variables, and
non-environmental factors in the data analysis. Eye irritation, for example,
one of the most common complaints associated with photochemical pollution, is
not characteristic of clinical exposures to 0,, even at concentrations several
times higher than any likely to be encountered in ambient air. There is
limited qualitative evidence to suggest that at low concentrations of CL,
other respiratory and nonrespiratory symptoms, as well, are more likely to
occur in populations exposed to ambient air pollution than in subjects exposed
in chamber studies (Chapter 11).
Discomfort caused by irritative symptoms may be responsible for the
impairment of athletic performance reported in high school students during
cross-country track meets in Los Angeles (Chapter 11). Only a few control!ed-
exposure studies, however, have been designed to examine the effects of 0^ on
exercise performance (Chapter 10). In one study, light intermittent exercise
(Vp = 20-25 L/min) at a high 0~ concentration (0.75 ppm) reduced postexposure
maximal exercise capacity by limiting maximal oxygen consumption; submaximal
oxygen consumption changes were not significant. The extent of ventilatory
and respiratory metabolic changes observed .during or following the exposure
appears to have been related to the magnitude of pulmonary function impairment.
Whether such changes are consequent to respiratory discomfort (i.e., symptomatic
effects) or are the result of changes in lung mechanics or both is still
unclear and needs to be elucidated.
Environmental conditions such as heat and relative humidity may alter
subjective symptoms and physiological impairment associated with 0, exposure.
Modification of the effects of 0- by these factors may be attributed to in-
creased ventilation.associated with elevated body temperature but there may
12-83
-------
also be an independent effect of elevated body temperature on pulmonary function
(VC). . . , ,
Numerous additional factors have the potential for altering responsiveness
to ozone. For example, children and older individuals may be more responsive
than young adults. Other factors such as gender differences (at any age),
personal habits such as smoking, nutritional deficiencies, or differences in
immunologic status may predispose individuals to susceptibility to ozone. In
addition, social, cultural, or economic factors may be involved. Those actually
known to alter sensitivity, however, are few, largely because they have not
been examined adequately to determine definitively their effects on sensitivity
to 0~. The following briefly summarizes what is actually known from the data
regarding the importance of these factors (see Section 12.3.3 for details);
!• Age- Although changes in growth and development of the lung with
age have been postulated as one of many factors capable of modifying responsive-
ness to 03, sufficient numbers of studies have not been performed to provide
any sound conclusions for effects of different age groups on responsiveness
to 03.
2. Sex. Sex differences in responsiveness to ozone have not been
adequately studied. Lung function of women, as assessed by changes in FEV-. Q,
might be affected more than that of men under similar exercise and exposure
conditions, but the possible differences have not been tested systematically.
3. Smoking Status. Differences between smokers and nonsmokers have
been studied often, but the smoking histories of subjects are not documented
well. There is some evidence, however, to suggest that smo.kers may be less
responsive to 0, than nonsmokers.
4. Nutriti onal Status. Antioxidant properties of vitamin E in preventing
ozone-initiated peroxidation i_n vitro are well demonstrated and their protective
effects i_n vivo are clearly demonstrated in rats and mice. No evidence indi-
cates, however, that man would benefit from increased vitamin E intake relative
to ambient ozone exposures.
5. Red Blood Cell Enzyme Deficiencies. There have been too few studies
performed to document reliably that individuals with a hereditary deficiency
of glucose-6-phosphate dehydrogenase may be at-risk to significant hematolog-
ical effects from 03 exposure. Even if 03 or a reactive product of Og-tissue
12-84
-------
interaction were to penetrate the red blood cell after jji vivo exposure, it is
unlikely that any depletion of glutathione or other reducing compounds would
be of functional significance for the affected individual.
Successive daily brief exposures of healthy human subjects to 0~ (<0,7 ppm
for approximately 2 hr) induce a typical temporal pattern of response (Chap-
ter 10, Section 10.3). Maximum functional changes that occur after the first
or second exposure day become progressively attenuated on each of the subsequent
days. By the fourth day of exposure, the average effects are not different
from those observed following control (air) exposure. Individuals need between
3 and 7 days of exposure to develop full attenuation, with more sensitive
subjects requiring more time. The magnitude of a peak response to CL appears
to be directly related to Og concentration. It is not known how variations in
the length or frequency of exposure will modify the time course of this altered
responsiveness. In addition, concentrations of 0« that have no detectable
effect appear not to invoke changes in response to subsequent exposures at
higher 0~ concentrations. Full attenuation, even in ozone-sensitive subjects,
does not persist for more than 3 to 7 days after exposure in most individuals,
while partial attenuation might persist for up to 2 weeks. Although the
severity of symptoms "is generally related to the magnitude of the functional
response, partial attenuation of symptoms appears to persist longer, for up to
4 weeks after exposure.
Whether populations exposed to photochemical air pollution develop at
least partial attenuation is unknown. No epidemiological studies have been
designed to test this hypothesis and additional information is required from
controlled laboratory studies before any sound conclusions can be made.
Ozone toxicity, in both humans and laboratory animals, may be mitigated
through altered responses at the cellular and/or subcellular level. At present,
the mechanisms underlying altered responses are unclear and the effectiveness
of such mitigating factors in protecting the long-term health of the indivi-
dual against ozone is still uncertain. A growing body of experimental evidence
suggests the involvement of vagal sensory receptors in modulating the acute
responsiveness to ozone. It is highly probable that most of the decrements in
lung volume reported to result from exposures of greatest relevance to standard-
setting (£0.3 ppm 0™) are caused by the inhibition of maximal inspiration rather
than by changes in airway diameter. None of the experimental evidence, however,
12-85
-------
is definitive and additional research is needed to elucidate the precise
mechanism(s) associated with ozone exposure.
12.8.2 Health Effects inIndividuals with Preexisting Disease
Currently available evidence indicates that individuals with preexisting
disease respond to Q~ exposure to a similar degree as normal, healthy subjects.
Patients with chronic obstructive lung disease and/or asthma have not shown
increased responsiveness to 0~ in controlled human exposure studies, but there
is some indication from epidemiological studies that asthmatics may be sympto-
matically and possibly functionally more responsive than healthy individuals
to ambient air exposures. Appropriate inclusion and exclusion criteria for
selection of these subjects, however, especially better clinical diagnoses
validated by pulmonary function, must be considered before their responsiveness
to OQ can be adequately determined. None of these factors has been sufficiently
studied in relation to 0"3 exposures to give definitive answers,
12.8.3 Extrapolation of Effects Observed in Animals to HumanPopulations
Animal experiments on a variety of species have demonstrated increased
susceptibility to bacterial respiratory infections following 0, exposure.
Thus, it could be hypothesized that humans exposed to 0- could experience
decrements in their host defenses against infection. At the present time,
however, these effects have not been studied in humans exposed to Q».
Animal studies have also reported a number of extrapulmonary responses to
Og, including cardiovascular, reproductive, and teratological effects, along
with changes in endocrine and metabolic function. The implications of these
findings for human health are difficult to judge at the present time. In
addition, central nervous system effects, alterations in red blood cell mor-
phology and enzymatic activity, as well as cytogenetic effects on circulating
lymphocytes, have been observed in laboratory animals following exposure to
0~. While similar effects have been described in circulating cells from human
subjects exposed to high concentrations of Og, the results were either incon-
sistent or of questionable physiological significance (Section 12.3.8). It is
not known, therefore, if extrapulmonary responses would be likely to occur in
humans when exposure schedules are used that are representative of exposures
that the population at large might actually experience.
12-86
-------
Despite wide variations in study techniques and experimental designs,
acute and subchronic exposures of animals to levels of ozone < 0.5 ppm produce
remarkably similar types of responses in all species examined. A characteristic
ozone lesion occurs at the junction of the conducting airways and the gas-
exchange regions of the lung after acute 03 exposure. Dosimetry model simula-
tions predict that the maximal tissue dose of 0, occurs in this region of the
lung. Continuation of the inflammatory process during longer G\ exposures is
especially important since it appears to be correlated with increased airway
resistance, increased lung collagen content, and remodeling of the centriacinar
airways, suggesting the development of distal airway narrowing. No convincing
evidence of emphysema in animals chronically exposed to 0~ has yet been pub-
lished, but centriacinar inflammation has been shown to occur.
Since substantial animal data exist for CU-induced changes in lung struc-
ture and function, biochemistry, and host defenses, it is conceivable that man
may experience more types of effects from exposure to ozone than have been
established in human clinical studies. It is important to note, however, that
the risks to man from breathing ambient levels of ozone cannot fully be deter-
mined until quantitative extrapolations of animal results can be made.
12.8.4 HealthEffects of Other Photochemical Oxidants and Pollutant Mixtures
Controlled human studies have not consistently demonstrated any modifica-
tion of respiratory effects for combined exposures of 0., with SO,,, N02» CO, or
HpSQ. and other particulate aerosols. Ozone alone is considered to be respon-
sible for the observed effects of those combinations or of multiple mixtures
of these pollutants. Combined exposure studies in laboratory animals have
produced varied results, depending upon the pollutant combination evaluated,
the exposure design, and the measured variables (Section 12.6.3). Thus, no
defjnitive conclusions can be drawn from animal studies of pollutant interac-
tions. There have been far too few controlled toxicological studies with
other oxidants, such as peroxyacetyl nitrate or hydrogen peroxide, to permit a
sound scientific evaluation of their contribution to the toxic action of
photochemical oxidant mixtures. There is still some concern, however, that
combinations of oxidant pollutants with other pollutants may contribute to the
symptom aggravation and decreased lung function described in epidemiologicai
studies on individuals with asthma and in children and young adults. For this
reason, the effects of interaction between inhaled oxidant gases and other
12-87
-------
environmental pollutants on the lung need to be systematically studied using
exposure regimens that are more closely representative of ambient air ratios
of peak concentrations, frequency, duration, and time intervals between events.
12.8.5 Identification ofPotentially At-Risk Groups
Despite uncertainties that may exist in the data, it is possible to
identify the groups that may be at potential risk from exposure to ozone,
based on known health effects, activity patterns, personal habits, and actual
or potential exposures to ozone.
The first group that appears to be at potential risk from exposure to
ozone is that group of the general population characterized as having preex-
isting respiratory disease. Available data on actual differences in responsive-
ness between these and healthy members of the general population indicate
that, under the exposure conditions studied to date, individuals with pre-
existing disease are as responsive to ozone as healthy individuals. Neverthe-
less, two primary considerations place individuals with preexisting respiratory
disease among groups at potential risk from exposure to ozone. First, it must
be noted that concern with triggering untoward reactions has necessitated the
use of low concentrations and low exercise levels in most studies on subjects
with mild, but not severe, preexisting disease. Therefore, few or no data on
responses at higher concentrations, at higher exercise levels, and in subjects
with more severe disease states are available for comparison with responses in
healthy subjects. Thus, definitive data on the modification by preexisting
disease of responses to ozone are not available. Second, however, it must be
emphasized that in individuals with already compromised pulmonary function,
the decrements in function produced by exposure to ozone, while similar to or
even the same as those experienced by normal subjects, represent a further
decline in volumes and flows that are already diminished. It is possible that
such declines may impair further the ability to perform normal activities. In
individuals with preexisting diseases such as asthma or allergies, increases
in symptoms upon exposure to ozone, above and beyond symptoms seen in the
general population, may also impair or further curtail the ability to function
normally.
The second group at potential risk from exposure to ozone consists of the
general population of normal, healthy individuals. Two specific factors place
members of the general population at potential risk from exposure to ozone.
First, unusual responsiveness to ozone has been observed in some individuals
12-88
-------
("responders"), not yet characterized medically except by their response to
ozone, who experience greater decrements in lung function from exposure to
ozone than the average response of the groups studied. It is not known if
"responders" are a specific population subgroup or simply represent the upper
5 to 20 percent of the ozone response distribution. As yet no means of deter-
mining in advance those members of the general population who are "responders"
has been devised. Second, data presented in this chapter underscore the
importance of exercise in the potentiation of effects from exposure to ozone.
Thus, the general population potentially at risk from exposure to ozone includes
those individuals whose activities out of doors, whether vocational or avocational,
result in increases in minute ventilation, which is the most prominent modifier
of response to ozone.
Other biological and nonbiological factors have the potential for influ-
encing responses to ozone. Data remain inconclusive at the present, however,
regarding the importance of age, gender, and other factors in influencing
response to ozone. Thus, at the present time, no other groups are thought to
be biologically predisposed to increased sensitivity to ozone. It must be
emphasized, however, that the final identification of those effects that are
considered "adverse" and the final identification of "at-risk" groups are both
the domain of the Administrator of the U.S. Environmental Protection, Agency.
12-89
-------
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APPENDIX A: GLOSSARY OF PULMONARY TERMS AND SYMBOLS*
Acetylcholine (ACh): A naturally occurring substance in the body having
important parasympathetic effects; often used as a bronchoconstrictor.
Aerosol: Solid particles or liquid droplets that are dispersed or suspended
in a gas, ranging in size from 10 to 10 micrometers (urn).
Air spaces: All alveolar ducts, alveolar sacs, and alveoli. To be contrasted
with AIRWAYS.
Airway conductance (Gaw): Reciprocal of airway resistance. Gaw = (I/Raw).
Airway resistance (Raw): The (frictional) resistance to airflow afforded by
the airways between the airway opening at the mouth and the alveoli.
Airways: All passageways of the respiratory tract from mouth or nares down to
and including respiratory bronchioles. To be contrasted with AIR SPACES.
Allergen: A material that, as a result of coming into contact with appropriate
tissues of an animal body, induces a state of allergy or hypersensitivity;
generally associated with idiosyncratic hypersensitivities.
Alveolar-arterial oxygen pressure difference [P(A-a)0?]: The difference in
partial pressure of 0? in the alveolar gas spaces and that in the systemic
arterial blood, measured in torr.
Alveolar-capillary membrane: A fine membrane (0.2 to 0.4 prn) separating
alveolus from capillary; composed of epithelial cells lining the alveolus,
a thin layer of connective tissue, and a layer of capillary endothelial
cells.
Alveolar carbon dioxide pressure (P.CQ?): Partial pressure of carbon dioxide
in the air contained in the lung alveoli.
Alveolar oxygen partial pressure (PyvO™): Partial pressure of oxygen in the
air contained in the alveoli or tne lungs.
Alveolar septum (pi. septa): A thin tissue partition between two adjacent
pulmonary alveoli, consisting of a close-meshed capillary network and
interstitium covered on both surfaces by alveolar epithelial cells.
^References: Bartels, H.; Dejours, P.; Kellogg, R. H.; Mead, J. (1973) Glossary
on respiration and gas exchange. J. Appl. Physiol. 34: 549-558.
American College of Chest Physicians - American Thoracic Society
(1975) Pulmonary terms and symbols: a report of the ACCP-ATS
Joint Committee on pulmonary nomenclature. Chest 67: 583-593.
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Alveolitis: (interstitial pneumonia): Inflammation of the lung distal to the
terminal non-respiratory bronchiole. Unless otherwise indicated, it is
assumed that the condition is diffuse. Arbitrarily, the term is not used
to refer to exudate in air spaces resulting from bacterial infection of
the lung.
Alveolus: Hexagonal or spherical air cells of the lungs. The majority of
alveoli arise from the alveolar ducts which are lined with the alveoli.
An alveolus is an ultimate respiratory unit where the gas exchange takes
place. >••
Anatomical dead space (VQ ana+): Volume of the conducting airways down to the
level where, during air oreathing, gas exchange wi:£h blood can occur, a
region probably situated at the entrance of the alveolar ducts.
Arterial oxygen saturation (SaO?): Percent saturation of dissolved oxygen in
arterial blood. ;:
Arterial partial pressure of carbon dioxide (PaC02): Partial pressure of
dissolved carbon dioxide in arterial blood.
Arterial partial pressure of oxygen (PaO,,): Partial pressure of dissolved
oxygen in arterial blood.
Asthma: A disease characterized by an increased responsiveness of the airways
to various stimuli and manifested by slowing of forced expiration which
changes in severity either spontaneously or as a result of therapy. The
term asthma may be modified by words or phrases indicating its etiology,
factors provoking attacks, or its duration.
Atelectasis: State of collapse of air spaces with elimination of the gas
phase.
ATPS condition (ATPS): Ambient temperature and pressure, saturated with water
vapor. These are the conditions existing in a water spirometer.
Atropine: A poisonous white crystalline alkaloid, C-jjhL-NO-j, from belladonna
and related plants, used to relieve spasms of sTnodtn muscles. It is an
anticholinergic agent.
Breathing pattern: A general term designating the characteristics of the
ventilatory activity, e.g., tidal volume, frequency of breathing, and
shape of the volume time curve.
Breuer-Hering reflexes (Hering-Breuer reflexes): Ventilatory reflexes originat-
ing in the lungs. The reflex arcs are formed by the pulmonary mechanore-
ceptors, the vagal afferent fibers, the respiratory centers, the modulio-
spinal pathway, the motor neurons, and the respiratory muscles. The af-
ferent link informs the respiratory centers of the volume state or of the
rate of change of volume of the lungs. Three types of Breuer-Hering re-
flexes have been described: 1) an inflation reflex in which lung inflation
tends to inhibit inspiration and stimulate expiration; 2) a deflation
reflex in which lung deflation tends to inhibit expiration and stimulate
inspiration; and 3) a "paradoxical reflex," described but largely disre-
garded by Breuer and Hering, in which sudden inflation may stimulate
inspiratory muscles.
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Bronchiole: One of -the finer subdivisions of the airways, less than 1 mm in
diameter, and having no cartilage in its wall.
Bronchiolitis: Inflammation of the bronchioles which may be acute or chronic.
If the etiology is known, it should be stated. If permanent occlusion of
the lumens is present, the term bronchiolitis obliterans may be used.
Bronchitis: A non-neoplastic disorder of structure or function of the bronchi
resulting from infectious or noninfectious irritation. The term bronchitis
should be modified by appropriate words or phrases to indicate its etiol-
ogy, its chronicity, the presence of associated airways dysfunction, or
type of anatomic change. The term chronic bronchitis, when unqualified,
refers to a condition associated with prolonged exposure to nonspecific
bronchial irritants and accompanied by mucous hypersecretion and certain
structural alterations in the bronchi. Anatomic changes may include
hypertrophy of the mucous-secreting apparatus and epithelial metaplasia,
as well as more classic evidences of inflammation. In epidemiologic
studies, the presence of cough or sputum production on most days for at
least three months of the year has sometimes been accepted as a criterion
for the diagnosis.
Bronchoconstrictor: An agent that causes a reduction in the caliber (diame-
ter) of airways.
Bronchodilator: An agent that causes an increase in the caliber (diameter) of
airways.
Bronchus: One of the subdivisions of the trachea serving to convey air to and
from the lungs. The trachea divides into right and left main bronchi
which in turn form lobar, segmental, and subsegmental bronchi.
BTPS conditions (BTPS): Body temperature, barometric pressure, and saturated
with water vapor. These are the conditions existing in the gas phase of
the lungs. For man the normal temperature is taken as 37°C, the pressure
as the barometric pressure, and the partial pressure of water vapor as 47
torr.
Carbachol: A parasympathetic stimulant (carbamoylcholine chloride, CM^cCinJ)?)
that produces constriction of the bronchial smooth muscles.
Carbon dioxide production (VCO?): Rate of carbon dioxide production by organ-
isms, tissues, or cells. Common units: ml C02 (STPD)/kg*min.
Carbon monoxide (CO): An odorless, colorless, toxic gas formed by incomplete
combustion, with a strong affinity for hemoglobin and cytochrome; it
reduces oxygen absorption capacity, transport, and utilization.
Carboxyhemoglobin (COHb): Hemoglobin in which the iron is associated with
carbon monoxide. The affinity of hemoglobin for CO is about 300 times
greater than for 0^.
A-3
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Chronic obstructive lung disease (COLD): This term refers to diseases of
uncertain etiology characterized by persistent slowing of airflow during
forced expiration. It is recommended that a more specific term, such as
chronic obstructive bronchitis or chronic obstructive emphysema, be used
whenever possible. Synonymous with chronic obstructive pulmonary disease
(COPD).
Closing capacity (CC): Closing volume plus residual volume, often expressed
as a ratio of TLC, i.e. (CC/TLC%).
Closing volume (CV): 'The volume exhaled after the expired gas concentration
is inflected from an alveolar plateau during a controlled breathing
maneuver. Since the value obtained is dependent on the specific test
technique, the method used must be designated in the text, and when
necessary, specified by a qualifying symbol. Closing volume is often
expressed as a ratio of the VC, i.e. (CV/VC%). ;
Collateral resistance (R nll): Resistance to flow through indirect pathways.
See COLLATERAL VENTITATION and RESISTANCE. :
Collateral ventilation: Ventilation of air spaces via indirect pathways,
e.g., through pores in alveolar septa, or anastomosing respiratory bron-
chioles.
Compliance (C.,C .): A measure of distensibility. Pulmonary compliance is
given by the slope of a static volume-pressure curve at a point, or the
linear approximation of a nearly straight portion of such a curve, ex-
pressed in liters/cm FkO or ml/cm H^O. Since the static volume-pressure
characteristics of lungs are nonlinear (static compliance decreases as
lung volume increases) and vary according to the previous volume history
(static compliance at a given volume increases immediately after full
inflation and decreases following deflation), careful specification of
the conditions of measurement are necessary. Absolute values also depend
on organ size. See also DYNAMIC COMPLIANCE.
Conductance (G): The reciprocal of RESISTANCE. See AIRWAY CONDUCTANCE.
Diffusing capacity of the lung (D, , ®i®?' ^ip^5 D.CO): Amount of gas (0-,
CO, CO,,) commonly expressed as mi gas CSTTO) diffusing between alveofar
gas ana pulmonary capillary blood per torr mean gas pressure difference
per min, i.e., ml 0?/(min-torr). Synonymous with transfer factor and
diffusion factor.
Dynamic compliance (C, ): The ratio of the tidal volume to the change in
intrapleural pressure between the points of zero flow at the extremes of
tidal volume in liters/cm FLO or ml/cm H^O. Since at the points of zero
airflow at the extremes of ^tidal volume, volume acceleration is usually
other than zero, and since, particularly in abnormal states, flow may
still be taking place within lungs between regions which are exchanging
volume, dynamic compliance may differ from static compliance, the latter
pertaining to condition of zero volume acceleration and zero gas flow
throughout the lungs. In normal lungs at ordinary volumes and respiratory
frequencies, static and dynamic compliance are the same.
A-4
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Elastance (E): The^reciprocal of COMPLIANCE; expressed in cm H90/liter or cm
H20/ml. :, •
Electrocardiogram (ECG3 EKG): The graphic record of the electrical currents
that are associated with the heart's contraction and relaxation.
Emphysema: A condition of the lung characterized by abnormal, permanent
enlargement of^airspaces distal to the terminal bronchiole, accompanied
by the destruction of their walls, and without obvious fibrosis.
Expiratory reserve volume (ERV): The maximal volume of air exhaled from the
end-expiratory/level.
FEV./FVC; A ratio of timed (t = 0.5, 1, 2, 3 s) forced expiratory volume
(FEV,) to forced vital capacity (FVC). The ratio is often expressed in
percent 100 x FEV./FVC. It is an index of airway obstruction.
Flow volume curve: Graph of instantaneous forced expiratory flow recorded at
the mouth, against corresponding lung volume. When recorded over the
full vital capacity, the curve includes maximum expiratory flow rates at
all lung volumes in the VC range and is called a maximum expiratory
flow-volume curve (MEFV). A partial expiratory flow-volume curve (PEFV)
is one which describes maximum expiratory flow rate over a portion of the
vital capacity only.
Forced expiratory flow (FEFx): Related to some portion of the FVC curve.
Modifiers refer to the amount,of the FVC already exhaled when the measure-
ment is made. For example: .
FEF7ro/ = instantaneous forced expiratory flow after 75%
/3/0 of the FVC has been exhaled.
FEF9nn 19nn = mean forced expiratory flow between 200 ml
- and 12QO ml Qf the pvc (formerly ca-]led the
maximum expiratory flow rate (MEFR).
mean forced expiratory flow during the middle
half Qf the pvc [formerly caned the maximum
mid-expiratory flow rate (MMFR)].
FEF „ = the maximal forced expiratory flow achieved during
max an FVC.
Forced expiratory volume (FEV): Denotes the volume of gas which is exhaled in
a given time interval during the execution of a forced vital capacity.
Conventionally, the times used are 0.5, 0.75, or 1 sec, symbolized FEV,, g,
FEVn 7r, FEV-, n. These values are often expressed as a percent of the"
forHeat)vital-Lelipacity, e.g. (FEVX Q/VC) X 100.
Forced inspiratory vital capacity (FIVC): The maximal volume of air inspired
with a maximally forced effort from a position of maximal expiration.
Forced vital capacity (FVC): Vital capacity performed with a maximally forced
expiratory effort.
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Functional residual capacity (FRC): The sum of RV and ERV (the volume of air
remaining in the lungs at the end-expiratory position). The method of
measurement should be indicated as with RV.
Gas exchange: Movement of oxygen from the alveoli into the pulmonary capillary
blood as carbon dioxide enters the alveoli from the blood. In broader
terms, the exchange of gases between alveoli and lung capillaries.
Gas exchange ratio (R); See RESPIRATORY QUOTIENT. !
Gas trapping: Trapping of gas behind small airways that were opened during
inspiration but closed during forceful expiration. It is a volume differ-
ence between FVC and VC.
i"
Hematoerit (Hct): The percentage of the volume of red blood cells in whole
blood.
Hemoglobin (Hb): A hemoprotein naturally occurring in" most vertebrate blood,
consisting of four polypeptide chains (the globulin) to each of which
there is_ attached a herna. group. The heme is made of four pyrrole rings
and a divalent iron (Fe -protoporphyrin) which combines reversibly with
molecular oxygen.
Histamine: A depressor amine derived from the ami no acid histidine and found
in all body tissues, with the highest concentration in the lung; a powerful
stimulant of gastric secretion, a constrictor of bronchial smooth muscle,
and a vasodilator that causes a fall in blood pressure.
Hypoxemia: A state in which the oxygen pressure and/or concentration in
arterial and/or venous blood is lower than its normal value at sea level.
Normal oxygen pressures at sea level are 85-100 torr in arterial blood
and 37-44 torr in mixed venous blood. In adult humans the normal oxygen
concentration is 17-23 ml 02/100 ml arterial blood; in mixed venous blood
at rest it is 13-18 ml 02/100 ml blood.
Hypoxia: Any state in which the oxygen in the lung, blood, and/or tissues is
abnormally low compared with that of normal resting man breathing air at
sea level. If the P0p is low in the environment, whether because of
decreased barometric pressure or decreased fractional concentration of
02, the condition is termed environmental hypoxia. Hypoxia when referring
to the blood is termed hypoxemia. Tissues are said to be hypoxic when
their P02 is low, even if there is no arterial hypoxemia, as in "stagnant
hypoxiaw which occurs when the local circulation is low compared to the
local metabolism.
Inspiratory capacity (1C): The sum of IRV and TV.
Inspiratory reserve volume (IRV): The maximal volume of air inhaled from the
end-inspiratory level.
Inspiratory vital capacity (IVC): The maximum volume of air inhaled from the
point of maximum expiration.
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Kilogram-meter/mfn (kg-m/min): The work performed each min to move a mass of 1
kg through a. vertical distance of 1 m against the force of gravity.
Synonymous with kilopond-meter/min.
Lung volume (V,): -Actual volume of the lung, including the volume of the
conducting airways.
Maximal aerobic capacity (max VO^): The rate of oxygen uptake by the body
during repetitive maximal respiratory effort. Synonymous with maximal
oxygen consumption.
Maximum breathing capacity (MBC): Maximal volume of air which can be breathed
per minute by a subject breathing as quickly and as deeply as possible.
This tiring lung function test is usually limited to 12-20 sec, but given
in liters (BTPS,)/min. Synonymous with maximum voluntary ventilation (MVV).
Maximum expiratory flow (V ): Forced expiratory flow, related to the
total lung capacity or tne actual volume of the lung at which the measure-
ment is made. ; Modifiers refer to the amount of lung volume remaining
when the measurement is made. For example:
V _ 7[-y = instantaneous forced expiratory flow when the
max
V -3 n ~'' instantaneous forced expiratory flow when the
max. lung volume is 3.0 liters
Maximum expiratory flow rate (MEFR): Synonymous with 1^200-1200"
Maximum mid-expiratory flow rate (MMFR or MMEF): Synonymous with
Maximum ventilation (max Vp): The volume of air breathed in one minute during
repetitive maximal respiratory effort. Synonymous with maximum ventilatory
minute volume.
Maximum voluntary ventilation (MVV): The volume of air breathed by a subject
during voluntary maximum hyperventilation lasting a specific period of
time. Synonymous with maximum breathing capacity (MBC).
Methemoglobin (MetHb:): Hemoglobin in which iron is in the ferric state.
Because the iron is oxidized, methemoglobin is incapable of oxygen trans-
port. Methemoglobins are formed by various drugs and occur under pathol-
ogical conditions. Many methods for hemoglobin measurements utilize
methemoglobin (chlorhemiglobin, cyanhemiglobin).
Minute ventilation (VV): Volume of air breathed in one minute. It is a
product of tidal Volume (VT) and breathing frequency (fn). See VENTILA-
TION. : ' B
Minute volume: Synonymous with minute ventilation.
Mucociliary transport: The process by which mucus is transported, by ciliary
action, from the lungs.
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Mucus: The clear, viscid secretion of mucous membranes*,; consisting of mucin,
epithelial cells, leukocytes, and various inorganic salts suspended in
water,
Nasopharyngeal : Relating to the nose or the nasal cavity and the pharynx
(throat).
Nitrogen oxides: Compounds of N and 0 in ambient air; ii.e., nitric oxide (NO)
and others with a higher oxidation state of N, of ;. which NCL is the most
important toxicologically. -,:
Nitrogen washout (AN2, dN2): The curve obtained by plotting the fractional
concentration of N2 in expired alveolar gas vs. time, for a subject
switched from breathing ambient air to an inspired .mixture of pure 0,,. A
progressive decrease of Ng concentration ensues which may be analyzed
into two or more exponential components. Normally, after 4 min of pure
On breathing the fractional N? concentration in expired alveolar gas is
down to less than 2%.
Normoxia: A state in which the ambient oxygen pressure is approximately 150 ±
10 torr (i.e., the partial pressure of oxygen in air at sea level).
Oxidant: A chemical compound that has the ability to remove, accept, or share
electrons from another chemical species, thereby oxidizing it.
Oxygen consumption (V0?, QQ/>): Rate of oxygen uptake;of organisms, tissues,
or cells. Common unit?: ml 02 (STPD)/(kg«min) or ml 02 (STPD)/(kg*hr).
For whole organisms the oxygen Consumption is commonly expressed per unit
surface area or. some power of the body weight. For tissue samples or
isolated cells (L2 = Ml 0,/hr per mg dry weight.
Oxygen saturation (S02): The amount of oxygen combined with hemoglobin,
expressed as a percentage of the oxygen capacity of that hemoglobin. In
arterial blood,
Oxygen uptake (V02): Amount of oxygen taken up by the body from the environ-
ment, by the blood from the alveolar gas, or by an organ or tissue from
the blood. When this amount of oxygen is expressed per unit of time one
deals with an "oxygen uptake rate." "Oxygen consumption" refers more
specifically to the oxygen uptake rate by all tissues of the body and is
equal to the oxygen uptake rate of the organism only when the Op stores
are constant.
Particulates: Fine solid particles such as dust, smoke, fumes, or smog, found
in the air or in emissions.
Pathogen: Any virus, microorganism, or etiologic agent causing disease.
Peak expiratory flow (PEF): The highest forced expiratory flow measured with
a peak flow meter.
Peroxyacetyl nitrate (PAN): Pollutant created by action of UV component of
sunlight on hydrocarbons and NO in the air; an ingredient of photochem-
ical smog.
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Physiological dead space (Vr,): Calculated volume which accounts for the
difference between the pressures of COp in expired and alveolar gas (or
arterial blood). Physiological dead space reflects the combination of
anatomical dead space and alveolar dead space, the volume of the latter
increasing with, the importance of the nonuniformity of the
ventilation/perfusion ratio in the lung.
PTethysmograph: A rigid chamber placed around a living structure for the
purpose of measuring changes in the volume of the structure. In respira-
tory measurements, the entire body is ordinarily enclosed ("body plethys-
mograph") and the plethysmograph is used to measure changes in volume of
gas in the system produced 1) by solution and volatilization (e.g.,
uptake of foreign gases into the blood), 2) by changes in pressure or
temperature (e.gi, gas compression in the lungs, expansion of gas upon
passing into thevwarm, moist lungs), or 3) by breathing through a tube to
the outside. Three types of plethysmograph are used: a) pressure, b)
volume, and c) pressure-volume. In type a, the body chambers have fixed
volumes and volume changes are measured in terms of pressure change
secondary to gas compression (inside the chamber, outside the body). In
type b, the body;chambers serve essentially as conduits between the body
surface and devices (spirometers or integrating flowmeters) which measure
gas displacements. Type c combines a and b by appropriate summing of
chamber pressure "and volume displacements.
Pneumotachograph: A device for measuring instantaneous gas flow rates in
breathing by recording the pressure drop across a fixed flow resistance
of known pressure-flow characteristics, commonly connected to the airway
by means of a mouthpiece, face mask, or cannula. The flow resistance
usually consists either of parallel capillary tubes (Fleisch type) or of
fine-meshed screen (SiIverman-Lilly type).
Pulmonary alveolar proteinosis: A chronic or recurrent disease characterized
by the filling of alveoli with an insoluble exudate, usually poor in
cells, rich in lipids and proteins, and accompanied by minimal histologic
alteration of the alveolar walls.
Pulmonary edema: An accumulation of excessive amounts of fluid in the lung
extravascular tissue and air spaces.
Pulmonary emphysema: An abnormal, permanent enlargement of the air spaces
distal to the terminal nonrespiratory bronchiole, accompanied by destructive
changes of the alveolar walls and without obvious fibrosis. The term
emphysema may be modified by words or phrases to indicate its etiology,
its anatomic subtype, or any associated airways dysfunction.
Residual volume (RV): That volume of air remaining in the lungs after maximal
exhalation. The method of measurement should be indicated in the text
or, when necessary, by appropriate qualifying symbols.
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Resistance flow (R): The ratio of the flow-resistive*components of pressure
to simultaneous flow, in cm hLO/liter per sec. Flow-resistive components
of pressure are obtained by subtracting any elastic or inertia! components,
proportional respectively to volume and volume acceleration. Most flow
resistances in the respiratory system are nonlinear, varying with the
magnitude and direction of flow, with lung volume and lung volume history,
and possibly with volume acceleration. Accordingly, careful specification
of the conditions of measurement is necessary; see AIRWAY RESISTANCE,
TISSUE RESISTANCE, TOTAL PULMONARY RESISTANCE, COLLATERAL RESISTANCE.
Respiratory cycle: A respiratory cycle is constituted by the inspiration
followed by the expiration of a given volume of gas, called tidal volume.
The duration of the respiratory cycle is the respiratory or ventilatory
period, whose reciprocal is the ventilatory frequency.
Respiratory exchange ratio: See RESPIRATORY QUOTIENT.
Respiratory frequency (fn): The number of breathing cycles per unit of time.
Synonymous with breaxhing frequency (fn)- *
Respiratory quotient (RQ, R): Quotient of the volume of C0« produced divided
by the volume of 02 consumed by an organism, an organ, or a tissue during
a given period of Time. Respiratory quotients are measured by comparing
the composition of an incoming and an outgoing medium, e.g., inspired and
expired gas, inspired gas and alveolar gas, or arterial and venous blood.
Sometimes the phrase "respiratory exchange ratio" is used to designate
the ratio of COp output to the 0? uptake by the lungs, "respiratory
quotient" being Testricted to the actual metabolic C0« output and Oy
uptake by the tissues. With this definition, respiratory quotient and
respiratory exchange ratio are identical in the steady state, a condition
which implies constancy of the 02 and C02 stores;
Shunt: Vascular connection between circulatory pathways so that venous blood
is diverted into vessels containing arterialized blood (right-to-left
shunt, venous admixture) or vice versa (left-to-right shunt). Right-to-
left shunt within the lung, heart, or large vessels due to malformations
are more important in respiratory physiology. Flow from left to right
through a shunt should be marked with a negative sign.
Specific airway conductance (SGaw): Airway conductance divided by the lung
volume at which it was measured, i.e., normalized airway conductance.
SGaw = Gaw/TGV. :
Specific airway resistance (SRaw): Airway resistance multiplied by the volume at
which it was measured. SRaw = Raw x TGV.
Spirograph: Mechanical device, including bellows or other scaled, moving
part, which collects and stores gases and provides a graphical record of
volume changes. See BREATHING PATTERN, RESPIRATORY CYCLE.
Spirometer: An apparatus similar to a spirograph but without recording facil-
Ity.
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Static lung compliance (C, ,): Lung compliance measured at zero flow (breath-
holding) over linear portion of the volume-pressure curve above FRC. See
COMPLIANCE.
Static transpulmonary pressure (Pg*): Transpulmonary pressure measured at a
specified lung volume; e.g., Y .TLC is static recoil pressure measured at
TLC (maximum recoil pressure).
Sulfur dioxide (S02): Colorless gas with pungent odor, released primarily from
burning of fossil fuels, such as coal, containing sulfur.
STPD conditions (STRD): Standard temperature and pressure, dry. These are
the conditions of a volume of gas at 0°C, at 760 torr, without water
vapor, A STPD volume of a given gas contains a known number of moles of
that gas.
Surfactant, pulmonary: Protein-phospholipid (mainly dipalmitoyl lecithin)
complex which lines alveoli (and possibly small airways) and accounts for
the low surface tension which makes air space (and airway) patency possible
at low transpulmonary pressures.
Synergism: A relationship in which the combined action or effect of two or
more components is greater than the sum of effects when the components
act separately.
Thoracic gas volume (TGV): Volume of communicating and trapped gas in the
lungs measured by body plethysmography at specific lung volumes. In
normal subjects, TGV determined at end expiratory level corresponds to
FRC.
Tidal volume (TV): That volume of air inhaled or exhaled with each breath
during quiet breathing, used only to indicate a subdivision of lung
volume. When tidal volume is used in gas exchange formulations, the
symbol Vj should be used.
Tissue resistance (R*,-): Frictional resistance of the pulmonary and thoracic
tissues.
Torr: A unit of pressure equal to 1,333.22 dynes/cm2 or 1.33322 millibars.
The torr is equal to the pressure required to support a column of mercury
1 mm high when the mercury is of standard density and subjected to standard
acceleration. These standard conditions are met at 0°C and 45° latitude,
where the acceleration of gravity is 980.6 cm/sec . In reading a mercury
barometer at other temperatures and latitudes, corrections, which commonly
exceed 2 torr, must be introduced for these terms and for the thermal
expansion of the measuring scale used. The torr is synonymous with
pressure unit mm Hg.
Total lung capacity (TLC): The sum of all volume compartments or the volume
of air in the lungs after maximal inspiration. The method of measurement
should be indicated, as with RV.
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Total pulmonary resistance (R,): Resistance measured by relating flow-dependent
transpulmonary pressure xo airflow at the mouth. Represents the total
(frictional) resistance of the lung tissue (R+.) and the airways (Raw).
RL=Raw+Rtr
Trachea: Commonly-known as the windpipe; a cartilaginous air tube extending
from the larynx (voice box) into the thorax (chest) where it divides into
left and right branches.
Transpulmonary pressure (P.): Pressure difference between airway opening
(mouth, nares, or cannula opening) and the visceral pleura! surface, in
cm HnO. Transpulmonary in the sense used includes extrapulmonary struc-
ture?, e.g., trachea and extrathoracic airways. This usage has come
about for want of an anatomic term which includes all of the airways and
the lungs together.
Ventilation: Physiological process by which gas is renewed in the lungs. The
word ventilation sometimes designates ventilatory flow rate (or ventila-
tory minute volume) which is the product of the tidal volume by the
ventilatory frequency. Conditions are usually indicated as modifiers;
i.e.,
VV = Expired volume per minute (BTPS),
. and
V-r = Inspired volume per minute (BTPS).
Ventilation is often referred to as "total ventilation" to distinguish it
from "alveolar ventilation" (see VENTILATION, ALVEOLAR).
Ventilation, alveolar (V*): Physiological process by which alveolar gas is
completely removed and replaced with fresh gas. Alveolar ventilation is
less than total ventilation because when a tidal volume of gas leaves the
alveolar spaces, the last part does not get expelled from the body but
occupies the dead space, to be reinspired with the next inspiration.
Thus the volume of alveolar gas actually expelled completely is equal to
the tidal volume minus the volume of the dead space. This truly complete
expiration volume times the ventilatory frequency constitutes the alveolar
ventilation. 1
Ventilation, dead-space (VQ): Ventilation per minute of the physiologic dead
space (wasted ventilation), BTPS, defined by the following equation:
VD = VE(PaC02 - PEC02)/(PaC02 - PjCOg)
Ventilation/perfusion ratio (VA/Q): Ratio of the alveolar ventilation to the
blood perfusion volume flow through the pulmonary parenchyma. This ratio
is a fundamental determinant of the 02 and CO^ pressure of the alveolar
gas and of the end-capillary blood. Throughout the lungs the local
ventilation/perfusion ratios vary, and consequently the local alveolar
gas and end-capillary blood compositions also vary.
Vital capacity (VC): The maximum volume of air exhaled from the point of
maximum inspiration.
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