EPA
United States
Environmental Protection
Agency
Environmental Criteria and
Assessment Office
Research Triangle Park NC 27711
600884020A5
July 1984
External Review Draft C^ /"
Research and Development
Air Quality
Criteria for
Ozone and Other
Photochemical
Oxidants
Review
Draft
(Do Not
Cite or Quote)
Volume V of V
NOTICE
This document is a preliminary draft. It has not been formally
released by EPA and should not at this stage be construed to
represent Agency policy. It is being circulated for comment on its
technical accuracy and policy implications.
-------
NOTICE
Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.
US. Envrronmental Protection Agencrf '
-------
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 1983 and early 1984.
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. Separate chapters are presented 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 proper-
ties, chemistry, 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 epidemio-
logical 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.
iii
0190LG/B May 1984
-------
CONTENTS
Page
VOLUME I
Chapter 1. Summary and Conclusions 1-1
VOLUME II
Chapter 2. Introduction 2-1
Chapter 3. Precursors to Ozone and Other Photochemical
Oxidants 3-1
Chapter 4. Chemical and Physical Processes in the Formation
and Occurrence of Ozone and Other Photochemical
Oxidants 4-1
Chapter 5. Properties, Chemistry, and Measurement of Ozone
and Other Photochemical Oxidants 5-1
Chapter 6. Concentrations of Ozone and Other Photochemical
Oxidants in Ambient Air 6-2
VOLUME III
Chapter 7. Effects of Ozone and Other Photochemical Oxidants
on Vegetation 7-1
Chapter 8. Effects of Ozone and Other Photochemical Oxidants
on Natural and Agroecosystems 8-1
Chapter 9. Effects of Ozone and Other Photochemical Oxidants
on Nonbiological Materials 9-1
VOLUME IV
Chapter 10. Toxicological Effects of Ozone and Other
Photochemical Oxidants 10-1
VOLUME V
Chapter 11. Controlled Human Studies of the Effects of Ozone
and Other Photochemical Oxidants 11-1
Chapter 12. Field and Epidemiological Studies of the Effects
of Ozone and Other Photochemical Oxidants 12-1
Chapter 13. Evaluation of Integrated Health Effects Data for
Ozone and Other Photochemical Oxidants 13-1
0190LG/B
IV
May 1984
-------
TABLE OF CONTENTS
LIST OF TABLES viii
LIST OF FIGURES ix
LIST OF ABBREVIATIONS xi
AUTHORS, CONTRIBUTORS, AND REVIEWERS xvi i
11. CONTROLLED HUMAN STUDIES OF THE EFFECTS OF OZONE AND
OTHER PHOTOCHEMICAL OXIDANTS 11-1
11.1 INTRODUCTION 11-1
11.2 ACUTE PULMONARY EFFECTS OF OZONE 11-6
11.2.1 At-Rest Exposures 11-6
11.2.2 Exposures with Exercise 11-10
11.2.3 Intersubject Variability and Reproducebility of
Responses 11-18
11.2.4 Prediction of Acute Pulmonary Effects 11-21
11.2.5 Bronchial Reactivity 11-25
11.2.6 Mechanisms of Acute Pulmonary Effects 11-27
11.2.7 Pre-existing Di sease 11-29
11.2.8 Other Factors Affecting Pulmonary Responses to
Ozone 11-34
11.2.8.1 Cigarette Smoking 11-34
11.2.8.2 Age and Sex Di fferences 11-36
11.2.8.3 Environmental Conditions 11-38
11.3 PULMONARY EFFECTS FOLLOWING REPEATED EXPOSURE TO OZONE 11-39
11.4 EFFECTS OF OZONE ON VIGILANCE AND EXERCISE PERFORMANCE 11-52
11.5 INTERACTIONS BETWEEN OZONE AND OTHER POLLUTANTS 11-57
11.5.1 Ozone Plus Sulfates or Sulfuric Acid 11-57
11.5.2 Ozone and Carbon Monoxide 11-65
11.5.3 Ozone and Nitrogen Dioxide 11-66
11.5.4 Ozone and Other Mixed Pol 1utants 11-67
11.6 EXTRAPULMONARY EFFECTS OF OZONE 11-68
11.7 PEROXYACETYL NITRATE 11-75
11.8 SUMMARY 11-78
11.9 REFERENCES 11-86
12. FIELD AND EPIDEMIOLOGICAL STUDIES OF THE EFFECTS OF OZONE
AND OTHER PHOTOCHEMICAL OXIDANTS 12-1
12.1 INTRODUCTION 12-1
12.2 FIELD STUDIES OF EFFECTS OF ACUTE EXPOSURE 12-2
12.2.1 Symptoms and Pulmonary Function in General Field
Conditions 12-2
12.2.2 Symptoms and Pulmonary Function under High-
Altitude Conditions 12-10
12.3 EPIDEMIOLOGICAL STUDIES OF EFFECTS OF ACUTE EXPOSURE 12-13
12.3.1 Acute Exposure Morbidity Effects 12-13
12.3.1.1 Respiratory and Other Symptoms of
Irritation 12-13
12.3.1.2 Altered Performance 12-15
12.3.1.3 Acute Effects on Pulmonary Function 12-17
019DH/G 6/30/84
-------
TABLE OF CONTENTS (continued)
12.3.1.4 Aggravation of Existing Respiratory
Di seases 12-21
12.3.1.5 Incidence of Acute Respiratory Illness 12-28
12.3.1.6 Physician, Emergency Room, and Hospital
Visits 12-28
12.3.1.7 Occupational Studies 12-32
12.3.2 Trends in Mortality 12-32
12.4 EPIDEMIOLOGICAL STUDIES OF EFFECTS OF CHRONIC EXPOSURE 12-35
12.4.1 Pulmonary Function and Chronic Lung Disease 12-35
12.4.2 Chromosomal Effects 12-37
12.5 SUMMARY AND CONCLUSIONS 12-39
12.6 REFERENCES 12-45
13. EVALUATION OF INTEGRATED HEALTH EFFECTS DATA FOR OZONE AND
OTHER PHOTOCHEMICAL OXIDANTS 13-1
13.1 INTRODUCTION 13-1
13.2 EXPOSURE ASPECTS 13-3
13.2.1 Exposures to Ozone 13-3
13.2.2 Potential Exposures to Other Photochemical
Oxidants 13-9
13.2.2.1 Concentrations 13-9
13.2.2.2 Patterns 13-11
13.2.3 Potential Combined Exposures and Relationship of
Ozone and Other Photochemical Oxidants 13-12
13.3 HEALTH EFFECTS IN THE GENERAL HUMAN POPULATION 13-14
13.3.1 Clinical Symptoms 13-14
13.3.2 Pulmonary Function at Rest and with Exercise and
Other Stresses 13-16
13.3.2.1 At-Rest Exposures 13-16
13.3.2.2 Exposures with Exercise 13-17
13.3.2.3 Environmental Stresses 13-33
13.3.3 Other Factors Affecting Pulmonary Response to
Ozone 13-34
13.3.3.1 Age 13-34
13. 3. 3. 2 Sex 13-35
13.3.3.3 Smoking Status 13-36
13.3.3.4 Nutritional Status 13-36
13.3.3.5 Red Blood Cell Enzyme Deficiencies 13-38
13.3.4 Effects of Repeated Exposure to Ozone 13-39
13.3.4.1 Introduction 13-39
13.3.4.2 Development of Altered Responsiveness to
Ozone 13-39
13.3.4.3 Mechanisms of Altered Responsiveness to
Ozone 13-40
13.3.4.4 Conclusions Relative to Attenuation with
Repeated Exposures 13-43
13.3.5 Relationship Between Acute and Chronic Ozone
Effects 13-44
vi
019DH/G 6/29/84
-------
TABLE OF CONTENTS (continued)
13.3.6 Resistance to Infection 13-47
13.3.7 Extrapulmonary Effects of Ozone 13-49
13.4 HEALTH EFFECTS IN POTENTIALLY SUSCEPTIBLE INDIVIDUALS 13-51
13.4.1 Patients with Chronic Obstructive Lung Disease
(COLD) 13-51
13.4.2 Asthmatics 13-52
13.4.3 Subjects with Allergy, Atopy, and Hyperreactive
Airways 13-54
13.5 EXTRAPOLATION OF EFFECTS OBSERVED IN ANIMALS TO HUMAN
POPULATIONS 13-55
13.5.1 Species Comparisons 13-55
13.5.2 Dosimetry Modeling 13-61
13.6 HEALTH EFFECTS OF OTHER PHOTOCHEMICAL OXIDANTS AND
POLLUTANT MIXTURES 13-62
13.6.1 Effects of Peroxyacetyl Nitrate 13-63
13.6.2 Effects of Hydrogen Peroxide 13-64
13.6.3 Interactions with Other Pollutants 13-64
13.7 IDENTIFICATION OF POTENTIALLY AT-RISK POPULATIONS OR
SUBPOPULATIONS 13-66
13.7.1 Introduction 13-66
13.7.2 Potentially At-Risk Individuals 13-67
13.7.3 Potentially At-Risk Subpopulations 13-70
13.7.4 Demographic Distribution of the General Popula-
tion 13-72
13.7.5 Demographic Distribution of Individuals with
Chronic Respiratory Conditions 13-73
13.8 SUMMARY AND CONCLUSIONS 13-76
13.9 REFERENCES 13-84
APPENDIX A A-l
VI 1
019DH/G 6/29/84
-------
LIST OF TABLES
Table
11-1 Human experimental exposure to ozone up to 1978 11-2
11-2 Studies on acute pulmonary effects of ozone since 1978 11-7
11-3 Estimated values of oxygen consumption and minute
ventilation associated with levels of exercise 11-12
11-4 Ozone exposure in subjects with pulmonary disease 11-30
11~5 Changes in lung function after repeated daily exposure
to ambient ozone 11-41
11-6 Effects of ozone on exercise performance 11-55
11-7 Interactions between ozone and other pollutants 11-58
11-8 Human extrapulmonary effects of ozone exposure 11-69
11-9 Acute human exposure to peroxyacetyl nitrate 11-76
11-10 Summary table: controlled human exposure to ozone 11-79
12-1 Subject characteristics and experimental conditions of
the mobile laboratory studies 12-4
12-2 Pollutant levels (mean ± S.D.) monitored inside a mobile
laboratory during ambient air exposures 12-4
12-3 The relationship between average standardized deviations
of peak flow and outdoor concentrations of ozone and
total suspended particulate matter 12-20
12-4 The relationship between average standardized deviations
of peak flow in asthmatics and the interaction of ozone
and temperature 12-27
12-5 Studies of acute respiratory illness 12-29
12-6 Studies of acute effects from occupational exposure 12-33
12-7 Additional studies of chronic morbidity 12-38
12-8 Summary table: acute effects of ozone and other
photochemical oxidants in population studies 12-41
13-1 Probability that specified concentrations of ozone will
persist for stated consecutive days or longer 13-7
13-2 Relationship of ozone and peroxyacetyl nitrate at urban
and suburban sites in the United States in reports
pub! ished 1978 or 1 ater 13-14
13-3 Effects of intermittent exercise and ozone concentration
on 1-sec forced expiratory volume 13-26
13-4 Comparison of the acute effects of ozone on breathing
patterns in animals and man 13-58
13-5 Comparison of the acute effects of ozone on airway reactivity
i n animal s and man 13-59
13-6 Geographical distribution of the resident population of
the United States, 1980 13-73
13-7 Total population of the United States by age, sex, and
race, 1980 13-74
13-8 Prevalence of chronic respiratory conditions by sex and
age for 1979 13-75
vm
019DH/G 6/30/84
-------
LIST OF FIGURES
Figure Page
11-1 Change in forced vital capacity (FVC), forced expiratory
volume in 1-sec (FEV, „), and maximal mid-expiratory flow
(FEF ?c_7c
-------
LIST OF FIGURES (continued)
Figure Rage
12-1 Mean symptom score changes with exposure for all subjects,
normal and allergic subjects, and asthmatic subgroup of
subjects 12-7
12-2 Relationship of average daily percent adjusted (i.e.,
without fever, chill, or temperature) symptoms to photo-
chemical oxidant level, May 1961 - May 1964 (868 days) 12-16
13-1 Collective distributions of the three highest 1-hr ozone
concentrations for 3 years (1979, 1980, and 1981) at valid
sites (906 station - years) 13-5
13-2 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 13-20
13-3 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 13-21
13-4 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 13-22
13-5 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 size, was used to plot a concentration-
response curve with 95 percent confidence limits 13-23
13-6 Group mean decrements in 1-sec forced expiratory volume
during 2-hr ozone exposures with different levels of
intermittent exercise: light (Vp < 25 L/min); moderate
(VE = 26-43 L/min); heavy (VV = 44-63 L/min); and very
heavy (V_ > 64 L/min). Concentration-response curves
are taken from Figures 13-2 through 13-5 13-24
019DH/G 6/30/84
-------
LIST OF ABBREVIATIONS
ACh
AM
ANOVA
AOD
ATPS
BTPS
CC
Cdyn
CE
CHEM
CHESS
CL
CLst
CNS
CO
COHb
COLD
COPD
co2
CV
D,
D
LCO
E
ECG,
EEC
EPA
ERV
FEFn
FEF
EKG
max
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
Carboxyhemogiobi n
Chronic obstructive lung disease
Chronic obstructive pulmonary disease
Carbon dioxide
Closing volume
Diffusing capacity of the lungs
Carbon monoxide diffusion capacity of the lungs
Elastance
Electrocardiogram
Electroencephalogram
U.S. Environmental Protection Agency
Expiratory reserve volume
The maximal forced expiratory flow achieved
during an FVC.
Forced expiratory flow
019DH/G
6/29/84
-------
LIST OF ABBREVIATIONS (continued)
FEF200-1200 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
fR 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
HO- Hydroxy radical
H20 Water
1C Inspiratory capacity
IE Intermittent exercise
IRV Inspiratory reserve volume
IVC Inspiratory vital capacity
LDH Lactate deyhydrogenase
LDrQ Lethal dose (50 percent)
LM Light microscopy
MAST Kl-coulometric (Mast meter)
XII
019DH/G 6/29/84
-------
LIST OF ABBREVIATIONS (continued)
max VE
max V02
MBC
MEFR
MEFV
MetHb
MMAD
MMFR or MMEF
MVV
NBKI
V
°3
P(A-a)0
PABA
PAco2
PaC02
PAN
PA°2
Pa02
PBZN
PEF
PEFV
PG
rl_
PMN
Pst
PUFA
R
Raw
019DH/G
Maximum ventilation
Maximal aerobic capacity
Maximum breathing capacity
Maximum expiratory flow rate
Maximum expiratory flow-volume curve
Methemoglobin
Mass median aerodynamic diameter
Maximum mid-expiratory flow rate
Maximum voluntary ventilation
Neutral buffered potassium iodide
Ammonium sulfate
Nitrogen dioxide
Nitrogen washout
Oxygen
Oxygen radical
Ozone
Alveolar-arterial oxygen pressure difference
para-aminobenzoic acid
Alveolar partial pressure of carbon dioxide
Arterial partial pressure of carbon dioxide
Peroxyacetyl nitrate
Alveolar partial pressure of oxygen
Arterial partial pressure of oxygen
Peroxybenzoyl nitrate
Peak expiratory flow
Partial expiratory flow-volume curve
Prostaglandin
Arterial pH
Transpulmonary pressure
Polymorphonuclear leukocyte
Static transpulmonary pressure
Polyunsaturated fatty acid
Resistance to flow
Airway resistance
xiii
6/29/84
-------
LIST OF ABBREVIATIONS (continued)
RBC Red blood cell
RCO]-| Collateral resistance
rh Relative humidity
R[_ Total pulmonary resistance
RQ, R Respiratory quotient
Rt Total respiratory resistance
RJ..J Tissue resistance
RV Residual volume
Sa02 Arterial oxygen saturation
SBNT Single-breath nitrogen test
SCE Sister chromatid exchange
Se Selenium
SEM Scanning electron microscopy
SGaw Specific airway conductance
SH Sulfhydryls
SOD Superoxide dismutase
SO^ Sulfur dioxide
S04 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
VCO£ Carbon dioxide production
VQ Physiological dead space
xi v
019DH/G 6/29/84
-------
LIST OF ABBREVIATIONS (continued)
V Dead- space ventilation
D
. Anatomical dead space
Vr: Minute ventilation; expired volume per minute
V, Inspired volume per minute
V. Lung volume
V Maximum expiratory flow
fflclX
VOp Oxygen uptake
* *
V0> Q0 Oxygen consumption
xv
019DH/G 6/29/84
-------
MEASUREMENT ABBREVIATIONS
9
hr/day
kg
kgm/mi n
L/min
L/s
ppm
nig/ kg
/ 3
mg/m
min
ml
mm
pro
MM
sec
gram
hours per day
kilogram
ki1ogram-meter/mi n
liters/min
liters/sec
parts per million
milligrams per kilogram
milligrams per cubic meter
minute
fliilliliter
millimeter
micrograms per cubic meter
micrometers
micromole
second
019DH/G
xvi
6/29/84
-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS
Chapter 11: 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 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. 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
xv ii
019DH/G 6/29/84
-------
Dr. Lawrence J. Folinsbee
Institute of Environmental Stress
University of California
Santa Barbara, CA 93106
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-82
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
xvi i i
019DH/G 6/29/84
-------
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 12: Field and Epidemiological Studies of the Effects of Ozone
and Other Photochemical Oxidants
Principal Author
Dr. Michael D. Lebowitz
Department of Internal Medicine
College of Medicine
University of Arizona
Tucson, AZ 85724
Contributing Authors
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.
701 W. Broad Street
Falls Church, VA 22046
xix
019DH/G 6/29/84
-------
Authors also reviewed individual sections of the chapter. The following addi-
tional persons reviewed chapter 12 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. Patricia A. Buffler
School of Public Health
University of Texas
P.O. Box 21086
Houston, TX 77025
Dr. George L. Carlo
Dow Chemical, U.S.A.
1803 Building, U.S. Medical
Midland, MI 48640
Dr. Robert S. Chapman
Health Effects Research Laboratory
MD-58
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
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-82
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
XX
019DH/G 6/29/84
-------
Dr. Victor Hasselblad
Health Effects Research Laboratory
MO-55
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. Dennis J. Kotchmar
Environmental Criteria and
Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Thomas J. Kulle
Department 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
Mr. James A. Raub
Environmental Criteria and
Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Jonathan M. Samet
Department of Medicine
University of New Mexico Hospital
Albuquerque, NM 87131
xxi
019DH/G 6/29/84
-------
Dr. Jan A. J. Stolwijk
Department of Epidemiology and
Public Health
School of Medicine
Yale University
New Haven, CT 06510
Ms. Beverly E. Tilton
Environmental Criteria and
Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Harry M. Walker
Monsanto Fibers and Intermediates
Company
P.O. Box 711
Alvin, TX 77511
Chapter 13: 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, MD 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
MD-82
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
xxn
019DH/G 6/29/84
-------
Dr. Donald H. Horstman
Health Effects Research Laboratory
MD-58
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. 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. Til ton
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
XXTM
019DH/G 6/29/84
-------
Authors also reviewed individual sections of the chapter. The following addi-
tional persons reviewed parts of chapter 13 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
xxiv
019DH/G 6/29/84
-------
11. CONTROLLED HUMAN STUDIES OF THE EFFECTS OF
OZONE AND OTHER PHOTOCHEMICAL OXIDANTS
11.1 INTRODUCTION
Four major summaries on the effects of controlled human exposure to ozone
(Oo) 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 11-1). 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 03 ("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 11-1 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
019PO/A 11-1 5/2/84
-------
TABLE 11-1. HUMAN EXPERIMENTAL EXPOSURE TO OZONE UP TO 1978
Ozone
concentration
jjg/m3
196
196
784
1176
1960
294
— 588
i
NJ
392
980
451
490
725
980
ppm
0
0
0
0
1
0
0
0
0
0
0
0
0
10
1
4
6
0
15
30
2
5
23
25
37
50
. Exposure
Measurement ' duration and
method activity
CHEM, 2 hr
NBKI IE (2xR)
@ 15-min intervals
I 1 hr
R
UV, 1 hr (mouth-
NBKI piece) R (11)
& CE (29, 43,
66)
I 3 hr/day
6 days/week
x 12 weeks
CHEM, 2 hr
NBKI IE (2xR)
@ 15-min intervals
CHEM, 2-4 hr
NBKI R & IE (2xR)
@ 15-min intervals
No. and sex
Observed effect(s) of subjects Reference
P(A-a)02 and R increased. 12 male von Niedinq et al . , 1977
dw
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 ppm), 5% (0.6
and 1.0 ppm) at 1 hr after exposure; one
subject had history of asthma and experi-
enced hemoptysis 2 days after 1 ppm. No
symptoms at 0.1 ppm; odor detected at 0.4
and 0.6 ppm; throat irritation and cough
at 1.0 ppm.
RV, FEVj.Q, MMFR, and VT decreased and fg 6 male DeLucia and Adams, 1977
increased at 0.30 ppm during IE (66); small
but nonsignificant changes at 0.15 ppm.
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
within 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 spirometry, closing volume, and 20 male (asthma) Linn et al., 1978
N2 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 liyperreactors
(R) at 0.5 ppm
-------
TABLE 11-1. HUMAN EXPERIMENTAL EXPOSURE TO OZONE UP TO 1978 (continued)
Ozone
concentration
ug/m3 ppm
725 0.37
725 0.37
725 0.37
1470 0.75
725 0.37
980 0.50
1470 0.75
725 0.37
980 0. 50
1470 0.75
784 0.4
784 0.4
980 0.5
Exposure
Measurement 'C duration and
method activity
CHEM,
NBKI
CHEM,
NBKI
MAST,
NBKI
MAST,
NBKI
MAST,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
2 hr
IE (2xR)
@ 15-min intervals
2 hr
IE (2xR)
@ 15-min intervals
2 hr
IE (2xR)
@ 15-min intervals
2 hr
R (11) & IE (29)
@ 15-min intervals
2 hr
R (11) & IE (29)
@ 15-min intervals
1-4 hr
IE (4xR) for two
15-min periods
2.25 hr
IE (2xR)
@ 15-min intervals
4 days
2.5 hr/day
IE (2xR)
@ 15-min intervals
Observed effect(s)6
No changes in spirometry or small airway
function in the combined group; sensitive
subjects had decreased FEV^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 ppm, severe decrements
in spirometric variables (20%-55%). Smokers
more responsive, with RV and CC increased.
0.75 ppm: at rest, less than 21% decrements
in spirometry, 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.
fn increasea and V, decreased with exercise;
V02 not affected by exposure. Variables
correlated to total dose of ozone.
FVC and MMEF decreased and R increased at
2 hr and 4 hr; FEVj.0) V50, and V25 decreased
at 4 hr only.
FVC, FEV,.0, 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
4 normal (L. A. )
4 sensitive (L. A. )
2 male (Toronto)
2 female (Toronto)
3 male (L.A. )
1 female (L.A. )
12 male
20 male
8 female (divided into
6 exposure groups)
20 male
8 female (divided into
6 exposure groups)
22 male
6 female (L.A )
7 female (new arrival)
2 male (new arrival )
6 male (atopic)
Reference
Bell et al. , 1977
Hackney et al. , 1977b
Bates and Hazucha, 1973
Hazucha et al. , 1973
Hazucha, 1973
Silverman et al . , 1976
Folinsbee et al. , 1975
Knelson et al. , 1976
Hackney et al , 1976
Hackney et al. , 1977a
-------
TABLE 11-1. HUMAN EXPERIMENTAL EXPOSURE TO OZONE UP TO 1978 (continued)
Ozone
concentration
ug/mj ppm
980 0. 5
980 0. 5
1176 0.6
1176 0.6
1176 0.6
1568 0.8
1470 0. 75
1470 0. 75
Measurement >c
method
CHEM,
NBKI
MAST,
NBKI
CHEM,
NBKI
CHEM,
NBKI
MAST
MAST,
NBKI
MAST,
NBKI
Exposure
duration and
activity
2 hr
R (9) & IE (37)
for 30 min
6 hr
IE (44) for two
15-min periods
2 hr (noseclips)
R
2 hr
IE for two
15-rain periods
2 hr
R(9)
2 hr
IE
@ 15-min intervals
2 hr
R & IE (2XR)
@ 15-rain intervals
Observed effect(s)e
Changes in pulmonary function (FVC, FEV^u,
FEF^a,^) were greatest immediately following
exercise. Heat stress potentiated the re-
sponse while relative humidity had insignifi-
cant effects.
FVC, FEVj.u, and SG decreased and R, in-
creased. Nonsmokerl were more susceptible.
Inconsistent changes in lung mechanics and
small airway function.
Bronchoreactivity to histamine 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).
VCru mean decrease of 10% (10/10 subjects).
FEV0./5 x 40: mean decrease of 10%. FEF
25-75: 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).
Substernal soreness and trachea! irritation
6 to 12 hr after exposure.
HR , Vr, VT, VO^ , and maximum workload
all^Secreased. At maximum workload only,
fg decreased (45%) and V-j- increased (29%).
FEF3U and PrjTLC decreased, R, increased;
returned to control levels within 24 hr.
IE attenuated changes in R, , C. , maxP,
and spirometry. Cough and substernal 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 11-1. HUMAN EXPERIMENTAL EXPOSURE TO OZONE UP TO 1978a (continued)
Ozone
concentration
ug/m3 ppm
1764 0.9
2940 1.5
3920 2.0
Up to Up to
7840 4. 0
i
U1
9800 5-10
19600
b Exposure
Measurement ' duration and
method activity Observed effect(s)6
MAST> 5 mi'n SG decreased during and 5 min following
NBKI CE exposure. Recovery complete within 30 min
post-exposure.
1 2 hr VC: decreased 13%; returned to normal in
R 22 hr. FEV3.0: decreased 16.8% after 22 hr.
Maximum breathing capacity decreased very
slightly. CNS depression, lack of coordina-
tion, chest pain, tiredness for 2 weeks.
MAST 10-30 min VC: mean decrease of 16.5% (4/8 subjects
R showed decrease > 10%). FEV^o: mean
decrease of 20% (5/8 subjects showed
decrease > 10%. FEF2S_75: mean decrease
of 10.5% (5/6 subjects showed a decrease).
MBC: decrease of 12% (5/8 subjects showed
decrease). DL-,.: 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 OLpQ- Headache, shortness of
breath, lasting more than 1 hr.
I Not available Drowsiness and headache reported.
ality Criteria for Ozone and Other Photochemical Oxidants, Research Trianqle Park. NC: U.S.
No. and sex
of subjects Reference
4 male Kagawa and Toyama, 1975
1 male Griswold et al., 1957
11 subjects Hallett, 1965
3 male Jordan and Carlson, 1913
Environmental Protection Agency,
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 (V,.) given in L/min or in multiples of resting
ventilation. E' a K M
p
See Glossary for the definition of symbols.
-------
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 presented
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 5.
11.2 ACUTE PULMONARY EFFECTS OF OZONE
11.2.1 At-Rest Exposures
Results from studies reported prior to 1978 (Table 11-1) indicate that
impairment of pulmonary function and pulmonary symptoms occur when normal
subjects are exposed for 2 hr at rest to 1176-1568 ug/m (0.6-0.8 ppm) of 03
(Young et al., 1964), to 1479 ug/m3 (0.75 ppm) of 0 (Bates et al. , 1972;
3
Silverman et al. , 1976), and to 980 ug/m (0.5 ppm) of 03 (Folinsbee et al. ,
1977b). In addition to decrements in the usual indicators of pulmonary func-
tion, Young et al. (1964) also found decreases in diffusion capacity of the
lung (DLCO).
Results from studies of at-rest exposures published since 1978 (Table 11-2)
have generally confirmed these earlier findings. Folinsbee et al. (1978)
observed decrements in forced vital capacity (FVC), forced expiratory volume
in 1 s (FEV-. n), and other spirometric variables when 10 normal subjects rested
1. u 3
for 2 hr while exposed to 980 ug/m (0.5 ppm) of 03; airway resistance (Raw)
was not affected. No changes in pulmonary function resulted from exposures to
588 or 196 ug/m3 (0.3 or 0.1 ppm) of 03- Horvath et al. (1979) reported that
decreases in FVC and FEV, n resulted from 2-hr at-rest exposures of 15 subjects
3
(8 males, 7 females) to 980 and 1470 ug/m (0.50 and 0.75 ppm) of 03; the
decreases at 0.75 ppm were greater than those at 0.50 ppm of 0~. No changes
3
in pulmonary function were observed at 490 ug/m (0.25 ppm) of 03_
Kagawa and Tsuru (1979a) observed small decreases in specific airway
conductance (SG ) when three subjects rested for 2 hr while exposed to 588
^ clW
and 980 ug/m (0.3 and 0.5 ppm) of 03- In contrast to other studies, this is
the only report of changes in airway resistance resulting from at rest exposures
to03.
Konig et al. (1980) exposed 14 healthy nonsmokers (13 men, 1 woman) for 2
hr at rest to 0, 196, 627, and 1960 ug/m3 (0.0, 0.10, 0.32, and 1.0 ppm) of 03-
019PO/A 11-6 5/2/84
-------
TABLE 11-2. STUDIES ON ACUTE PULMONARY EFFECTS OF OZONE SINCE 1978
Ozone
concentration
ug/mj
196
196
588
980
196
627
1960
235
353
470
588
784
294
588
392
392
ppm
0.1
0.1
0.3
0.5
0.1
0.32
1.0
0.12
0.18
0.24
0.30
0.40
0.15
0.3
0.2
0.2
Measurement '
method
CHEM,
NBKI
CHEM,
NBKI
MAST,
NBKI
CHEM,
UV
CHEM,
NBKI
UV,
NBKI
UV,
NBKI
. Exposure
duration and
activity
2 hr
IE (2xR)
@ 15-min intervals
2 hr
R (10), IE (31,
50, 67)
@ 15-min intervals
2 hr
R
2.5 hr
IE (65)
@ 15-min intervals
2 hr
IE
@ 15-min intervals
2 hr
IE (2xR)
@ 15-min intervals
2 hr
IE (2xR)
@ 15-min intervals
j
Observed effect(s)
No effect on Pa02 or R taking into account
intra-individual variation
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 following exposure; SR
increased with Acfi challenge at ^0.32 ppmf
SR increased in 2/3 COLD patients at 0.1 ppm.
aw
Small decreases in FVC, FEV^o, and
FEF25_75<£ at 0.12 and 0.18 ppm with larger
decreases at £0.24 ppm; f and SR in-
creased and V, decreased at £0.2$wppm;
regression curves produced; coughing
reported at all concentrations, pain and
shortness of breath at iO.24 ppm.
SG and FVC decreased at 0.15 and 0.30
ppm 03. Increased AN2 at 0.15 ppm 03.
Questionable statistics.
No meaningful changes in PA02 , Pa02, and
P(A-a)02. Inconsistent changes in spirometric,
plethysmographic, and ventilatory distribution
variables.
Variable changes in FEV].0. Possible
calibration error for spirometry.
No. and sex
of subjects Reference
11 male von Nieding et al. , 1979
40 male Folinsbee et al . , 1978
(divided into 4
exposure groups)
13 male Kdnig et al . , 1980
1 female
(3 COLD)
(1 asthma)
135 male McDonnell et al . , 1983
(divided into six
exposure groups)
15 male Kagawa, 1983a
13 male Linn et al . , 1979
5 female
9 reactive subjects; Linn et al., 1980
4 (normal)
5 (asthma)
-------
TABLE 11-2. STUDIES OF ACUTE PULMONARY EFFECTS OF OZONE SINCE 1978 (continued)
Ozone
concentration
ug/m3
392
588
784
392
686
392
823
980
i ^^_^__™
oo 392
784
412
490
980
1470
ppm
0.2
0.3
0.4
0.20
0.35
0.2
0.42
0.50
0.2
0.4
0.21
0.25
0.50
0.75
. Exposure
Measurement ' duration and
method activity
UV, 30-80 min
UV (mouthpiece)
CE (34.9, 61.8)
UV, 1 hr (mouthpiece)
UV IE (77.5) @ vari-
able competitive
intervals
CE (77.5)
UV, 2 hr
UV IE (30 for
male, 18 for
female subjects)
@ 15-min intervals
UV, 2 hr
NBKI IE (2xR)
@ 15-min intervals
UV, 1 hr
UV CE (81)
CHEM, 2 hr
NBKI R (8)
Observed effect(s)
Progressive impairment of lung function with
increasing effective dose; questionable sig-
nificance during CE (61.8).
FVC, FEVi.0, and FEF25_75 decreased, subjective
symptoms increased with 03 concentration; f»
increased and V-, decreased during CE; no effect
on V02, HR, Vc, or V.. No exposure mode effect.
t n
Pre-exposure to 0.2 ppm did not alter response
to higher concentrations; FEV^o decreased
in sensitive subjects (n = 9) at 0.2 ppm;
no significant sex differences.
SR increased with histamine challenge
in * subjects at 0.4 ppm. "Adaptation" shown
with repeated exposures.
Decreases in FVC (6.9%), FEVj.o (14.8%),
FEF25_75% (18%), 1C (11%), and MVV (17%).
Symptoms reported: laryngeal and tracheal
irritation, soreness, and chest tightness
on inspiration.
Spirometry: FVC, FEVj.0, and MMFR decreased
immediately following 0.75 ppm; FVC and FEV,.0
decreased immediately following 0.5 ppm. Meta-
bolism: 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.
No. and sex
of subjects Reference
8 male Adams et al., 1981
10 male Adams and Schelegle,
(distance runners) 1983
8 male Gliner et al., 1983
13 female
12 male Dimeo et al., 1981
7 female
(divided into three
exposure groups)
6 male Folinsbee et al . , 1984
1 female
(distance cyclists)
8 male Horvath et al. , 1979
7 female
-------
TABLE 11-2. STUDIES OF ACUTE PULMONARY EFFECTS OF OZONE SINCE 1978 (continued)
Ozone
concentration
ug/ma ppm
588 0.3
980 0.5
588 0.3
7 784 0.4
£>
1176 0.6
Measurement3 '
method
CHEM,
NBKI
MAST,
BAKI
CHEM,
NBKI
UV,
NBKI
Exposure
duration and
activity
2 hr
R
1 hr (mouthpiece)
CE (34.7 for
female and 51
for male subjects)
3 hr
IE (4-5xR)
for 15 min
2 hr (noseclip)
IE (2xR)
@ 15-min intervals
Observed effect(s)d
SG decreased at 0.3 and 0.5 ppm.
Tefioency toward increased bronchial
reactivity to ACh challenge. Smoking
effects were similar to those of ozone.
FVC, FEVj.o and flfzs.tsv decreased; fg
increased and V,. decreased with exercise;
nonsmokers and females may be more sensi-
tive; increase in subjective complaints
noted.
FVC and FEVj.o decreased and bronchial re-
activity to methacholine increased following
exposure. Adaptation shown with repeated
exposure.
SR increased in nonatopic subjects (n = 7)
witrl histamine and methacholine and in atopic
subjects (n = 9) with histamine following
exposure, returning to control values by the
following day; response prevented by pre-
treatment with atropine aerosol.
No. and sex
of subjects
6 male
(equally divided
by smoking history)
12 male
12 female
(equally divided
by smoking history)
13 male
11 female
(divided into 2
phases)
11 male
5 female (divided
by history of atopy)
Reference
Kagawa and Tsuru, 1979a
DeLucia et- al. , 1983
Kulle et al. , 1982b
Kulle, 1983
Holtzman et al . , 1979
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 (Vc) given in L/min or as a multiple of resting
ventilation. fc
See Glossary for the definition of symbols.
-------
Specific airway conductance was measured and samples of arterialized ear lobe
capillary blood were taken for determinations of oxygen tension (P0?) before
and after the exposures. No changes in P07 or SG were observed. Subjective
O
symptoms (substernal burning) were reported by two individuals at 196 ug/m
(0.1 ppm), by three at 627 ug/m3 (0.32 ppm), and by eight at 1960 ug/m3 (1.0 ppm)
of 03.
11.2.2 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 11-2). Exercise during these
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 07. Therefore, results from
O
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 11.3 entitled "Pulmonary Effects Following Repeated Exposures."
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 03 concen-
tration (see Chapter 5) 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 03, such as smoking history, sex, and environmental conditions,
are discussed in this section. Studies on the interaction between 0., and other
pollutants are presented in Section 11.5.
019PO/A 11-10 5/2/84
-------
As previously stated, increased V,. accompanying exercise is one of the
most important contributors to pulmonary decrements during CL 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 11-3 may aid the reader in estimating the VF associated with a
given exercise regimen.
The values for CL consumption and VV in Table 11-3 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
•
the Vp and 0« consumption. If exercise is conducted on a treadmill, adequate
relative standards for Op consumption and Vr 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 03 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) ng/m3 (0.37 or 0.75 ppm) of CL. 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 ug/m (0.75 ppm) of 0,.. 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 0 • the
decrease was greater at the higher level of 0~. 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
inconclusive, RV and CC increased and TLC was unchanged after exposure to
0.75 ppm of 0-
019PO/A 11-11 5/2/84
-------
TABLE 11-3. ESTIMATED VALUES OF OXYGEN CONSUMPTION AND MINUTE VENTILATION ASSOCIATED WITH LEVELS OF EXERCISE0
FV>
Level of work
Light
Light
Light
Moderate
Moderate
Moderate
Heavy
Heavy
Very heavy
Very heavy
Severe
Watts
25
50
75
100
125
150
175
200
225
250
300
Kgm/minb
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)
13
19
25
30
35
40
55
63
72
85
100+
Representative
activities
Level walking at 2 mph; 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
a,
See text for discussion.
Kgm/rain = work performed each minute to move a mass of 1 kg through a vertical distance of 1 m against the force of gravity.
^Adapted from Astrand and Rodahl (1977).
-------
Kerr et al. (1975) reported small, but significant, decreases in FVC, FEV3
RI , and SG when 20 subjects were exposed to 980 ug/m (0.5 ppm) of 0, for 6 hr
L oW O
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,
RV, Cst, dN2, or DLCO were observed.
Von Nieding et al. (1977) exposed normal subjects to 196 ug/m (0.1 ppm)
Og 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 P02 difference and airway
resistance (~ 0.5 cm H20/L/s).
Folinsbee et al. (1977b) demonstrated that the heightened pulmonary
effect of 0, associated with intermittent exercise during exposure occurred
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
2
980-ug/m (0.50-ppm) 0, exposure, the maximum impairment of forced expiratory
spirometry appeared immediately (2 to 4 min) after exercise (Figure 11-1).
Despite continued exposure to 0^, but at rest, pulmonary function either
improved or showed no further impairment. No change in RV or R, was observed,
clw
while TLC was reduced.
Folinsbee et al. (1978) reported results from 40 subjects in studies
designed to evaluate the effects of various concentrations of 0, at several
different levels of activity from rest through heavy exercise. Half of the
subjects had previously resided in an area having high 0, 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/m3 (0, 0.10, 0.30, or 0.50 ppm)
of 0,. 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
019PO/A 11-13 5/2/84
-------
GROUP A
GROUP B
6.5
(0
CD
~ 6.0
O
fc
5.5
(A
0.
5.0
4.5
25 4.0
ffi
u
o
-55 5.0
UJ
"- 4.0
3.5 —
5.5
I I
30 60 90 120 "0 30 60
EXERCISE EXERCISE
EXPOSURE, minutes
90 120
Figure 11-1. Change in forced vital capacity (FVC), forc-
ed expiratory volume in 1-sec (FEV 1.0), and maximal
mid-expiratory flow (FEF25-75%) during exposure to
filtered air (o) or ozone (A) (0.5 ppm) for 2 hr. Exercise
at 45% maximal aerobic capacity (max VO2) was per-
formed for 30 min by Group A after 60 min of ozone
exposure and by Group B after 30 min of ozone ex-
posure.
Source: Folinsbee et al. (1977b).
019PO/A
11-14
5/2/84
-------
3
exposure to filtered air or 196 ug/m (0.10 ppm) of 0~. At rest (10 L/min),
3
pulmonary function changes were confined to 980 ug/m (0.50 ppm) 0,. exposures.
3
Some changes were apparent at the lowest work load (30 L/min) and 588 (jg/m
3
(0.30 ppm) of 0-., 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 function changes
3
occurred at both 588 and 980 ug/m (0.30 and 0.50 ppm), with the changes at
3
980 ug/m (0.50 ppm) of 0,, usually significantly greater than those at
3
588 ug/m (0.30 ppm) of 0~. During exercise, respiratory frequency was greater
and tidal volume lower with 0- exposure than with sham exposure. The change
in respiratory pattern was progressive and was most striking at the two heavi-
est work loads and at the highest 0- concentrations. Reductions in TLC and
inspiratory capacity (1C), but not RV or functional residual capacity (FRC),
were also noted.
In a study similar to that of von Nieding et al. (1977), Linn et al.
(1979) exposed normal subjects to 392 ug/m (0.2 ppm) of 0_. The 12 subjects
had blood and alveolar gas samples taken shortly after 1 and 2 hr of their
2.5 hr of exposure. These subjects also exercised at twice resting ventilation
for 15 min of every half hour. Blood samples were taken both from an arterial-
ized ear lobe and a brachial artery. Alveolar P0? exhibited no changes with
time or exposure. Brachial artery P0? showed highly significant variations
with time, decreasing between the 0 and 1-hr samples and being partially
reversed at 2 hr. The alveolar-arterial oxygen pressure difference [P(A-a)0?]
was increased at 1 hr and reversed at 2 hr. This pattern was seen on both the
no-O,, and 0,, exposure days. Ear lobe sample data showed some differences but
were not related to Q- exposure. In six subjects (bringing the total number
of subjects exposed to 18) on whom both ear lobe and arterial samples were
obtained, the authors reported a significant change in arterial P0?. An
explanation for the differences in response of the P(A-a)0? obtained by these
two groups of investigators was not readily apparent.
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 ug/m3 (0.0, 0.2, 0.3, and 0.4 ppm) of 0^. 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 ug/m (0.30 and 0.40 ppm) of 0- with the
019PO/A 11-15 5/2/84
-------
magnitude of decrement greater at the higher minute ventilation. The magnitude
of decrement also increased with increasing exposure time. No pulmonary
O
effects were observed for exposures to clean air or 392 ug/m (0.2 ppm) of 03.
The authors suggested that the detectable level for 03 functional effects in
healthy subjects during sustained exercise at a moderately heavy work load (V£
of ~62 L/min) occurred between 03 concentrations of 392 and 588 ug/m3 (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) presented data on 15 subjects exercising intermittently
f\
(15 min exercise, 15 min rest) during a 2-hr exposure to 294 or 588 ug/m
(0.15 or 0.30 ppm) of Q^. These subjects reported the typical symptoms at the
higher 03 concentrations. Paired t-tests were used to compare responses to
filtered air and 0~. SGauj decreased 6.4 percent (P <0.05) following the
•^ *3 ClW
294-ug/m (0.15-ppm) exposure and 16.7 percent (P <0.01) following the
588-ug/m (0.30-ppm) exposure. In the latter environment, only FVC showed a
significant (P <0.05) decrement; FEV1 was unaffected. These subjects had
resided in a low-oxiriant-pollutant environment.
McDonnell et al. (1983) provided further information related to high
levels of ventilation during exercise in 135 subjects exposed to 03. 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 03- The subjects were exposed for 2.5 hr, with exposure consist-
ing of alternating 15-min periods of rest and exercise (VE/BSA of = 35 L/m or
VE = 64 to 68 L/min) during the first 2 hr. With continued 03 exposure, forced
expiratory spirometry and pulmonary symptoms were measured between 5 and 10 min
after the final exercise, while plethysmography was performed between 25 and
30 min after the final exercise. The pulmonary symptom, cough, showed the
3
greatest sensitivity to 03 (it occurred at the lowest concentration, 235 ug/m
or 0.12 ppm of 0.,). Small changes in forced expiratory spirometric measures
3
(FVC, FEV-p maximal mid-expiratory flow [FEFpS-75%^ were suggested at 235 ug/m
(0.12 ppm) of 0- and were definitely present at 353 ug/m (0.18 ppm) of 0,.
3
Greater changes were found at and 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
3W
019PO/A 11-16 5/2/84
-------
breath occurred at 03 levels of >470 ug/m (0.24 ppm). The sigmoid-shaped
dose-response curves indicated a relatively large decrease in FVC, FEV,, and
3
FEF25_75c/ between 353 and 470 ug/m (0.18 and 0.24 ppm) 0~. However, in
contrast to the results of other investigations, a plateau in response was
3
observed at the higher levels (>470 ug/m ; 0.24 ppm) of 0_. In contrast to
3
the spirometric tests, SR increased significantly at 470 ug/m (0.24 ppm) of
oW
0~ and continually increased with increasing 0- levels, in agreement with the
results of other investigators. These two different patterns in response plus
the observation that individual changes in SR and FVC were poorly correlated
clW
prompted these investigators to suggest that more than a single mechanism
might have to be implicated to define the effects of 0- on pulmonary functions.
Findings from this study are particularly relevant in that a large subject
population was studied and pulmonary effects were present at an 0,. concentra-
3
tion (235 ug/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
3
ergometer for 1 hr while breathing filtered air or 412 ug/m (0.21 ppm) of 0.,
O
(Folinsbee et al. , 1984). They worked at 75 percent maximal aerobic capacity
(max Vgp) 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), ^^2b-7b% (18 Percent) • IC (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-ug/m (0.35-ppm) 0- environ-
O
ment. Symptoms included laryngeal and/or trachea! irritation and soreness as
well as chest tightness upon taking a deep breath.
Adams and Schelegle (1983) exposed 10 well-trained distance runners to
3
0.0, 392, and 686 ug/m (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 80 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
019PO/A 11-17 5/2/84
-------
increased as a function of 0_ concentration for both continuous and competitive
levels. The high ventilation volumes (80 L/min) resulted in marked pulmonary
function impairment and altered ventilatory patterns (increased fR and decreased
3
VT) when exercise was performed in 392 ug/m (0.20 ppm) of Og. 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%- These
investigators noted that percent decrement in FEV, g was similar to that
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.
11.2.3 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 0- 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 0^ 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. Characterization of reports of individual res-
ponses to 0- is pertinent since it permits the assessment of the proportion of
O
the population that may actually be affected during exposure to 03-
Results from a small number of studies (Horvath et al., 1981; Gliner et
al., 1983; McDonnell et al. , 1983) that have reported individual responses
indicate that a considerable amount of intersubject variability does exist in
the magnitude of response to 03. Figure 11-2 illustrates the variability of
responses in FEV, n and SR obtained from subjects exposed to different 0-
r 1.0 aw °
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
ug/m3 (0.42 ppm) of 0- while performing moderate intermittent exercise. When
J
these same subjects were exposed to clean air under the same conditions, the
response of FEV, _ ranged from an 8-percent increase to an 11-percent decrease
(mean = 0 percent).
019PO/A 11-18 5/2/84
-------
NUMBER OF SUBJECTS
O Ul O OUIO OUIO OUIO OUIO OUIO
1 1 1 1 1 1 1 1 1 1
0.40 ppm
~,rl fflnF
1 1 1 1 1 1 1
0.30 ppm
i H H rn i r
i i i 1 1 i i i
0.24 ppm
TfLrTTJ
i 1 1 In M i !-•
ii i i i i i i i
r~j 0.18 ppm
i "hi n i i i
i i i i i i i i i
0.12 ppm
>-r "T-i i i i i
i i I i i i i i i i
0.00 ppm
1 -1 1 1 1 1 1 1
1 1 1 1 1 1 1 1 1 1
0.40 ppm
-r-Tl H M 1-r-i
1 1 1 I 1 1 1 1 1 1
0.30 ppm
-HThrn n i
1 1 1 1 1 1 1 1 1 1
0.24 ppm
"rlhfL , , ,"
II 1 1 1 1 1 1 1
0.18 ppm
TuTn ,,,,"
i i i i i I i i i i
0.12 ppm
1 I r-i-r-i I I I
I 1 I 1 1 I I 1 M
0.00 ppm
1 1 M 1 1 I 1 1 1
019PO/A
-10 0 10 20 30 40 -20 0 20 40 60 80
AFEV-|.o(DECREASE), percent ASRaw(INCREASE), percent
Figure 11-2. Frequency distributions of
response (percent change from baseline)
in specific airway resistance (SRaw) and
forced expiratory volume in 1-sec (FEVi.o)
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).
11-19
5/2/84
-------
Gliner et al . (1983) exposed subjects (13 females, 8 males) performing
o
intermittent light exercise for 2 hr to clean air and 392 (jg/m (0.20 ppm) of
0.,. 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-. n was +6.0 to -16.6 percent (mean = -4 percent) with exposure to 392
T 1. U
ug/m (0.20 ppm) of 03.
For subjects performing 2 hr of intermittent heavy exercise while exposed
to 0.,, McDonnell et al . (1983) observed changes in FEV, n ranging from -3 to
-43 percent (mean = -16 percent) at 784 ug/m (0.40 ppm), -4 to -38 percent
3
(mean = -17 percent) at 588 ug/m (0.30 ppm), -2 to -41 percent (mean = -15 per-
cent) at 470 |jg/m3 (0.24 ppm), -2 to -22 percent (mean = -7 percent) at 353
3 3
ug/m (0.18 ppm), +7 to -17 percent (mean = -4 percent) at 235 ug/m (0.12
ppm), and +3 to -7 percent (mean = -2 percent) in clean air. Large intersub-
ject variability was also reported for changes in SR , during these exposures
aw
(Figure 11-2).
The factors that contribute to the observed variability of individual
responses have not been identified. One factor to be considered is real
intersubject differences in the stable intrinsic level of responsiveness to
0-. 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
that subject's intrinsic responsiveness. In a 1983 study, Gliner et al .
3
exposed subjects performing intermittent light exercise for 2 hr to 392 ug/m
(0.20 ppm) of 0~ on three consecutive days, followed the next day by an expo-
o
sure to either 823 or 980 ug/m (0.42 or 0.50 ppm) of 0Q. 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) 03. For individual responses of FEv^ Q, a moderate corre-
lation (r = 0.58) between changes resulting from the first exposure to 392
ug/m3 (0.20 ppm) of 03 and the first exposure to 823 or 980 ug/m3 (0.42 or
0.50 ppm) of OT was observed. When responses in FEV-, Q from the first and
second exposures to 0.42 or 0.50 ppm 0- were compared, the correlation between
the two exposures was quite high (r = 0.92). Although these comparisons were
confounded by possible effects of prior 03 exposure, they do suggest that
individual changes in FEV., Q resulting from 03 exposure are reasonably repro-
ducible. Moreover, a given individual's response to a single 03 exposure is
probably a reliable estimate of that individual's intrinsic responsiveness to
019PO/A 11-20 5/2/84
-------
11.2.4 Prediction of Acute Pulmonary Effects
Nomograms for predicting changes in lung function resulting from the
performance of light intermittent exercise while exposed to different CL
O
concentrations were included in one of the earliest reports of the effects of
0~ 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 0~, defined as the
product of concentration, exposure duration, and V.-. Equations were derived
from lung function measurements at 1 and 2 hr of exposure to 725, 980, and
3
1470 ug/m (0.37, 0.50, and 0.75 ppm) of 0_ under conditions of both rest and
intermittent exercise sufficient to increase Vr 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
0- 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 03 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 0_ exposure. 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
980 ug/m (0.0, 0.10, 0.30, and 0.50 ppm) of 03- The exercise loads required
VE of some three, five, and seven times greater than resting ventilations.
Again, the effective dose was calculated as the product of 0, concentration x
Vp (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 Vp, and second on all subject groups together
after computing the effective dose. Figure 11-3 (an example of the calcula-
tions made) presents the linear and polynomial regression lines for percent
change in pulmonary functions (FVC and FEV-. 0) as a function of 0~ concentra-
tion during the 2-hr exposure. Figure 11-4 presents the polynomial regression
lines for percentage change in FEV, 0 as a function of "effective dose" of 0,..
Data from other investigators are also presented. Predictions of pulmonary
function changes in FEV, based on effective doses up to 1.5 ml 03 agreed with
019PO/A 11-21 5/2/84
-------
o
u
O
oc
2
O
O
O
CC
LL
LL
O
2
<
*?•
O
O
>
c
«>
U
a
_J
O
O
o
o
a,
LL
U
CJ
Z
O
cs
>"
LU
LL.
-30
25
-20
-15
MiNUTE VENTILATION
A 10 l/min
S 30 l/min
C 50 i/min
D 70 i/min
0.10 0.20 0.30 0/,0 0,50 0.80
OZONE, spr.i
.25
! I f i
MiiMUTE VENTILATION
S 30 i/min
0 0.10 0.20 0.30 0.40 0.50 0.60
OZONE, ppm
Figure 11-3. Linear and polynomiai
regression iines for percentage
change In pulmonary function [forced
vital capacity (FVC) and 1-sec forced
expiratory volume tF^V^.j)/] as a func-
tion of ozone concentration during a
2-hr exposure with intermittent exer-
cise. Letters indicate groups in which
exercise levels were adjusted to
achieve a given minute ventiiation: A
(rest), B (30 l/min), C ISO i/min), and D
{70 S/min). Nonsignificant Jlnes were
omitted.
Source: Foiinsbee et ai. 11978).
019PO/A
11-22
5/2/84
-------
8
o
GC
O
o
5
o
£
LU
0
<
o
-20
-15
-10
I TTT
T I
I I
+ +S50
J50DI
J37DI
A1.B1.C1.D1
D2
A2 B2A3'C2 I A4 B3
I I II I I I
B4
_L
03
I
C4
I
D4
I
0.0
0.5
1.0
1.5
2.0
2.5
EFFECTIVE DOSE OF OZONE, milliliters
Figure 11-4. Polynomial regression line of percentage change in 1-sec
forced expiratory volume (FEV-j Q) as a function of "effective dose" of
ozone calculated as the product of ozone concentration (ppm),
minute ventilation (l/min), and exposure time (min). A, B, C, D, and
subgroups (•)<= Folinsbee et al., 1978; other studies ( + ) are H =
Hazucha et al., 1973; S = Silverman et al., 1976; F = Folinsbee et al.,
1977a; J = Hackney et al., 1975c; L = Folinsbee et al., 1977b; for which
accompanying numbers indicate ozone concentrations in pphm. Dl
after J37 and J50 refers to the first of two exposure days. SR75 refers
to resting exposure at 0.75 ppm from reference S.
Source: Adapted from Folinsbee et al. (1978).
019PO/A
11-23
5/2/84
-------
data collected by other investigators. Prediction equations using the effec-
tive 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 0- exposure. Duration of exposure was not analyzed as
a contributing factor since all exposures were of equal time. Their analyses
indicate that essentially all of the variance of pulmonary responses could be
explained by 0_ concentration and Vp. For example, these two predictors
accounted for approximately 80 percent (multiple r = 0.89) of the variance in
FEV-. n. Moreover, 0- concentration accounted for more of variance than did
J. * U J
Vp, and for a given effective dose, exposure to a high concentration with a
low VV induced greater functional decrements than exposure to a lower concen-
tration with elevated VV. Equations (with appropriately weighted 03 concentra-
tion and Vp) 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 VF, 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 jjg/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-
O
tories. Basically, he examined changes in R and FEV, „ as functions of
dW -L • \J
exposure rate (0- concentration x Vp) 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 FEV1 Q. The
author states that he elected to use linear equations to fit the data rather
019PO/A 11-24 5/2/84
-------
than polynomials because he found little difference in the degree of correla-
tion between the two methods. This statement somewhat contradicts his observa-
•
tion of an attenuation in the rate of increase of SR as Vc increased to
aw t
higher levels; there was no attenuation of the decrease in FEV, g as a function
of increasing Vp. This observation suggested to Colucci that different mecha-
nisms may be involved in the effects on R and FEV, n. Whether expressed as
d w J- • \J
functions of exposure rate or total exposure dose, the patterns of pulmonary
responses were approximately 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 0^ concentration
and Vp. The overall finding, that increases in R and decreases in FEV^^ Q
are reasonably correlated with increases in effective dose of 0.,, 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.
11.2.5 Bronchial Reactivity
In addition to overt changes in pulmonary function, several studies have
reported increased nonspecific airway sensitivity resulting from 0^ 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
•3
1176 ug/m (0.6 ppm) of 0~. The resting subjects breathed orally (a nose-clip
was worn). These investigators concluded that 0~ 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 ug/m3 (0.0, 0.3, and 0.5 ppm) 03- 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.
019PO/A 11-25 5/2/84
-------
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
o
exposed by mouthpiece to filtered air and 1176 ug/m (0.6 ppm) of 0~. Bronchial
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
aw 3 aw
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,
dw
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 al., 1978), which indicated that
enhanced bronchial responsiveness persisted for a more prolonged period.
Premedication with atropine sulfate aerosol prevented the increase in SR
aw
histamine inhalation. Atopic subjects appeared to respond to a greater degree
than nonatopic subjects, although the pattern of change and the induction and
time course of increased bronchial reactivity after exposure to CL were un-
related to the presence of atopy.
Kb'nig et al. (1980) exposed 14 healthy nonsmokers (13 men, 1 woman) for
2 hr to 0, 196, 627, and 1960 |jg/m3 (0.0, 0.10, 0.32, and 1.00 ppm) of 0,.
Bronchial reactivity to ACh was determined after exposure. Significant in-
creases in bronchial reactivity were observed with the ACh challenge at
3 3
627 ug/m (0.32 ppm) and 1960 ug/m (1.0 ppm) of 0-.
Bronchial reactivity of normal adult subjects was assessed by measuring
the increase in SR produced by inhalation of histamine aerosol (Dimeo et al.,
1981). Seven subjects, intermittently exercising (15 min exercise, 15 min
3
rest) at a load sufficient to double their resting VE, were exposed to 392 ug/m
(0.2 ppm) of 0,. 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
019PO/A 11-26 5/2/84
-------
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
3
and to 784 ug/m (0.4 ppm) of 0~ 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 aW
0.4-ppm exposure remained unchanged.
As part of a study of repeated exposures to 0.. (discussed in detail in
Section 11.3), 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 0,. One hour before the end of exposure, 15 min of exercise
at 100 W was performed approximating a Vp 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
0,, as compared to filtered-air exposure.
11.2.6 Mechanisms of Acute Pulmonary Effects
The primary acute respiratory responses to 0~ exposure are decrements in
O
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 fD and
K
decreased VT with V,. remaining unchanged) and small increases in airway resis-
tance have also been observed.
Decrements in FVC observed at relatively high (1470-ug/m ; 0.75-ppm) 03
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 0, on small airway smooth muscle or by interstitial pulmonary
edema.
3
At 0_ 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 et al., 1975c; Folinsbee
et al. , 1977b; Folinsbee et al. , 1978). Moreover, a decrease in inspiratory
effort, rather than a decrease in lung compliance, most likely causes the
019PO/A 11-27 5/2/84
-------
reduced inspiratory capacity resulting from 03 exposure (Bates and Hazucha,
1973; Silverman et al., 1976; Folinsbee et al., 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 et al., 1976; Folinsbee et al., 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).
Unless measured at absolute lung volumes, decrements in forced expiratory
flows (e.g., FEV ~, FEFpc.ycy) are difficult to interpret. Surely, most of
the decline in flow is related to reduced maximal expiratory position, while a
smaller portion results from 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 0.,-induced, locally released substance) on smooth muscle or mucosa (Folinsbee
et al., 1978; Holtzman et al., 1979; McDonnell et al., 1983). While it is
possible that stimulation of airway receptors is the mechanism common to
changes in airway resistance as well as in volumes and flows, McDonnell et al.
(1983) have postulated the existence of more than one mechanism of action for
Ov They base this postulation on their observed lack of correlation between
O
individual changes in FVC and SR and on differences in dose-response curves
d.W
for these two variables.
Two hypotheses have been proposed that are consistent with the observations
of increased airway reactivity to histamine and methacholine following 03
exposure (Holtzman et al., 1979). The first suggests that 03 increases airway
epithelial permeability, resulting in greater access of histamine and methacholine
to bronchial smooth muscle and vagal sensory receptors. The second hypothesis
suggests that 0- or a byproduct of CL causes an increase in the number or the
binding affinity of acetylcholine receptors on bronchial smooth muscle.
019PO/A 11-28 5/2/84
-------
11.2.7 Pre-existing 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 emphysematics 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 individ-
uals experienced chronic respiratory conditions. That the effects of air
pollutants on this large segment of our population have not received more
attention by clinical investigators is surprising. In clinical studies that
have been published, individuals with asthma or chronic obstructive lung
disease (COLD) do not appear to be more sensitive to the effects of 0, exposure
than are normal subjects. Table 11-4 presents a summary of data from 0.,
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 CL, and 392 \jg/m
(0.20 ppm) 0- with secondary stressors of heat (31°C, 35 percent rh) and
intermittent light exercise (VV = 2 x resting Vp). 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
o J
chamber), and a 392- to 490-pg/m (0.20- to 0.25-ppm) 03 condition (a 3-day
control study was conducted over 3 days [0 ppm 0.,] on 14 of these individuals).
During each 2-hr exposure condition, subjects exercised for the first 15 min
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
019PO/A 11-29 5/2/84
-------
TABLE 11-4. OZONE EXPOSURE IN SUBJECTS WITH PULMONARY DISEASE
Ozone ,
concentration Measurement
ug/m3 ppiii method
h-1
1 — i
1
CO
o
196 0.1
627 0.32
1960 1.0
235 0.12
353 0.18
490 0.25
392 0. 2
392 0.2
588 0.3
490 0. 25
784 0.4
MAST,
NBKI
UV,
NBKI
UV,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
UV/CHEM,
UV
Exposure
duration and
activity
2 hr
R
1 hr
IE (variable)
& 15-min intervals
1 hr
IE (variable)
@ 15-min intervals
2 hr
IE (2xR)
@ 15-min intervals
2 hr
IE (28) for
7.5 min each
half hour
2 hr
R
3 hr/day
6 days
IE(4-5xR)
for 15 min
Observed effect(s)
No effect on SR and Pa02 ; increased bronchial
reactivity to ACn at 0.32 and 1.0 ppm in healthy
subjects. SR increased following ACh
challenge in f/3 COLD subjects at 0.1 ppm.
No significant changes in forced expiratory
performance or symptoms. Decreased Sa02
during exercise was observed.
No significant changes in forced expiratory
performance or symptoms. Group mean Sa02 was
not altered by 03 exposure.
No significant changes in pulmonary function.
Small changes in blood biochemistry. Increase
in symptom frequency reported.
No significant changes in pulmonary function or
symptoms. SaOz decreased during exposure to
0.2 ppm.
No significant effect on pulmonary function.
V50 decreased in approximately 1/3 of the
subjects demonstrating selective sensitivity
to 03.
FVC and FEV3 decreased on the first of five
consecutive exposure days and with re-exposure.
No. and
description
of subjects Refe'rence
3 COLD Konig et al. , 1980
1 asthma
14 healthy
25 COLD Linn et al. , 1982a
Hackney et al. , 1983
28 COLD Linn et al. , 1983
22 asthma Linn et al., 1978
13 COLD Solic et al., 1982
Kehrl et al. , 1983
17 asthma Silverman, 1979
20 smokers with Kulle et al., 1984
chronic bronchitis
Measurement method: MAST = Kl-Coulometric (Mast meter); CHEM = gas-phase chemiluminescence; UV = ultraviolet photometry.
Calibration method: NBKI = neutral buffered potassium iodide; UV = ultraviolet photometry.
Activity level: R = rest; IE = intermittent exercise; minute ventilation (V^) given in L/min.
See Glossary for the definition of symbols.
-------
despite the investigators' suggestion that asthmatics may react biochemically
at lower 0, concentrations than nondiseased individuals.
Clinically documented asthmatics (16 years duration of asthma) were
3
exposed either to filtered air or 490 jjg/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.
Data from clinical studies have not indicated that asthmatics are more
sensitive to 0~ than are normal subjects. However, the relative paucity of
studies and some of the experimental design considerations (subject popula-
tion, control of medication, exposure VE, appropriateness of pulmonary function
measurements) in the two studies that have been published suggest that the
responsiveness of asthmatics to 0^, relative to normal subjects, may be an
unresolved issue. (This issue is treated in more detail in Chapter 13).
Linn et al. (1982a) studied 25 individuals (46 to 70 years old) with
COLD; 12 percent were nonsmokers and the remainder were moderate to heavy
smokers, with 11 individuals not smoking at this time. All had chronic res-
piratory symptoms with subnormal forced expiratory flow rates. Each subject
3
underwent a control filtered air and a 235-pg/m (0.12-ppm) 0_ exposure (ran-
domized) 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 VF 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 (SaO?) (Hewlett-Packard ear oximeter) were made.
Only one pulmonary function test showed a significant difference related to 03
019PO/A 11-31 5/2/84
-------
(no tabulated data were presented). From pre-exposure values at rest (normal
saturations) to mid-exposure values during exercise, mean SaCL increased by
0.65 ± 2.28 percent with purified air, but decreased by 0.65 ± 2.86 percent
with 0-. This difference was significant. However, the decrement attributable
to 03 was near the limit of resolution 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, inter-
preting changes in SaO,, 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
days, one to filtered air (sham OO and one to 392 |jg/m (0.2 ppm) of 0, in a
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 Vp to 20 to 30 L/min
and an oxygen uptake of *» I L/min. SaOp 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 0_
exposure in any of the spirometric measurement values or symptoms. The only
significant alteration resulting from 0,, exposure was found in SaO«, 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-. However, in this experiment the
3
subjects were exposed to 588 |jg/m (0.3 ppm) of 03- Kehrl et al. used a
protocol similar to that used by Solic et al. Data presented consisted of
3
measurements made during the 392-ug/m (0.2-ppm) exposure, as well as new data
3
obtained during the 588-ug/m (0.3-ppm) exposures. The second exposure occurred
6 to 9 months later. No statistically significant Og-induced changes in
respiratory mechanics or symptoms were found in the COLD patients at either 0-
019PO/A 11-32 5/2/84
-------
concentration. These observations are consistent with those obtained on
normal individuals who exercised intermittently at similar levels of ventila-
tion. Patients with COLD are exercise-limited, and studies that would induce
higher ventilation are apparently not feasible. Therefore, it cannot be
determined whether the failure to detect respiratory decrements could have
been demonstrated if these individuals had been exercising more vigorously at
3
588 |jg/m (0.3 ppm) of 0,, inducing changes similar to those observed in
normals at the same concentration.
Linn et al. (1983) presented data on 28 COLD patients exposed for 1 hr to
3
0, 353, and 490 |jg/m (0.0, 0.18, and 0.25 ppm) of 0_. These subjects exer-
cised for the first and third 15-min periods and rested in the second and
fourth periods. The exercise performed varied in intensity as did the corre-
sponding VE. 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 0- exposures even at levels of 0_
exceeding first-stage alert levels. In contrast to other reports of a small
decrement in SaO?, 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 Sa02 may be of some significance, although they were not
confirmed in subsequent studies at higher 03 concentrations. The exercise
performed in these studies was of very low intensity, and results from 0^
J
exposures where COLD patients exercised at higher intensities may be of
interest. However, the possibility that increased exercise intensity will be
a relevant factor is unlikely; COLD patients in general cannot sustain much
higher work outputs than used in these studies because of their limited maximal
ventilation and possible cardiovascular insufficiency.
Kb'nig 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
019PO/A 11-33 5/2/84
-------
3
to 196 ug/m (0.1 ppm) of 0_ 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
dw
after the 03 exposure. The asthmatic patient was not affected by exposure to
this level of 0.,. 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 for 3 hr to
3
filtered air and 804 ug/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 FEV~ decreased significantly with exposure to 0~ compared
to clean-air exposure; the decreases were small in magnitude (< 3 percent),
and respiratory symptoms were mild.
11.2.8 Other Factors Affecting Pulmonary Responses to Ozone
11.2.8.1 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 ug/m3 (0.37 and 0.75 ppm) 03- 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 03 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 FEFrc were greater for
nonsmokers after either 0., exposure, whereas smokers exhibited greater decre-
3
ments in FEV, „ and 50% V . Smokers exposed to 1470 ug/m (0.75 ppm) of 0_
i. u max -j
had a greater decrease in FEF^Try than did nonsmokers. The ^25-757 cnan9es
were much larger than the changes in FEV, ,,, regardless of 0., concentration,
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)
to 980 ug/m (0.5 ppm) of 0, for 6 hr, during which time the subjects exercised
twice for 15 min each (Vp = 44 L). For the remainder of the exposure time the
subjects were resting. Follow-up measurements were made 2 and 24 hr later. A
019PO/A 11-34 5/2/84
-------
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
O
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 was observed, for the most part in nonsmokers
aw
experiencing subjective symptoms. (All nonsmokers experienced 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 filtered-
0
air environment or one containing 588 ug/m (0.3 ppm) of O^. 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_V1
clw
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 OT. 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
exposed to 294 jjg/m (0.15 ppm) of 0^ for 2 hr to his standard intermittent
rest-exercise regime. SG was measured three times: at 1 and 2 hr during
dW
exposure and also at 1 hr post-exposure. Significant decreases were found
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 (L, were not presented in
enough detail to permit independent evaluation of the findings.
019PO/A 11-35 5/2/84
-------
DeLucia et al. (1983) reported that smokers (six men and six women) were
0
relatively resistant to the oral inhalation of 588 ug/m (0.3 ppm) of Or Few
O
smokers detected the presence of 0,, whereas the majority of nonsmokers (six
men and six women) experienced significant discomfort. Pulmonary function
tests (FVC, FEV, and FEVo5-757^ were made Pre~ anc' 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
that women nonsmokers were more sensitive to 588 (jg/m (0.3 ppm) of 0^ 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 Oo-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 0, environment.
Ozone exposure alone (no smoking during exposure) resulted in the typical and
anticipated decreases in pulmonary functions (FVC, FEV-, Q, 25% V , and 50%
V ) 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
(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 03 exposure. There was no significant interaction
between cigarette smoking and responses to Do-
ll. 2. 8. 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
019PO/A 11-36 5/2/84
-------
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. 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
3
1470 ug/m (0.50 and 0.75 ppm), with greater changes occurring at the highest
OT concentration. The average decrements in FEV-, Q were 3.1 and 10.8 percent,
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/m3 (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 £^25-75% indicated tnat Pr"i°r 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 11.3). Although differences between men and
women were reported for all three measurements, with men having expected
larger expired volumes and flows, there were no pollutant interactions for six
subjects, indicating that male and female subjects responded to 0^ in a similar
fashion.
019PO/A 11-37 5/2/84
-------
DeLucia et al. (1983) reported on 12 men and 12 women (equally divided by
smoking history) exercising for 1 hr at 50 percent of their max V00 while
2
breathing 588 ug/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, ~ (7.9 percent), and ^25-75?
(12.9 percent), there were no significant differences between the sexes.
These investigators also found increases in fn and decreases in VT during
exercise. These effects are similar to those reported by other investigators.
Gibbons and Adams (1984) recently reported the effects of exercising 10
young women for 1 hr at 66 percent of max V00 while the women breathed 0, 297,
3
or 594 ug/m (0, 0.15, or 0.30 ppm) of 0Q. Significant decrements in forced
3
expiratory function were reported at 594 ug/m (0.30 ppm) of O^. Comparison
of these effects with the results from male subjects previously studied by the
authors (Adams et al. , 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 subjects.
11.2.8.3 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 0~. 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 03 exposure at standard environmental conditions in other controlled
studies.
Folinsbee et al. (1977b) studied the effects of a 2-hr exposure to
o
980 ug/m (0.5 ppm) of 03 on 14 male subjects under four separate environmental
conditions: (1) 25X 45 percent rh; (2) 31
-------
Figure 11-1). 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 0- exposure were combined
(WBGT=92.0gF), but this effect was only significant for FVC. In a similar
3 3
study with eight subjects exposed to 980 ug/m (0.5 ppm) of 0~ plus 940 |jg/m
(0.5 ppm) of nitrogen dioxide (NOO (Folinsbee et al . , 1981) (Section 11.6.3),
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 increased ventilation since ventilatory volume and tidal volume
increased significantly at the highest thermal condition studied (40yC,
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 OT. These studies were conducted at two ambient conditions,
i.e. 24y 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
3
297 pg/m (0.15 ppm) of 03. Significant reductions in FVC, FEV, Q, TLC, and
P < 0-004) were reported as a consequence of exercising at 594 ug/m
(0.30 ppm). Pre-post decrements in FVC, FEV, Q, and ^25-757 in the 0.30 ppm,
24yC 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 O^ and 35yC condition. Only FVC differed significantly between the
two temperature conditions. Some subjects failed to complete the exercise
period in 35PC and 0.30 ppm 0~, 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.
11.3 PULMONARY EFFECTS FOLLOWING REPEATED EXPOSURE TO OZONE
Just as pulmonary function decrements following a single exposure to 0,.
are well documented, several studies of the effects of repeated daily exposures
019PO/A 11-39 5/2/84
-------
to 0,. have also been completed (Table 11-5). In general, results from these
studies indicate that with repeated daily exposures to CL, 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 CL exposure similar to that observed
prior to repeated exposures. Repeated daily exposure to a given low concentra-
tion of 0., does not affect the magnitude of decrement in pulmonary function
resulting from exposure at higher CL concentration.
All the reported studies of repeated responses to CL 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 CL 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 CL-induced pulmonary
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 CL exposure, such as cell damage and death. 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 03 exposure and changes
in response or responsiveness of the subject to imply alterations in the
magnitude of these decrements will be retained.
019PO/A 11-40 5/2/84
-------
TABLE 11-5. CHANGES IN LUNG FUNCTION AFTER REPEATED DAILY EXPOSURE TO AMBIENT OZONE
Ozone
Concentration
ug/n3
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
Measurement8'
method
CHEH, NBKI
UV, UV
UV, UV
CHEH, NBKI
CHEH, NBKI & HAST, NBKI
CHEM, NBKI & HAST, NBKI
CHEH, NBKI & HAST, NBKI
UV, NBKI
CHEH, NBKI & UV, UV
UV, UV
UV, NBKI
CHEH, NBKI
CHEM, 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 hr
IE(30)
IE(18 &
IEQ8 &
IE(30)
IE(4-5
IE(4-5
IE(4-5
IE(2 x
IE(4-5
IE(30)
IE(3 x
IE(30)
, IE(2
30)
30)
x R)
x R)
x R)
R)
x R)
R)
x R)
No. of
subjects
10
21
9d
10
14
13e
lle
7f
209
24
ll(7)h
8
6
Percent change in FEVt.0 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
References
Third Fourth Fifth
-1.
-1.
-3.
-2.
-4.
-5.
-4.
0
0
'-18.
-11.
-3.
-2.
6
1
2
2
7 -3.2 -2.0
3 -0.7 -1.0
1 -3.0 -1.6
-0.6 -1.1
0 -6.3 -2.3
9 -4.3
5
4 -0.7
Folinsbee et al. , 1980
Gliner et al . , 1983
Gliner et al. , 1983
Folinsbee et al. , 1980
Farrell 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
given in L/min or as a multiple of resting
0 of more than 20%.
Measurement methods: HAST = Kl-coulometric (Hast meter); CHEM = gas-phase chemiluminescence, UV = ultraviolet photometry.
Calibration methods: NBKI = neutral buffered potassium iodide; UV = UV photometry.
Exposure duration and intermittent exercise (IE) intensity were variable; minute ventilation (VV)
ventilation.
Subjects especially sensitive on prior exposure to 0.42 ppm 03 as evidenced by a decrease in FEVj
These nine subjects are a subset of the total group of 21 individuals used in this study.
p
Bronchial 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.
-------
Hackney et al. (1977a) performed the initial experiments that demon-
strated that repeated daily exposures to ()„ 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 O
a history of allergies. They were exposed for approximately 2.5 hr to 980 ug/m
(0.5 ppm) of 0- 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 FEF75 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 (AN?), 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 1 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
3
filtered-air environment, followed in a second week with exposures to 784 ug/m
(0.4 ppm) of 03. Pulmonary function (FVC, FEV-^ FEV3, SGgw, and FRC) was
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 analysis of variance for significant differences
between the control and 0« exposure weeks, using each day of each exposure to
make the comparisons. The analysis of variance showed that FVC, FEV,, FEV_,
and SG differed significantly between control and 0~ exposure weeks. No
oW O
changes in FRC were found. In the 0_ exposure, SG decreased significantly
*5 dw
019PO/A 11-42 5/2/84
-------
only on the first 2 days; this response was similar to air exposure day values
on the last 3 days. The decrements were significantly greater on the second
day than on the first. Decrements in FEV, ,. and FEV~ Q 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, „) and fourth day
(FEV, n) of 0_ 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 03- Reporting of symptoms was maximal on the
second 0~ day. These investigators noted that five consecutive days of expo-
3
sure (10 subjects) to 588 ug/m (0.3 ppm) of 0_ failed to induce significant
changes in FVC or SG , implying that measurable changes are likely to occur
clw f~j
in pulmonary function at 0- concentrations between 588 and 784 ug/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 35°C and 45 percent rh to filtered air on day 1, to 0- 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 0~: group 1 (n=10),
o 3
392 ug/m (0.20 ppm) of 0~; group 2 (n=10), 686 ug/m (0.35 ppm) of 0,; group 3
3
(n=8), 980 ug/m (0.50 ppm) of 0.,. Subjects alternately rested and exercised
at a VP of 30 L/min for 15-min periods. There were no significant acute or
3
cumulative effects of repeated exposure to 392 (jg/m (0.20 ppm) of Ov With
3
exposure to 686 ug/m (0.35 ppm) of 0,, decrements in forced expiratory varia-
bles appeared on the first 0- exposure day. Similar decrements occurred on
the second 0_ 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
2 days. In group 3, marked decrements in pulmonary function occurred (FEV, ,.
3
decreased 8.7 percent) after the first exposure to 980 ug/m (0.50 ppm) of 0.,;
these decrements were even greater (FEV, Q decreased 16.5 percent) after the
second 0- exposure (Figure 11-5). While not totally abolished, an attenuation
O
of these decrements (FEV, Q decreased 3.6 percent) was observed following the
third 0- exposure. The subjects claimed the most discomfort for the second 03
exposure. Many noted marked reductions in symptoms on the third consecutive
3
day of exposure to 0-. Two additional subjects were exposed to 980 ug/m
(0.50 ppm) of 0_ for four consecutive days. Although effects of 03 on pulmonary
019PO/A 11-43 5/2/84
-------
A. GROUP 2
CO
P- 5.0
» 4.8
4-6
4.4
"FILTERED!
AIR
_ DAY1
OZONE
DAY 2
1
1
1
I ' ' ' ' I
OZONE
DAY 3
OZONE
DAY 4
i
i
•FILTERED!
AIR
DAY 5 _
£ 1 2 3 4 fc £1234Hg1234Hg1234fc £ 1 2 3 4 fc
Q. OB- 0°- OB- O °- O
o. a. o. a. a.
B. GROUP 3
CO
Q.
m
CO
05
UJ
5.2
5.0
4.8
4.6
? 4.4
4.2
4.0
IFILTEREDI
AIR
DAY1
3 B i I I I I I I I I I
OZONE
DAY 2
i i
OZONE
DAYS
OZONE
DAY 4
TFILTEREDI
AIR
DAY 5
O
a.
l i i i i I I I i i I I ) i i i i I
1 2 3 4fc g ! 2 3 4&
00- 00- C
a. Q. Q,
Figure 11-5. Forced expiratory volume in 1-sec (FEV*).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.
Source: Folinsbee et al. (1980).
019PO/A
11-44
5/2/84
-------
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 0~. 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 980 ug/m
(0.5 ppm), but to estimate the persistence of the attenuation of pulmonary
responses. During the 125 min of exposure, 24 male subjects alternately rested
*
and exercised (Vp = 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 0,. exposures. Selected subjects were
then randomly assigned to return after 6 to 7, 10 to 12, and 17 to 21 days for
a single exposure to 0-. Ambient 0- levels in the locations where the subjects
lived seldom exceeded 235 ug/m (0.12 ppm). The major pulmonary function
measurements made and subjected to statistical analysis on these subjects were
FVC, FEV-., and FEF-j. 7cc/- Changes with time in all three measurements were
similar and major emphasis was directed toward FEV-. changes, since it was
believed that this measurement would be commonly used in later epidemiological
studies. 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 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,
on days 4 and 5 had decreased significantly from day 3, but were still signifi-
cantly larger than those with exposure to filtered air. Subjective symptoms
followed a similar pattern, with subjects on the fifth day indicating that
019PO/A 11-45 5/2/84
-------
they had not perceived any 0-. Two subjects showed little attenuation of
response to 03, and one subject was not affected by the 0- exposures. Subjects
who were more responsive on the first day of exposure required more frequent
daily exposure to attenuate response to 0.,. Sixteen subjects were randomly
requested to return for an additional 03 exposure on days noted in Figure
11-6. 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 CL was directly related to the magnitude of the initial response;
(2) the longer it took for attenuation of pulmonary response to 03 to occur,
the longer attenuation persisted; and (3) in some individuals, attenuation of
pulmonary response to CL may persist up to 3 weeks. The mechanism responsible
for attenuation of response 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 0.,. 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 ug/m (0.47 ppm) CL. Exposure consisted of alternating
15-min periods of moderate exercise (Vp = 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 CL 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 03 exposure day FEV, decreased 11 percent,
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.
019PO/A 11-46 5/2/84
-------
FILTERED
AIR
PRE-EXPOSURE
DAILY 2-hr EXPOSURE
TO 0.42 ppm O3
12345
I I I T
H
0.42 ppm O3,
1 WK
POST EXPOSURE
a>
tl
&
q
^
UJ
<
-I- IU
o
10
-20
-30
-40
—
1
I
'%& W/A
A
- GROUP 1 -
n = 4
FILTERED
AIR
PRE-EXPOSURE
DAILY 2-hr EXPOSURE
TO 0.42 ppm O3
12345
\ I I I T
-I
0.42 ppm O3,
2 WKS
POST-EXPOSURE
0)
u
<5
a
LU
+ 10
0
10
-20
-30
-40
B
GROUP 2 H
n = 6
FILTERED
AIR
PRE-EXPOSURE
DAILY 2-hr EXPOSURE
TO 0.42 ppm O3
12345
0.42 ppm O3,
3 WKS
POST-EXPOSURE
I
v
a.
p
t-
Figure 11-6. Percent change (pre-post)
in 1-sec forced expiratory volume
(FEVi.Q), as the result of a 2-hr ex-
posure 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).
019PO/A
11-47
5/2/84
-------
To evaluate persistence of attenuated response, subjects repeated 0- exposures
O
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 identical to those observed after the first exposure to 0-
(FEV, Q decreased 11 percent). This magnitude of pulmonary decrement was also
observed with subsequent 0, exposures. Subjective symptoms generally paralleled
lung-function studies, as had been observed in all previous studies. Since
attenuation 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 a!., 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 |jg/m (0.4 ppm) of 0- on the
second day, while they exposed the remaining 13 subjects for 4 days to filtered
3
air and then to 784 ug/m (0.4 ppm) of 0_ 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
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 0, may be related to the magnitude of
decrement in response observed with the initial exposure to 03.
Gliner et al. (1983) performed a study to determine whether daily repeated
exposures to a low concentration of 0- (392 ug/m ; 0.20 ppm) would attenuate
pulmonary function decrements resulting from exposure to a higher 0., concentra-
•3 J
tion (823 or 980 ug/m ; 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
3
(0.0 ppm 0,) on day 1, to 392 ug/m (0.20 ppm) of 0, on days 2, 3, and 4, and
O
to 823 or 980 ug/m (0.42 or 0.50 ppm) of 0- on day 5. For comparison, subjects
019PO/A 11-48 5/2/84
-------
who were exposed to 0.42 or 0.50 ppm of 0, 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 0-
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
ug/m3; 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) 03.
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
3
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) 0, 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 00 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,
•
V^, and 03 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 03 did not attenuate the response to
a subsequent exposure at a higher effective dose of O,. The pattern of pulmonary
function decrements was evaluated following repeated daily 4-hr exposures to
784 ug/m (0.40 ppm) of 03 with two 15 min periods of heavy exercise (VV = 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 ug/m (0.4 ppm) of 03 for two consecutive days
019PO/A 11-49 5/2/84
-------
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
and Friday of week 1 (control days), were exposed to 804 ug/m (0.41 ppm) 03
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 0~ on Tuesday. Bicycle
ergometer exercise was performed at 2 hr of exposure at an intensity of 100 W
for 15 min (V£ ^ 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
FVC once again appear. These data also support the contention that persistence
cf an attenuated pulmonary response to 03 is related to the magnitude of the
initial response.
To determine if nonspecific bronchial reactivity is a factor involved in
the attenuation of pulmonary responses to 0~, Dimeo et al. (1981) evaluated
the effects of single and sequential 0- exposures on the bronchomotor response
to histamine. To determine the lowest concentration of 0- that causes an
increase in bronchial reactivity to histamine and to determine whether adapta-
tion to this effect of 0- 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-
tion of 10 breaths of histamine aerosol (1.6-percerit solution). In five
019PO/A 11-50 5/2/84
-------
subjects, bronchial reactivity was determined on four consecutive days without
exposure to (L (group I). In seven other subjects (group II), bronchial
reactivity was assessed on two consecutive days; subjects were exposed to
3
392 |jg/m (0.2 ppm) of 0, 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
3
next three consecutive days after 2-hr exposures to 784 ug/m (0.4 ppm) of 0-,.
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
o Q 3W Q
noted after the first exposure to 784 ug/m (0.4 ppm) but not to 392 (jg/m
(0.2 ppm) of 0~. With three repeated 2-hr exposures to 0.4 ppm on consecutive
days, the ASR produced by histamine progressively decreased, returning to
aW
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 OT developed
with repeated exposures. The lowest concentration of 0, (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 0, 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.
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 ug/m (0.4 ppm) 0^ during week 2. During week 3, they exposed 11 subjects
3
to filtered air on the first day and to 784 ug/m (0.4 ppm) 0~ on the second
day, while they exposed the remaining 13 subjects for 4 days to filtered air
3
and then to 784 ug/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 chal-
lenge test was performed to determine bronchial reactivity to methacholine,
019PO/A 11-51 5/2/84
-------
defined as the log of the methacholine dose that provoked a 35 percent decrease
in SGaw from control. Bronchial reactivity to methacholine observed after
exposure to 03 on the iniital 2 to 3 days was significantly increased over
that observed after exposure to filtered air, with no significant differences
on the fourth and fifth days of exposure or with re-exposure 7 days later.
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.
11.4 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 10) 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.
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
o
was as low as 39.2 ug/m (0.02 ppm of GO. Perception at this low level did
not persist, being seldom noted after some 0.5 to 12 min of exposure. The
o
odor of Oo became more intense at concentrations of 98 ug/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 0» was between 0.015 and 0.04 mg/m (0.008 and 0.02 ppm). The few subjects
019PO/A 11-52 5/2/84
-------
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 ug/m3 (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-ug/m
(0.75-ppm) 03 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 EEC during psychomotor performance.
In the first experiment, a 2-hr visual sustained attention task was unaffected
by exposure to filtered air or 1470 ug/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
03 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 0., expo-
sure and filtered air using the different parameters obtained from the EEG
spectral analysis. Given the inability to obtain a discrimination between
3
clean air and 1470 (jg/m (0.75 ppm) of 0, using these techniques, EEG analysis
does not appear to hold any promise as a quantitative method of assessing
health effects of low-concentration (i.e., < 1484-ug/m ; 0.3-ppm) 03 exposure.
Mihevic et al. (1981) examined the effects of 0_ exposure (0.0, 588,
3
980 ug/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/mi n, and finally
rested for an additional 40 min. Pulmonary function measurements (FVC, FEV
and MEFpryc-) were made during rest periods and after exercise. The primary
019PO/A 11-53 5/2/84
-------
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,, and MEF25_75 were signifi-
cantly greater (P <0.01) immediately after exercise than in the rest condition
3
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 0., 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 12) 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
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 11-6). Folinsbee et al. (1977a) observed that maximal aerobic
capacity (max V0?) decreased 10 percent, maximum attained work load was reduced
oy 10 percent, maximum ventilation (max Vp) decreased 16 percent, and maximum
3
heart rate dropped 6 percent after a 2-hr 0., exposure (1470 pg/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 pg/m (0.15 and 0.30 ppm)
0_ (mouthpiece inhalation). No effects on maximum work rate or max VO^ were
found, although a significant reduction in max VF was observed during the
3 . t
588-ug/m (0.30-ppm) exposure. Similarly, max VQ2 was not impaired in men and
019PO/A 11-54 5/2/84
-------
TABLE 11-6. EFFECTS OF OZONE ON EXERCISE PERFORMANCE
en
Ozone
concentration
ug/m3
294
588
392
686
412
490
980
1470
1470
ppm
0.15
0.30
0.20
0.35
0.21
0.25
0.50
0.75
0.75
Measurement '
method
UV,
NBKI
UV,
UV
UV,
UV
CHEM,
NBKI
MAST,
NBKI
k Exposure
duration and
activity
30 min (mouthpiece)
R & CE (8xR)
@ progressive work
loads to exhaustion
1 hr (mouthpiece)
IE (77.5) @ 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 VV
decreased with 0.30 ppm 03.
FVC, FEV,.0) and FEF25_75 decreased,
subjective symptoms increased with 03
concentration at 68% max V02 ; f., in-
creased and VT decreased during CE;
decreased during V02 , HR, VE, or V..
No exposure mode effect.
Decreases in FVC (6.9%), FEV^o (14.8%),
FEF25.75% (18%), 1C (11%), and MVV (17%) at
75% max V02. 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 , Vr, V,., V02 , and maximum workload
alT decreased. At maximum workload only,
fR decreased (45%) and VT increased (29%).
No. and sex
of subjects Reference
9 male Savin and Adams, 1979
(runners)
10 male Adams and Schelegle, 1983
(distance runners)
6 male Folinsbee et al., 1984
1 female
(distance cyclists)
8 male Horvath et al . , 1979
7 female
13 male Folinsbee et al., 1977a
Measurement method: CHEM = 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/min or as a multiple of resting
ventilation. b
See Glossary for the definition of symbols.
-------
women after 2-hr exposure and at-rest exposure to 0.0, 980, and 1470 |jg/m
(0.00, 0.50, and 0.75 ppm) of 0.. (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
ergometer for 1 hr while breathing filtered air or 412 [jg/m (0.21 ppm) of 0~
(Folinsbee et al. , 1984). They worked at 75 percent max Vn_ with mean minute
ventilations of 81 L/min. As previously noted (Section 11.2.2), pulmonary
function decrements as well as symptoms of laryngeal and/or tracheal 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 0~ 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 Vn?) to increase mean Vp 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
performed at their maximal levels. Three subjects were unable to complete
either the training or competitive simulation exercise bouts at 0.35 ppm 0^,
while a fourth failed to complete the competitive ride. As previously noted
(Section 11.2.2), 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 Vn? 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 sugges-
ted some decrement in performance, too limited a data base is available at
this time to provide judgmental decisions concerning the magnitude of such
impairment. Subjective statements by individuals engaged in various sport
activities indicate that these individuals may voluntarily limit strenuous
019PO/A 11-56 5/2/84
-------
exercise during high-oxidant concentrations. Several reviews on exercising
subjects have appeared in the literature (Horvath, 1981; Folinsbee, 1981).
11.5 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 11-7 presents a summary of data on interactions
between 0- and other pollutants.
O
11.5.1 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 (jg/m (0.37 ppm) of
0- and 0.37 ppm of sulfur dioxide (S0«) 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 03 alone resulted in decrements in pulmonary function. The
combination of gases resulted in more severe respiratory symptoms and pulmonary
changes than did 0» 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 SOp alone. However, during exposure to 725 ug/m
(0.37 ppm) 0, a 13 percent reduction occurred, while exposure to the mixture
3
of 725 ug/m (0.37 ppm) 03 and 0.37 ppm S02 resulted in a reduction of 37 per-
cent in this measure of pulmonary function. The effects resulting from 03 and
S0? 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 03 + SO™ mixture
had a greater detrimental effect on all pulmonary function measures than did
0- alone. However, only one out of eight functional parameters showed statis-
tically significant decrements when compared with 03; FEV, ~ decreased (4.7 per-
cent) in the sensitive subjects. 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
0190LG/A 11-57 5/2/84
-------
TABLE 11-7. INTERACTIONS BETWEEN OZONE AND OTHER POLLUTANTS
Ozone
concentration
Mg/m3
ppm
Pollutant3
Measurement '
method
Exposure
duration and
activity
No. and sex
Observed effect(s)6 of subjects
Reference
A. 03 + S02:
294
393
725
970
725
970
V 725
en 970
CO 100
784
1048
784
1048
0.15
0.15
0.37
0.37
0.37
0.37
0.37
0.37
0.4
0.4
0.4
0.4
03
S02
03
S02
o3
S02
03
S02
H2S04
03
S02
03
S02
CHEM, NBKI
EC
MAST, NBKI
EC
CHEM, NBKI
FP
UV, NBKI
FP
1C
CHEM, NBKI
FP
CHEM, NBKI
FP
2 hr
IE(25)
@ 15-min
interval s
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
livable. Statistical approach is weak.
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 0 exposure in 5 sensitive (L.A.)
combined group of normal and sensitive L.A. 4 normal (Montreal)
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
FEVll2,3, 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
FEV^o, FEF25 75~, FEFso,v) 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%, FEF50%, ERV, TLC)
and increase in symptoms reflected changes
due to 0^; no synergisni was found.
Kagawa and Tsuru, 1979c
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. Oj + H2S04-
294
200
588
100
0.15
0.3
03
H2S04
03
H2S04
CHEM, NBKI
1C
MAST, NBKI
& CHEM, NBKI
TS
2 hr
IE @15-min
intervals
2 hr
IE(35)
for 15 min
4 hr
IE(35)
for 15 min
SGaw decreased; no interaction reported. 7 male
Questionable statistics.
No significant 03-related changes in pulmo- 7 male
nary function or bronchial reactivity to 5 female
methacholine Bronchial reactivity decreased
following a 4-hr exposure to H2S04.
Kagawa, 1983a
Kulle et al. , 1982a
-------
TABLE 11-7. INTERACTIONS BETWEEN OZONE AND OTHER POLLUTANTS (continued)
I
en
i-O
Ozone
concentration
(jg/m-5
784
100
133
116
80
ppm
0.4
Pollutant3
03
H2S04
(NH4)2S04
NH4HS04
NH4N03
b c
Measurement '
method
CHEM, NBKI
Exposure
duration and
activity
2-4 hr
IE
for two 15-min
periods
Observed effect(s)6
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
124 male Stacy et al., 1983
(divided into
10 exposure
groups)
C. 03 + CO:
588
115000
0.3
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.0 and FEF25_75y
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
9400
294
280
490-
980
560
35000
980
940
0.1
5.0
0.15
0.15
0.25-
0.5
0.3
30.0
0.5
0.5
03
N02
03
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.,,, FEF25_75%. and
FEFsiw. ventilatory and metabolic variables
were iSot 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 11-7. INTERACTIONS BETWEEN OZONE AND OTHER POLLUTANTS (continued)
Ozone
concentration
ug/m3 ppm
980-
1372
940
1320
0.5-
0.7
0.5-
0.7
Measurement '
Pollutant method
N02
MAST, NBKI and
CHEM, NBKI
MAST (N02)
and CHEM, C
Exposure
duration and
activity
1 hr
(mouthpiece)
R
No. and sex
Observed effect(s)6 of subjects
No significant changes in SGaw, Vmax 50%, or 5 male
Vmax 25%.
Reference
Toyama et al . , 1981
E. 03 + N02 + S02:
49-
196
100-
9000
314
13000
157
£ 300
I 900
See Glossary for the definition of symbols.
Part of a larger study of 231 subjects.
-------
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
SOp-0- mixture when studied in Los Angeles compared to Montreal, Bell et al.
(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 0_ could have reacted rapidly with each other and
with ambient impurities like olefins, to form a large number of sulfuric acid
(h^SO^) nuclei which grew by homogeneous condensation, coagulation, and absorp-
tion of ammonia (NHL) during their 2-min average residence time in the chamber.
A retrospective sampling of the aerosol composition used for the original
S02~03 study in Montreal (Hazucha and Bates, 1975) using particle samplers and
chemical analysis in the chamber showed that acid sulfate particles could have
been 10- to 100-fold higher (100 to 200 ug/m3), 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 03 showed that the presence of 100 ug/m H-SO. did not alter the response
obtained with the S0p-03 mixture alone. (See later discussion in this section.)
Bedi et al. (1979) exposed nine young healthy nonsmoking men (18 to 27
3
years old) to 784 ug/m (0.4 ppm) 0_ and 0.4 ppm SO,, singly and in combination
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 SO- showed no significant changes in pulmonary
function. When exposed to either 0- or 0_ plus S0?, the subjects showed
statistically significant decreases in maximum expiratory flow (FEV-. „,
FEF-c.ycy. ar|d FEFcryy) ar>d FVC. There were no significant differences between
the effects of 0_ alone and the combination of 0., + S0?; thus, no synergistic
effects were discernible in their subjects. Although particulate 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 min of rest. The exposures were performed weekly in the following sequence:
filtered air, 0.15 ppm of 0 • filtered air, 0.15 ppm of SO ; filtered air; and
0190LG/A 11-61 5/2/84
-------
finally 0.15 ppm of 0_ + 0.15 ppm of SQ^. 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.
dw
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
Q W
with 03 exposure alone. Two other subjects had similar decreases with either
03 or 03 + SOp exposure. Subjective symptoms of cough and bronchial irrita-
tion were reported to occur in subjects exposed to either 0,, or the 0_ + S0?
combination. The authors suggested that the combined effect of the two gases
on SG is more than simply additive in some exercising subjects. This conclu-
ciW
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 S0? 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 SO,,. While
intermittently exercising (VF ~30 L/min), eight young adult nonsmoking males
were randomly exposed on separate occasions for 2 hr to filtered air, 0.4 ppm
S02, 748 (jg/m3 (0.4 ppm) of 03> and 0.4 ppm of S02 plus 784 ug/m3 (0.4 ppm) of
CL at 35°C and 85 percent rh. No functional changes in FEV, „ occurred as a
result of exposure to filtered air or 0.4 ppm of SCL, but decreases in FEV, „
occurred following exposure to either 784 ug/m (0.4 ppm) of 0, (6.9 percent)
3
or the combination of 784 ug/m (0.4 ppm) of 03 plus 0.4 ppm of SO^ (7.4 per-
cent). Thoracic gas volume (TGV) increased and FEE^y decreased in the 0,
exposures, while FVC, ^^25-75%' ^50%' ERV' and TLC a11 decreased in the
0~/S09 and 0, exposures. However, no significant differences were found
J C-, O
between the 0-, exposure and the 0, plus SO,, 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-
3
gistic effect consequent to exposure to 0.15 ppm of S02 and 294 ug/m (0.15
0190LG/A 11-62 5/2/84
-------
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 indicated that the SG was not altered in the 25°C-
aw
45 percent rh environment but decreased 10.6 percent (P < 0.05) in the S0?
exposure and 19 percent (P < 0.01) in 0, plus S09 exposure in hot, wet condi-
«J L-
tions. 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, "None-
dw
theless, 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."
Few studies have been reported in which subjects were exposed to 0,, and
H9SO.. Kagawa (1983a) summarized some results obtained on seven subjects
3
intermittently resting and exercising during a 2-hr exposure to 294 ug/m
2
(0.15 ppm) of 0,. 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 0~ (725 ug/m , 0.37
ppm), S02 (0.37 ppm), and H2S04 aerosol (100 ug/m3, MMAD = 0.5 urn; a = 3.0).
Chemical speciation data indicated that 93 percent of the H~SO. 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 H?SO, 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 0., 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, Q 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
exposed to 0- alone (expected decreases of 2.8 percent). The authors con-
cluded that the presence of H^SO. aerosols did not substantially alter the
irritability resulting from 0~-S09.
O f-
0190LG/A 11-63 5/2/84
-------
Stacy et al . (1983) studied 234 healthy men (18 to 40 years old) exposed
for 4 hr to air, 03, N02, or S02; to H2$04, ammonium sulfate [(NH^SO^,
ammonium bi sulfate (NhLHSO.), 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
groups of interest were filtered air (n = 10); 784 |jg/m (0.4 ppm) of 0^
(n = 12); 100 ug/m3 of H2S04 (n = 11); 133 ug/m3 of (NH4)2S04 (n - 13);
116 ug/m3 of NH4HS04 (n = 15); 80 ug/m3 of NH4N03 (n = 12); and the mixtures
03 + H2S04 (n = 13), 03 + (NH4)2S04 (n = 15), QS + NH4HS04 (n = 11), and DS +
NH4N03 (n = 12). Ambient conditions were 30°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. Pre-exposure resting pulmonary
functions were measured during a rest period. This battery of pulmonary
function tests was also made some 5 to 6 min following the termination of the
exercise and repeated 24 hr later. Unfortunately, the minute ventilations for
the exercise periods were not reported. Data were analyzed by multivariate
analyses of variance. All pulmonary functions (i.e., airway resistances, lung
volumes, and flow rates) except ERV, FEV,/FVC, and FRC showed a statistically
significant effect of the gaseous pollutant (0~). None of the particulates
significantly altered pulmonary functions compared with the filtered-air
exposure, and there was no indication of interaction between 0_ and the parti-
culates. Only 0, exposure affected pulmonary functions (16 of the 19 tests
administered) and no significant interactions occurred with the sulfate aero-
sols. Interestingly, after 4 hr of exposure, SR increased 27 percent with
clW
03; 41.7 percent with 03/H2S04; 28.5% with 03/(NH4)2S04; and 34.7 percent with
0^/NH.HSO,. Although there was a trend toward increased 03 effect in the
presence of acid sulfates, it did not reach statistical significance. The
reductions in FVC and PEP™ were approximately equivalent. At 24 hr post-
exposure, all pulmonary values had returned to pre-exposure levels. Exposure
to Q-, alone and with particles was associated with symptoms of irritation,
viz. shortness of breath, coughing, and minor throat irritation. This compre-
hensive study confirms other observations that 0« alone (at the levels of 0.,
and sulfate aerosol stated) produced significant changes in pulmonary functions,
albeit shortly after an exercise period. The data presented also suggested
that 0- induced greater changes at 4 hr than at 2 hr of exposure and that the
-------
Kulle et al. (1982a) studied the responses of 12 healthy nonsmokers
(seven men, five women) exposed to 0_ and H^SO. aerosols. Ozone concentra-
3 o ^ 4 ,
tions were 588 |jg/m (0.3 ppm) and HLSO. aerosol levels were 100 [jg/m (MMAD =
0.13 pm; or = 2.4). These studies were conducted over a 3-week period; a 2-hr
exposure to 0_, 4-hr exposure to HLSO., and 2-hr exposure to 0~ were followed
by a 4-hr exposure to H?SO.. 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 exposure. The work load was 100 W at 60 rpm, with an assumed
V_ of approximately 30 to 35 L. No discernible risk was apparent as a conse-
quence of exposing the nonsmoking healthy young adults to 0~ followed by
respirable HpSO. 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,, FEV-, and bronchial reactivity to
9W JL «3
methacholine) following the 0~ exposure were not significant. However, some
subjects did report typical symptoms observed in other 0,, exposures.
11.5.2 Ozone and Carbon Monoxide
DeLucia et al. (1983) reported the only study in which subjects were
exposed to carbon monoxide (CO) and 0~. Subjects exercised at 50 percent max
•
V,.,, for 1 hr in the following ambient conditions: filtered air, 100 ppm of
3 3
CO, 588 jjg/m (0.30 ppm) of 03, and 100 ppm of CO plus 588 ug/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 perfor-
mance, 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 Vn?, equivalent to a mean VF 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 0_ 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
nonsmokers' levels of 7.3 ± 0.8 percent.
0190LG/A 11-65 5/2/84
-------
Based on the limited data available, exposure to CO and CL does not
appear to result in any interactions. The effects noted appear to be related
primarily to CL.
11.5.3 Ozone and Nitrogen Dioxide
Studies describing the responses of subjects to the combination of these
two pollutants are summarized in Table 11-7. 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 0^ alone for the concentrations
present. Kagawa and Tsuru (1979b) evaluated the reactions of six subjects
(one smoker) to 294 ug/rn^ (0.15 ppm) 0- and 0.15 ppm NO™, 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
aw
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 ug/m (0.15 ppm) of 0_, 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 CL was present. Significant decreases in SG occurred in five of
O dW
six subjects exposed to 0,, three of six subjects exposed to NO,,, and six of
six subjects exposed to 0^ + NO™.
Kagawa (1983a) briefly reported that under the conditions of his exposure
(2 hr to 0.15 ppm 0., + 0.15 ppm N02) SGaw, V5Q%, and VC decreased. However,
no significant differences were observed between 03 alone and the combination
of 00 + NO,,. Subjective symptoms were equivalent in both 0- exposures.
3 Z -5
Five subjects sitting in a body plethysmograph inhaled orally either
filtered air, 0.7 ppm of N02, 1372 ug/m3 (0.7 ppm) of Og, or 0.5 ppm of 03 +
0,5 ppm of N02 for 1 hr (Toyama et al . , 1981). Specific airway conductance
and isovolume flows (V and ^ ^ were measured before and at tne
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
filtered air or 980 ug/m3 (0.5 ppm) of GS 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 V£ of 40 L/min during the
0190LG/A 11-66 5/2/84
-------
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, „, F^oc-ycy. and FEF,-,,^ during the 0..-NO_
exposure. Ventilatory and metabolic variables, expired ventilation, oxygen
uptake, tidal volume, and respiratory frequency were unaffected by 0,, and N09
O C.
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
interaction between 0., and N0_ was observed over the entire range of ambient
temperatures and relative humidities.
11.5.4 Ozone and Other Mixed Pollutants
Von Nieding et al. (1979) exposed 11 subjects to 0~, N0~, and S0« singly
O £- c~
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
PO,,, PCCL, and pH in arterialized capillary blood or in TGV. Arterial oxygen
tension (PaO?) was decreased (7 to 8 torr) by exppsure to 5.0 ppm of NO^ but
was not further decreased following exposures to 5.0 ppm of N0« and 5.0 ppm of
3
S02 or 5.0 ppm of N02, 5.0 ppm of S02 and 196 ug/m (0.1 ppm) of 03 or 5.0 ppm
of N09 and 196 ng/m (0.1 ppm) of 0,. Airway resistance increased significant-
ly (0.5 to 1.5 cm H?0/L/s) in the combination experiments to the same extent
as in the exposures to N0? alone. In the 1-hr post-exposure period of the
N09, S00, and 0., experiment, R. continued to increase. Subjects were also
<— <_ 3 \f Q
exposed to a mixture of 0.06 ppm N02, 0.12 ppm of S02, and 49 (jg/m (0.025 ppm)
of 0_. No changes in any of the measured parameters were observed. These
•3
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 NO
5.0-ppm S02, and 0.1-ppm 0, mixture, as well as after the 0.06-ppm N02, 0.12-
ppm S09, and 49-pg/m (0.025-ppm) 0~ 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
dW
TGV) was significantly greater following the combined pollutant exposures than
in the control study.
0190LG/A 11-67 5/2/84
-------
In another study of simultaneous exposure to SO-, N09, and 0.,, three
c. £- O
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
exposed at rest to 5.0 ppm of S02> 5.0 ppm of N02, and 196 ug/m3 (0.1 ppm) of
0-; and on the third day the environment was again 5.0 ppm of S00, 5.0 ppm of
3
NO-, and 196 (jg/m (0.1 ppm) of 0^, but the subjects exercised intermittently
during the exposure. Statistical evaluation of data for the 11 lung-function
test parameters and two blood gas parameters (PaO- and PaCO?) was not reported.
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 (1979b) studied 15 young healthy males during chamber
exposures to 0.9 mg/m (0.34 ppm) S02, 0.3 mg/m3 (0.16 ppm) N02, and 0.15 mg/m3
(0.08 ppm) 0_. 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 (PaO?,
PaCOp, 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. The
authors reported that some of the subjects exhibited unusual responses.
11.6 EXTRAPULMONARY EFFECTS OF OZONE
The high oxidation potential of 0,, 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
0190LG/A 11-68 5/2/84
-------
TABLE 11-8. HUMAN EXTRAPULMONARY EFFECTS OF OZONE EXPOSURE
I
CTi
Ozone b
concentrati on Measurement '
ug/m3
294
588
392
392
490
725
784
784
784
784
ppm method
0.15 UV,
0.30 NBKI
0.2 NO
0.2 CHEM,
0.25 NBKI
0.37 CHEM,
NBKI
0.4 CHEM,
NBKI
0.4 CHEM,
NBKI
0.4 CHEM,
NBKI
0.4 CHEM,
NBKI
Exposure
duration and
activity
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)d
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 11-8. HUMAN EXTRAPULMONARY EFFECTS OF OZONE EXPOSURE (continued)
Ozone £
concentration Measurement '
ug/m3 ppm method
784 0.4 CHEM,
NBKI
; 784 0.4 CHEM,
; NBKI
1176 0.6
980 0.5 CHEM,
NBKI
i
i — >
o 980 0.5 CHEM,
NBKI
980 0.5 CHEM,
NBKI
980 0.5 CHEM,
NBKI
980 0.5 UV,
NBKI
Exposure
duration and
activity
4 days
4 hr/day
IE for two
15-min periods
4 days
4 hr/day
2 hr
IE for two
15-min periods
2.5 hr
IE (2xR)
@ 15-min intervals
± Vit E
2.5 hr
IE (2xR)
@ 15-min intervals
intervals
2.75 hr
IE (2xR)
@ 15-min intervals
4 days
2.5 hr/day
IE (2xR)
@ 15-min 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 peroxidation
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 male
6 male (Atopic)
31 male and
female
Reference
Chaney et al. , 1979
McKenzie et al. , 1982
Hamburger et al. , 1979
Posin et al. , 1979
Buckley et al. , 1975
Hackney et al . , 1978
Gueri crn et al. , 1979
-------
TABLE 11-8. HUMAN EXTRAPULMONARY EFFECTS OF OZONE EXPOSURE (continued)
Ozone
concentration
ug/m3 ppm
980 0. 5
1176 0.6
1960 1.0
Measurement3 >b
method
MAST,
NBKI
CHEM,
NBKI
NO
Exposure
duration and
activity
6-10 hr
R
2 hr
IE for two
15-min periods.
10 min
Observed effect(s)
Frequency of chromatid aberrations increased
immediately following exposure with a peak
in number 2 weeks after exposure (not statis-
tically significant); no change in number
of chromosome aberrations.
Suppression to PHA- induced lymphocyte
transformation is questionable.
Decreased rate of cutaneous HbOj, desaturation
No. and sex
of subjects Reference
6 male and Merz et al. , 1975
female
16 male Peterson et al., 1981
e Brinkman and Lamberts, 1958
Measurement method: MAST = Kl-coulometric (Mast meter); CHEM = gas-phase chemiluminescence; UV = ultraviolet photometry; NO = not described.
Calibration method: NBKI = neutral buffered potassium iodide.
Activity level: R = rest; CE = continuous exercise; IE = intermittent exercise; minute ventilation (Vf) given in L/min or in multiples of resting
ventilation.
Abbreviations used: NPSH = nonprotein sulfhydryl; G-6-PD = glucose-6-phosphate dehydrogenase; 6-PG-D = 6-phosphogluconate dehydrogenase; GRase = glutathione
reductase; Hb = hemoglobin; RBC = red blood cell; LOH = lactate dehydrogenase; AChE = acetylcholinesterase; PHA = phytohemagglutinin; GSSRase = glutathione
reductase; GSH = reduced' glutathione; 2,3-DPG = 2,3-diphosphoglycerate; HbOj, = oxyhemoglobin; PMN = polymorphonucl ear leukocytes.
&
Details not given.
-------
statistically significant changes (P < 0.05) occurred in erythrocytes and sera
of seven young adult men following exposure to 980 ug/m (0.50 ppm) of 0_ for
2.75 hr. Erythrocyte 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 11-8).
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 ug/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 0~ 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 ug/m (0.4 ppm) of 0, for 4 hr on one day and on
3
four consecutive days, or to 1176 \ig/m (0.6 ppm) for 2 hr. One hundred
metaphases per blood sample per subject for chromosome 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 aberra-
tions, structural aberrations, or SCEs between 03 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
0., exposures.
O
0190LG/A 11-72 5/2/84
-------
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 Do for 6 to 10 hr. Increases in the frequency of chromatid aberrations
(achromatic lesions and chromatid deletions) were observed in lymphocytes
after 0_ 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 CL exposure, the results
did not differ significantly from pre-03 chromatid aberration frequencies
because of the small number (six) of subjects investigated.
Guerrero et al. (1979) exposed 31 male and female subjects to filtered
air followed on a second day by 2-hr exposure to 980 [jg/m (0.5 ppm) of 0.,.
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
•3
diploid human fetal lung cells (WI-38) exposed to 0.0, 490, 1470, and 1960 ug/m
(0.0, 0.25, 0.75, and 1.00 ppm) of 03 for 1 hr j_n vitro was shown to have a
dose-related increase in SCEs. The investigators suggested that the lack of
SCE changes in lymphocytes j_n 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
for 4 hr to to 784 ug/m (0.40 ppm) of 0, at rest with the exception of two
15-min 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 0_ exposure, or at 2 weeks after 0-
exposure. The nadir of neutrophil function was observed at 72 hours after 0,,
exposure. Since the neutrophil has an average lifespan of 6.5 hr, the mecha-
nism by which 0, 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
0190LG/A 11-73 5/2/84
-------
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
3
0» 764-ug/m (0.39-ppm) exposure (20 subjects), lymphocyte transformation
•3
responses to 2 ug/ml and 20 ug/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
study was conducted by these investigators (Peterson et al., 1981) on 16
3
subjects exposed to 1176 ug/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
784 ug/m3 (0.4 ppm) 0, for 4 hr, B-lymphocyte rosette formation was signifi-
O
cantly depressed. Rosette formation is an j_n vitro method that measures the
binding of antigenie 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 03 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) 03 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 III. 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
0190LG/A 11-74 5/2/84
-------
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 0_. 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 to 1960 yg/m (0.5 to
1.0 ppm).
11.7 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 11-9). 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 V0? 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 V0? was determined in 20 young men
who undertook a 20-min progressive modified Balke test while inhaling 0.27 ppm
at ambient conditions of either 25°C (Raven et al. 1974b) or 37°C (Drinkwater
et al. , 1974). Total exposure time was 40 min. No alterations in cardiores-
piratory functions or maximal aerobic capacity due to the pollutants were
observed regardless of the ambient temperatures. Raven et al. (1974a) evalu-
ated metabolic, cardiorespiratory, and body temperature responses of seven
middle-aged (40 to 57 years) smokers and nine nonsmokers during tests of
maximal aerobic power. Ambient conditions were 25°C or 35°C dry bulb and
0190LG/A 11-75 5/2/84
-------
TABLE 11-9. ACUTE HUMAN EXPOSURE TO PEROXYACETYL NITRATE
i
-^j
cr>
Concentration
ug/mj ppm
1187 0.24
1187 0.24
1336 0.27
1336 0.27
1336 0.27
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 min of each hr
40 min
IE (progressive) for
20 min
40 min
IE (progressive) for
20 min
40 min (mouthpiece)
IE (progressive) for
20 min
10 min (mouthpiece)
IE for 5 min
. 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% VOpmax in 10 young and nine middle-aged
subjects. No interaction between exposure
and temperature (25° & 35°C).
No significant change in V0~ x in young non- 20 male
smokers (n = 10) or smokers \n = 10) during
treadmill walk at 35°.
No significant change in V0~ in middle- 16 male
aged nonsmokers (n = 9) or sffloKers (n = 7)
during treadmill walk at 25°C and 35°C.
No significant change in V02 in 20 male
young nonsmokers (n = 10) or smokers
(n = 10) during treadmill walk at 25°C.
Oxygen uptake increased with exercise. 32 male
Maximum expiratory flow rate decreased
after exercise.
Reference
Raven et al. , 1976
Gliner et al. , 1975
Drinkwater, 1974
Raven et al. , 1974a
Raven et al. , 1974b
Smith, 1965
Activity level: IE = intermittent exercise; minute ventilation (VV) given in L/min.
See Glossary for the definition of symbols.
-------
25 percent rh. These subjects inhaled either filtered air or air containing
0.27 ppm PAN for 40 min. No effects of PAN were found. Effects related to
age, smoking history, and ambient temperatures were as anticipated.
In his studies of young men orally inhaling 0.30 ppm PAN, Smith (1965)
found a small reduction in MEFR following light exercise but no change in this
function during resting exposures. Raven et al. (1976) observed a small but
significant (4 to 7 percent) reduction in standing FVC in young men after
3.5 hr of light exercise (35 percent V00 ) during a 4-hr exposure to 0.24 ppm
£ max
PAN.
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. Metabolic, body temperature, and cardiorespiratory
responses of healthy middle-aged men, nine smokers and seven nonsmokers, were
obtained during tests of maximal aerobic power (max V^p) 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 ppm of CO and 0.27 ppm of PAN. Carboxyhemogl obi n was measured in these
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 V-?) for 210 min (Gliner et al., 1975). Five subjects
0190LG/A 11-77 5/2/84
-------
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 significant-
ly (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.
11.8 SUMMARY
A number of important controlled studies discussed in this chapter have
reported significant decrements in pulmonary function associated with 0,
O
exposure (Table 11-10). Results from studies of at-rest exposures to 0^ have
O
demonstrated decrements in forced expiratory volumes and flows occurring at
3
and above 980 ug/m (0.5 ppm) of 03 (Folinsbee et al., 1978; Horvath et al.,
1979). Airway resistance is not clearly affected at these 0Q concentrations.
3
At or below 588 ug/m (0.3 ppm) of 0~, changes in pulmonary function do not
occur during at rest exposure (Folinsbee et al., 1978), but the occurrence of
some 03 pulmonary symptoms has been suggested (Kb'nig et al. , 1980).
With moderate intermittent exercise at a VV of 30 to 50 L/min, decrements
in forced expiratory volumes and flows have been observed at and above 588
3
ug/m (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 ug/m (0.12 ppm) of 03 (McDonnell et al. , 1983). Symptoms
are present and decrements in forced expiratory volumes and flows definitely
3
occur at 353 to 470 ug/m (0.18 to 0.24 ppm) of 0., following 1 hr of continuous
very heavy exercise at a VV of 80 to 90 L/min (Adams and Schelegle, 1983;
Folinsbee et al., 1984) and following 2 hr of intermittent heavy exercise at a
VF of 65 L/min (McDonnell et al., 1983). Airway resistance is only modestly
3
affected even with heavy exercise while exposed at levels as high as 980 ug/m
(0.50 ppm) 03 (Folinsbee et al., 1978; McDonnell et al., 1983). Increased fR
and decreased VT, while maintaining the same VP, occur with prolonged heavy
i , t
exercise when exposed at 392 to 470 ug/m (0.20 to 0.24 ppm) of 03 (McDonnell
et al. , 1983; Adams and Schelegle, 1983). While an increase in RV has been
3
reported to result from exposure to 1470 ug/m (0.75 ppm) of 0^ (Hazucha et al.
3
1973), changes in RV have not been observed following exposures to 980 ug/m
0190LG/A 11-78 . 5/2/84
-------
TABLE 11-10. SUMMARY TABLE: CONTROLLED HUMAN EXPOSURE TO OZONE
c Exoosure
ug/i^
HEALTHY
627
1960
980
980
1470
ppm method duration
ADULT SUBJECTS AT REST
0.32 MAST, NBKI 2 hr
1.0
0.5 CHEM, NBKI 2 hr
0.50 CHEM, NBKI 2 hr
0.75
Activity
level (V,) Observed effects(s)
R Specific airway resistance increased with
acetylcholine challenge; subjective symptoms
in 3/14 at 0.32 ppm and 8/14 at 1.0 ppm.
R (10) Decrement in forced expiratory volume and
flow.
R (8) Decrement in forced expiratory volume and
flow.
No. and sex
of subjects Reference
13 male Konig et al . , 1980
1 female
40 male Folinsbee et al . ,
(divided into four 1978
exposure groups)
8 male Horvath et al . ,
7 female 1979
EXERCISING HEALTHY ADULTS
235
353
470
588
784
392
686
0.12 CHEM, UV 2.5 hr
0.18
0.24
0.30
0.40
0.20 UV, UV 1 hr
0.35 (mouth-
piece)
IE (65) Decrement in forced expiratory volume and
@ 15-min intervals 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 ppm; coughing reported at all
concentrations, pain and shortness of
breath at £ 0.24 ppm.
IE (77.5) @ vari- Decrement in forced expiratory volume and
able competitive flow with IE and CE; subjective symptoms
intervals increased with 03 concentration and may
CE (77.5) limit performance; respiratory frequency
increased and tidal volume decreased with
CE.
135 male McDonnell et al.,
(divided into six 1983
exposure groups)
10 male Adams and Schelegle,
(distance runners) 1983
-------
I
00
o
TABLE 11-10. SUMMARY TABLE: CONTROLLED HUMAN EXPOSURE TO OZONE (continued)
Ozone3
concentration Measurement >c Exposure Activity
ug/m3 ppm method duration level (V£)
392
823
980
412
588
980
0.2 UV, UV 2 hr
0.42
0.50
0.21 UV, UV 1 hr
0.3 CHEM, NBKI 2 hr
0.5
IE (30 for male,
18 for female
subjects)
@ 15-min intervals
CE (81)
R (10). IE (31,
50, 67)
@ 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.
Decrement in forced expiratory volume and
flow; subjective symptoms may limit per-
formance.
Decrement in forced expiratory volume and
flow; the magnitude of the change was
related to 03 concentration and Vr-
No. and sex
of subjects
8 male
13 female
6 male
1 female
(distance cyclists)
40 male
(divided into four
exposure groups)
Reference
Gliner et al. , 1983
Folinsbee et al. ,
1984
Folinsbee et al . ,
1978
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.
725 0.37
980 0.50
1470 0.75
MAST, NBKI 2 hr
R (11) & IE (29)
@ 15-min intervals
Good correjation between dose (concen-
tration x Vp) and decrement in forced
expiratory volume and flow.
20 male
8 female (divided into
six exposure groups)
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 was
greatest on the 2nd of 5 exposure days;
attenuated response by the 4th day of
exposure.
10 male
4 female
Parrel! et al., 1979
-------
TABLE 11-10. SUMMARY TABLE: CONTROLLED HUMAN EXPOSURE TO OZONE (continued)
Ozone
concentration Measurement >c Exposure Activity
M9/""3 ppm method duration level (V£)
Observed effects(s)
No. and sex
of subjects
Reference
784 0.4 CHEM, NBKI 3 hr
IE (4-5xR)
for 15 min
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
roethacholine on the first 3 days;
attenuation of response occurred by
the 4th and 5th day and persisted
for > 7 days.
13 male
11 female
(divided into two
exposure groups)
Kulle et a!., 1982b
>-> 823 0.42 UV, UV
oo
I—1
921 0.47 UV, NBKI
1176 0.6 UV, NBKI
1470 0.75 MAST, NBKI
2 hr IE (30)
2 hr IE (3xR)
2 hr IE (2xR)
(noseclip) @ 15-min intervals
2 hr IE (2xR)
@ 15-min intervals
Decrement in forced expiratory volume 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.
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.
Specific airway resistance increased in 7
nonatopic subjects with histamine and
methacholine and in 9 atopic subjects
with histamine.
Decrements in spirometric variables
(20%-55%); residual volume and closing
capacity increased.
24 male
8 male
3 female
11 male
5 female (divided
by history of atopy)
12 male
Horvath
Linn et
Holtzman
1979
Hazucha
1973
et al . . 1981
al . , 1982b
et al. ,
et al. ,
-------
TABLE 11-10. SUMMARY TABLE: CONTROLLED HUMAN EXPOSURE TO OZONE (continued)
Ozone3
concentration Measurement Exposure
ug/m3
ppm method duration
Activity
level (VJ
Observed effects(s)
No. and sex
of subjects
Reference
ASTHMATICS
392
490
0.2 CHEM, NBKI 2 hr
0.2S CHEM, NBKI 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
2 female
5 males
12 female
Linn et al . , 1978
' Silverman, 1979
SUBJECTS WITH CHRONIC OBSTRUCTIVE LUNG DISEASE
_ 235
h—"
1
co
ro
353
490
392
588
784
0.12 UV, NBKI 1 hr
0.18 UV, NBKI 1 hr
0.25
0.2 CHEM, NBKI 2 hr
0.3
0.41 UV, UV 3 hr
IE (variable)
@ 15-min intervals
IE (variable)
@ 15-min intervals
IE (28) for
7.5 min each
half hour
IE (4-5xR)
for 15 min
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 03
exposure.
No significant changes in pulmonary function
or symptoms. Decreased arterial oxygen
saturation during exposure to 0.2 ppm.
Small decreases in FVC and FEV3.0.
18 male
7 female
15 male
13 female
13 male
17 male
3 female
Linn et al. , 1982a
Linn et al . , 1983
Solic et al. , 1982
Kehrl et al. , 1983
Kulle et al. , 1984
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.
-------
(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 exposures to 980
ug/m (0.50 ppm) of 0, or less, with moderate and heavy exercise (Folinsbee et
al. , 1978).
Group mean decrements in pulmonary function can be predicted with some
degree of accuracy when expressed as a function of effective dose of 0~, the
simple product of 0- concentration, VV, and exposure duration (Silverman et
al., 1976). The relative contribution of these variables to pulmonary decre-
*
ments is greater for 0- concentration than for VF, which is greater than that
for exposure duration. A greater degree of predictive accuracy is obtained if
the contribution of these variables is appropriately 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 0^
(Horvath et al., 1981; Gliner et al, 1983; McDonnell et al., 1983). Individual
responses to a given 0- concentration have been shown to be quite reproducible
(Gliner et al., 1983; McDonnell et al., 1984), indicating that some individuals
are consistently more responsive to 0- than are others. No information is
available to account for these differences. Considering the great variability
in individual pulmonary responses to 0_ exposure, prediction equations that
only use some form of effective 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
3 3
as low as 588 ug/m (0.3 ppm) (Konig et al., 1980). Exposure to 392 |jg/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 0,, exposure
O
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; a modula-
tion of this pathway, however, has been proposed to account for the lack of
0190LG/A 11-83 5/2/84
-------
correlation between individual changes in SR and FVC (McDonnell et al. ,
aW
1983). The increased responsiveness of airways to histamine and methacholine
following 0,, exposure most likely results from an 0_-induced increase in
airways permeability or from an alteration of smooth muscle characteristics.
Decrements in pulmonary function were not observed for asthmatic subjects
exposed for 2 hours at rest (Silverman, 1979) or with intermittent light
exercise (Linn et al. , 1978) to 0, concentrations of 490 ug/m (0.25 ppm) and
less. Although this result indicates that asthmatics are not more sensitive
to 0- than are normal 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 03 concentrations of
588 ug/m3 (0.30 ppm) and less (Linn et al., 1982a; Solic et al., 1982; Kehrl
et al., 1983; Linn et al., 1983) and only small decreases in forced expiratory
3
volume are observed for 3-hr exposures to 804 ug/m (0.41 ppm) (Kulle et al.,
1984). Small decreases in SaO~ have also been observed, but 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 0- 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. While a few studies
have investigated sex differences, they have not conclusively demonstrated
that men and women respond differently to 03, and consideration of differences
in pulmonary capacities have not been adequately taken into account. Environ-
mental conditions such as heat and relative humidity may enhance subjective
symptoms and physiological impairment following 0- exposure, but the results
so far indicate that the effects are no more than additive. Other variables
such as seasonal effects and age, particularly the very young and the aged,
need to be considered. 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.,
0190LG/A 11-84 5/2/84
-------
1981; Kulle et al. , 1982b; Linn et al., 1982b); thereafter, pulmonary respon-
siveness to 03 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 4 (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 CL does not affect the magni-
tude of decrements in pulmonary function resulting from exposure at a higher
effective dose of 0 (Gliner et al., 1983).
<3
There is some evidence suggesting that exercise performance may be limited
by exposure to 03- Decrements in forced expiratory flow occurring with 0~
exposure during prolonged heavy exercise (Vp = 65 to 81 L/min) along with
increased fR and decreased V,. 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 VO^) 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 0, 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 03
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 03 with SOp, N02, and sulfuric acid or
particulate aerosols or with multiple combinations of these pollutants. Most
of the available studies with other photochemical oxidants have been limited
to a series of studies on the effects of peroxyacetyl nitrate (PAN) and carbon
monoxide (CO) on healthy young and middle-aged males during intermittent
exercise on a treadmill. No significant effects were observed at PAN concen-
trations of 0.25 to 0.27 ppm, which are higher than the daily maximum concen-
trations of PAN reported for relatively high oxidant areas (0.037 ppm). Two
additional studies at 0.24 and 0.30 ppm of PAN suggested a possible limitation
on forced expiratory volume and flow but there are not enough data to evaluate
the significance of this effect. Further studies are also required on the
more complex mix of pollutants found in the natural environment.
0190LG/A 11-85 5/2/84
-------
11.9 REFERENCES
Adams, W. C.; Savin, W. M.; Christo, H.E. (1981) Detection of ozone toxicity
during continuous exercise via the effective dose concept. J. Appl.
Physio!. Respir. Environ. Exercise Physio!. 51: 415-422.
Adams, W. C.; Schelegle, E. S. (1983) Ozone toxicity effects consequent to pro-
longed, high intensity exercise in trained endurance athletes. J. Appl.
Physio!. Respir. Environ. Exercise Physio!. 55: 805-812.
Astrand, P.-O.; Rodahl, K. (1977) Textbook of work physiology. New York, NY:
McGraw-Hill, Inc.
Bates, D. V.; Hazucha, M. (1973) The short-term effects of ozone on the human
lung. In: Proceedings of the conference on health effects of air pollu-
tants: prepared for the Committee on Public Works. U.S. Senate; October;
Washington, D.C. Washington, DC: Government Printing Office; pp. 507-540.
Available from: GPO, Washington, DC; S/N 5270-q2l05.
Bates, D. V.; Bel!, G. M.; Burnham, C. D.; Hazucha, M.; Mantha, J.; Pengelly,
L. D. ; Silverman, F. (1972) Short-term effects of ozone on the lung. J.
Appl. Physio!. 32: 176-181.
Bedi, J. F. ; Folinsbee, L. J.; Horvath, S. M.; Ebenstein, R. S. (1979) Human
exposure to sulfur dioxide and ozone: absence of a synergistic effect.
Arch. Environ. Health 34: 233-239.
Bedi, J. F.; Horvath, S. M.; Folinsbee, L. J. (1982) Human exposure to sulfur
dioxide and ozone in a high temperature-humidity environment. Am. Ind.
Hyg. Assoc. J. 43: 26-30.
Bel!, K. A.; Linn, W. S.; Hazucha, M.; Hackney, J. D.; Bates, D. V. (1977)
Respiratory effects of exposure to ozone plus sulfur dioxide in Southern
Californians and Eastern Canadians. Am. Ind. Hyg. Assoc. J. 38: 695-705.
Bennett, G. (1962) Oxygen contamination of high altitude aircraft cabins.
Aerosp. Med. 33: 969-973.
Brinkman, R. ; Lamberts, H.B; Vening, T.S. (1964) Radiomimetic toxicity of
ozonized air. Lancet 1: 133-136.
Brinkman, R. ; Lamberts, H.B. (1958) Ozone as a possible radiomimetic gas.
Nature (London) 181: 1202-1203.
Broad, W. J. (1979) High anxiety over flights through ozone. Science
(Washington, DC) 205: 767-769.
Bromberg, P. A.; Hazucha, M. J. (1982) Editorial: Is "adaptation" to ozone
protective? Am. Rev. Respir. Dis. 125: 489-490.
Buckley, R. D.; Hackney, J. D. ; Clark, K.; Posin, C. (1975) Ozone and human
blood. Arch. Environ. Health 30: 40-43.
0190LG/A 11-86 5/2/84
-------
Chaney, S.; DeWitt, P.; Blornquist, W. ; Muller, K. ; Bruce, B. ; Goldstein, G.
(1979) Biochemical changes in humans upon exposure to ozone and exercise.
Research Triangle Park, NC: U.S. Environmental Protection Agency, Health
Effects Research Laboratory; EPA report no. EPA-600/1-79-026. Available
from: NTIS, Springfield, VA; PB80-105554.
Colucci, A. V. (1983) Pulmonary dose/effect relationships in ozone exposures.
In: Mehlman, M. A.; Lee, S. D.; Mustafa, M. G., eds. International
symposium on the biomedical effects of ozone and related photochemical
oxidants; March 1982; Pinehurst, NC. Princeton, NJ: Princeton Scientific
Publishers, Inc.; pp. 21-44. (Advances in modern environmental toxicology:
v. 5.)
DeLucia, A. J. ; Adams, W. C. (1977) Effects of (L inhalation during exercise
on pulmonary function and blood biochemistry. J. Appl. Physio!. Respir.
Environ. Exercise Physio!. 43: 75-81.
DeLucia, A. J. ; Whitaker, J. A.; Bryant, L. R. (1983) Effects of combined
exposure to ozone and carbon monoxide in humans. In: Mehlman, M. A. ;
Lee, S. D. ; Mustafa, M. G. , eds. International symposium on the bio-
medical effects of ozone and related photochemical oxidants; March 1982;
Pinehurst, NC. Princeton, NJ: Princeton Scientific Publishers, Inc.;
pp. 145-159. (Advances in modern environmental toxicology: v. 5.)
Dimeo, M. J. ; Glenn, M. G. ; Holtzman, M. J.; Sheller, J. R.; Nadel, J. A.;
Boushey, H. A. (1981) Threshold concentration of ozone causing an increase
in bronchial reactivity in humans and adaptation with repeated exposures.
Am. Rev. Respir. Dis. 124: 245-248.
Drinkwater, B. L. ; Raven, P, B. ; Horvath, S. M. ; Gliner, J. A.; Ruhling, R.
W. ; Bolduan, N. W. (1974) Air pollution, exercise and heat stress. Arch.
Environ. Health 28: 177-181.
Eglite, M. E. (1968) A contribution to the hygienic assessment of atmospheric
ozone. Gig. Sanit. 33: 18-23.
F. R. (1.971 April 30) 36: 8186-8201. National primary and secondary ambient
air quality standards.
Parrel!, 8. P.; Kerr, H. D.; Kulle, T. J.; Sauder, L. R.; Young, J. L. (1979)
Adaptation in human subjects to the effects of inhaled ozone after
repeated exposure. Am. Rev. Respir. Dis, 119: 725-730.
Folinsbee, L. J. ; Silverman, F. ; Shephard, R. J. (1977a) Decrease of maximum work
performance following ozone exposure. J. Appl. Physiol. Respir. Environ.
Exercise Physiol. 42: 531-536.
Folinsbee, L. 0.; Silverman, F.; Shephard, R. J. (1975) Exercise responses
following ozone exposure. J. Appl. Physiol. 38: 996-1001.
Folinsbee, L. J. (1981) Effects of ozone exposure on lung function in man: a
review. Rev. Environ. Health 3: 24.!-240.
0190LG/A 11-87 5/2/84
-------
Folinsbee, L. J. ; Bedi, J. F.; Horvath S. M. (1984) Pulmonary function changes
in trained athletes following 1-hour continuous heavy exercise while
breathing 0.21 ppm ozone. J. Appl. Physio!. Respir. Environ. Exercise
Physio!. (In Press).
Folinsbee, L. J.; Bedi, J. F.; Horvath, S. M. (1981) Combined effects of ozone
and nitrogen dioxide on respiratory function in man. Am. Ind. Hyg. Assoc.
J. 42: 534-541.
Folinsbee, L. J.; Bedi, J. F.; Horvath, S. M. (1980) Respiratory responses in
humans repeatedly exposed to low concentrations of ozone. Am. Rev. Respir.
Dis. 121: 431-439.
Folinsbee, L. J. ; Drinkwater, B. L.; Bedi, J. F.; Horvath, S. M. (1978) The
influence of exercise on the pulmonary changes due to exposure to low
concentrations of ozone. In: Folinsbee, L. J.; Wagner, J. A.; Borgia, J.
F.; Drinkwater, B. L.; Gliner, J. A.; Bedi, J. F., eds. Environmental
stress: individual human adaptations. New York, NY: Academic Press;
pp. 125-145.
Folinsbee, L. J. ; Horvath, S. M.; Raven, P. B.; Bedi, J. F. ; Morton, A. R. ;
Drinkwater, B. L.; Bolduan, N. W.; Gliner, J. A, (1977b) Influence of
exercise and heat stress on pulmonary function during ozone exposure. J.
Appl. Physio!. Respir. Environ. Exercise Physio!. 43: 409-413.
Gibbons, S. I.; Adams, W. C. (1984) Combined effects of ozone exposure and
ambient heat on exercising females. J. Appl. Physiol. In Press.
Gliner, J. A.; Horvath, S. M. ; Folinsbee, L. J. (1983) Pre-exposure to low
ozone concentrations does not diminish the pulmonary function response on
exposure to higher ozone concentration. Am. Rev. Respir. Dis. 127: 51-55.
Gliner, J. A.; Horvath, S. M. ; Sorich, R. A.; Hanley, J. (1980) Psychomotor
performance during ozone exposure: spectral and discriminant function
analysis of EEC. Aviat. Space Environ. Med. 51: 344-351.
Gliner, J. A.; Matsen-Twisdale, J. A.; Horvath, S. M. (1979) Auditory and
visual sustained attention during ozone exposure. Aviat. Space Environ.
Med. 50: 906-910.
Gliner, J. A.; Raven, P. B.; Horvath, S. M.; Drinkwater, B. L.; Sutton, J. C.
(1975) Man's physiologic response to long-term work during thermal and
pollutant stress. J. Appl. Physiol. 39: 628-632.
Golden, J. A.; Nadel, J. A.; Boushey, H. A. (1978) Bronchial hyperirritability
in healthy subjects after exposure to ozone. Am. Rev. Respir. Dis.
118: 287-294.
Goldsmith, J. R. ; Nadel, J. (1969) Experimental exposure of human subjects to
ozone. J. Air Pollut. Control Assoc. 19: 329-330.
Griswold, S. M.; Chambers, L. A.; Motley, H. L. (1957) Report of a case of
exposure to high ozone concentrations for two hours. AMA Arch. Ind.
Health 15: 108-110.
0190LG/A 11-88 5/2/84
-------
Guerrero, R. R. ; Rounds, D. E.; Olson, R. S.; Hackney, J. D. (1979) Mutagenic
effects of ozone on human cells exposed jm vivo and jm vitro based on
sister chromatid exchange analysis. Environ. Res. 18: 336-346.
Haak, E. D.; Hazucha, M. J.; Stacy, R. W.; House, D. E.; Ketcham, B. T.; Seal,
E., Jr.; Roger, L. J.; Knelson, J. R. (1984) Pulmonary effects in healthy
young men of four sequential exposures to ozone. Research Triangle Park,
NC: U.S. Environmental Protection Agency, Health Effects Research Labora-
tory; EPA report no. EPA-600/1-84-033. Available from National Technical
Information Service, Springfield, VA.
Hackney, J. D.; Linn, W. S.; Buckley, R. D.; Pedersen, E. E.; Karuza, S. K.;
Law, D. C.; Fischer, D. A. (1975a) Experimental studies on human health
effects of air pollutants. I. Design considerations. Arch. Environ.
Health 30: 373-378.
Hackney, J. D. ; Linn, W. S.; Mohler, J. G.; Pedersen, E. E.; Breisacher, P.;
Russo, A. (1975b) Experimental studies on human health effects of air
pollutants. II. Four-hour exposure to ozone and in combination with
other pollutant gases. Arch. Environ. Health 30: 379-384.
Hackney, J. D.; Linn, W. S.; Law, D. C.; Karuza, S. K.; Greenberg, H.; Buckley,
R. D. ; Pedersen, E. E. (1975c) Experimental studies on human health
effects of air pollutants. III. Two-hour exposure to ozone alone and in
combination with other pollutant gases. Arch. Environ. Health
30: 385-390.
Hackney, J. D.; Linn, W. S.; Karuza, S. K.; Buckley, R. D.; Law, D. C.; Bates,
D. V.; Hazucha, M.; Pengelly, L. D. ; Silverman, F. (1977b) Effects of
ozone exposure in Canadians and Southern Californians. Evidence for
adaptation? Arch. Environ. Health 32: 110-116.
Hackney, J. D.; Linn, W. S.; Buckley, R. D. ; Collier, C. R. ; Mohler, J. G.
(1978) Respiratory and biochemical adaptations in men repeatedly exposed
to ozone. In: Folinsbee, L. J.; Wagner, J. A.; Borgia, J. F.; Drinkwater,
B. L. ; Gliner, J. A.; Bedi, J. F. eds. Environmental stress: individual
human adaptations. New York, NY: Academic Press; pp. 111-124.
Hackney, J. D.; Linn, W. S.; Buckley, R. D.; Hislop, H. J. (1976) Studies in
adaptation to ambient oxidant air pollution: effects of ozone exposure in
Los Angeles residents vs. new arrivals. EHP Environ. Health Perspect.
18: 141-146.
Hackney, J. D.; Linn, W. S.; Fischer, D. A.; Shamoo, D. A.; Anzar, U. T. ;
Spier, C. E. ; Valencia, L. M. ; Veneto, T. G. (1983) Effect of ozone in
people with chronic obstructive lung disease. In: Mehlman, M. A.; Lee,
S. D. ; Mustafa, M. G., eds. In: International symposium on the biomedical
effects of ozone and related photochemical oxidants; March 1982; Pinehurst,
NC. Princeton, NJ: Princeton Scientific Publishers, Inc.; pp. 145-159.
(Advances in modern environmental toxicology: v. 5.)
Hackney, J. D. ; Linn, W. S.; Mohler, J. G.; Collier, C. R. (1977a) Adaptation
to short-term respiratory effects of ozone in men exposed repeatedly. J.
v Appl. Physiol. Respir. Environ. Exercise Physiol. 43: 82-85.
0190LG/A 11-89 5/2/84
-------
Hallett, W. Y. (1965) Effect of ozone and cigarette smoke on lung function.
Arch. Environ. Health 10: 295-302.
Hamburger, S. J. ; Goldstein, B. D.; Buckley, R. p.; Hackney, J. D. ; Amoruso,
M. A. (1979) Effect of ozone on the agglutination of erythrocytes by
concanavalin A. Environ. Res. 19: 299-305.
Hazucha, M. (1973) Effects of ozone and sulfur dioxide on pulmonary function
in man. Montreal, Canada: McGill University. Dissertation.
Hazucha, M. (1981) Assessment of ozone-induced hyperreactivity by histamine in
normal healthy subjects. In: Proceedings of the research planning work-
shop on health effects of oxidants. Research Triangle Park, NC: U.S.
Environmental Protection Agency; EPA report no. EPA-600/9-81-001;
pp. 314-327. Available from National Technical Information Service,
Springfield, VA.
Hazucha, M. ; Bates, D. V. (1975) Combined effect of ozone and sulfur dioxide
on human pulmonary function. Nature (London) 257: 50-51.
Hazucha, M.; Parent, C.; Bates, D. V. (1977) Development of ozone tolerance in
man. In: Dimitriades, B., ed. International conference on photochemical
oxidant pollution and its control: proceedings: v. II; September 1976;
Raleigh, NC. Research Triangle Park, NC: U.S. Environmental Protection
Agency, Environmental Sciences Research Laboratory; pp. 527-541; EPA
report no. EPA-600/3-77-001a. Available from: National Technical
Information Service, Springfield, VA; PB 264232.
Hazucha, M.; Silverman, F.; Parent, C.; Field, S.; Bates, D. V. (1973) Pulmonary
function in man after short-term exposure to ozone. Arch. Environ. Health
27: 183-188.
Henschler, D. ; Stier, A.; Beck, H.; Neumann, W. (1960) Geruchsschevellen
einiger wichtiger Einavirkung Geringer Konzentrationen auf den menschen.
[Olfactory threshold of some important irritant gases and manifestations
in man by low concentrations.] Arch. Gewerbepathol. Gewerbehyg. 17: 547-
570.
Holtzman, M. I.; Cunningham, J. H.; Sheller, J. R.; Irsigler, G. B.; Nadel, J.
A. ; Boushey, H. A. (1979) Effect of ozone on bronchial reactivity in
atopic and nonatopic subjects. Am. Rev. Respir. Dis. 120: 1059-1067.
Horvath, S. M. (1981) Impact of air quality on exercise performance. Exercise
Sport Sci. Rev. 9: 265-296.
Horvath, S. M. ; Gliner, J. A.; Folinsbee, L. J. (1981) Adaptation to ozone:
duration of effect. Am. Rev. Respir. Dis. 123: 496-499.
Horvath, S. M.; Gliner, J. A.; Matsen-Twisdale, J. A. (1979) Pulmonary function
and maximum exercise responses following acute ozone exposure. Aviat.
Space Environ. Med. 40: 901-905.
Hughes, D. (1979) The toxicity of ozone. London, England: Science Reviews
Ltd. (Occupational hygiene monograph: no. 3.)
0190LG/A 11-90 5/2/84
-------
Islam, M. S.; Ulmer, W. T. (1979a) Beeinflussung der Lungenfunktion durch ein
Schodstoffgemisch aus Ozon (03), Schwefeldioxyd (S02) und Stickstoffdioxyd
(N02) in MAK-Bereich (KurzzeiE versuch). [The influence of acute exposure
against a combination of 5.0 ppm S02, 5.0 ppm NO^, and 0.1 ppm 0, on the
lung function in the MK (lower toxic limit) areci (short-term test).]
Wiss. Umwelt (3): 131-137.
Islam, M. S.; Ulmer, W. T. (1979b) Die Wirkung einer Langzeitexposition (8h/Tag
uber 4 Tage) gegen ein Gasgemisch von S0? + N02 + 0^ im dreifochen MIK-
Bereich auf die Lungenfunktion und Broncriialrectgibrlitat bei gesunden
Versuchspersonen. [Long-time exposure (8 h per day on four successive
days) against a gas mixture of SO,, NCL, and 03 in three-times MIC on
lung function and reagibility of tfte bronchial system on healthy persons.]
Wiss. Umwelt (4): 186-190.
Jordan, E. 0.; Carlson, A. J. (1913) Ozone: its bacteriological, physiologic
and deodorizing action. JAMA J. Am. Med. Assoc. 61: 1007-1012.
Kagawa, J. (1983a) Effects of ozone and other pollutants on pulmonary function
in man. In: Mehlman, M. A.; Lee, S. D.; Mustafa, M. G., eds. Interna-
tional symposium on the biomedical effects of ozone and related photochem-
ical oxidants; March 1982; Pinehurst, NC. Princeton, NJ: Princeton
Scientific Publishers, Inc., pp. 411-422. (Advances in modern environmen-
tal toxicology: v. 5.)
Kagawa, J. (1983b) Respiratory effects of two-hour exposure with intermittent
exercise to ozone, sulfur dioxide and nitrogen dioxide alone and in com-
bination in normal subjects. Am. Ind. Hyg. Assoc. J. 44: 14-20.
Kagawa, J.; Toyama, T. (1975) Effects of ozone and brief exercise on specific
airway conductance in man. Arch. Environ. Health 30: 36-39.
Kagawa, J.; Tsuru, K. (1979a) Effects of ozone and smoking alone and in combin-
ation on bronchial reactivity to inhaled acetylcholine. Nippon Kyobu
Shikkan Gakkai Zasshi 17: 703-709.
Kagawa, J.; Tsuru, K. (1979b) Respiratory effects of 2-hour exposure to ozone
and nitrogen dioxide alone and in combination in normal subjects perform-
ing intermittent exercise. Nippon Kyobu Shikkan Gakkai Zasshi 17: 765-774.
Kagawa, J. ; Tsuru, K. (1979c) Respiratory effect of 2-hour exposure with
Intermittent exercise to ozone and sulfur dioxide alone and in combina-
tion in normal subjects. Nippon Eiseigaku Zasshi 34: 690-696.
Kehrl, H. R. ; Hazucha, M. J.; Solic, J. ; Bromberg, P. A. (1983) Effects of
ozone exposure on humans with moderate irreversible chronic obstructive
lung disease. In: Mehlman, M. A.; Lee, S. D.; Mustafa, M. G., eds.
International symposium on the biomedical effects of ozone and related
photochemical oxidants; March 1982; Pinehurst, NC. Princeton, NJ:
Princeton Scientific Publishers, Inc.; pp. 213-225. (Advances in modern
environmental toxicology: v. 5.)
Kerr, H. D.; Kulle, T. J.; Mcllhany, M. L.; Swidersky, P. (1975) Effects of
ozone on pulmonary function in normal subjects. Am. Rev. Respir. Dis.
Ill: 763-773.
0190LG/A 11-91 5/2/84
-------
Ketcham, B. ; Lassiter, S. ; Haak, E. D., Jr.; Knelson, J. H. (1977) Effects of
ozone plus moderate exercise on pulmonary function in healthy young men.
In: Proceedings of the international conference on photochemical oxidant
pollution and its control. Research Triangle Park, NC: U.S. Environmental
Protection Agency; EPA report no. EPA-600/3-77-001a; pp. 495-504. Avail-
able from National Technical Information Service, Springfield, VA.
Kleinman, M. T.; Bailey, R. M.; Chung, C. Y-T.; Clark, K. W.; Jones, M. P.;
Linn, W. S. ; Hackney, J. D. (1981) Exposures of human volunteers to a
controlled atmospheric mixture of ozone, sulfur dioxide and sulfuric
acid. Am. Ind. Hyg. Assoc. J. 42: 61-69.
Knelson, J. H. ; Peterson, M. L.; Goldstein, G. M.; Gardner, D. E. ; Hayes, C.
G. (1976) Health effects of oxidant exposures: A research progress
report. In: Report on UC-ARB conference "Technical bases for control
strategies of photochemical oxidant: current status and priorities in
research"; December 1974; Riverside, CA. Riverside, CA: University of
California, Statewide Air Pollution Research Center; pp. 15-50.
Konig, G. ; Rb'mmelt, H.; Kienele, H.; Dirnagl, K. ; Polke, H. ; Fruhmann, G.
(1980) Changes in the bronchial reactivity of humans caused by the influ-
ence of ozone. Arbeitsmed. Sozialmed. Praeventivmed. 151: 261-263.
Kulle, T. J. (1983) Duration of pulmonary function and bronchial reactivity
adaptation to ozone in humans. In: Mehlman, M. A.; Lee, S. D. ; Mustafa,
M. G., eds. International symposium on the biomedical effects
of ozone and related photochemical oxidants; March 1982; Pinehurst, NC.
Princeton, NJ: Princeton Scientific Publishers, Inc.; pp. 161-173.
(Advances in modern environmental toxicology: v. 5.)
Kulle, T. J.; Kerr, H. D.; Parrel!, B. P.; Sauder, L. R.; Bermel, M. S. (1982a)
Pulmonary function and bronchial reactivity in human subjects with expo-
sure to ozone and respirable sulfuric acid aerosol. Am. Rev. Respir. Dis.
126: 996-1000.
Kulle, T. J.; Milman, J. H.; Sauder, L. R.; Kerr, H. D.; Parrel 1, B. P.;
Miller, W. R. (1984) Pulmonary function adaptation to ozone in subjects
with chronic bronchitis. Environ. Res. (In Press).
Kulle, T. J.; Sauder, L. R.; Kerr, H. D.; Parrel 1, B. P.; Bermel, M. S.;
Smith, D. M. (1982b) Duration of pulmonary function adaptation to ozone
in humans. Am. Ind. Hyg. Assoc. J. 43: 832-837.
Linn, W. S.; Buckley, R. D. ; Spier, C. E.; Blessey, R. L.; Jones, M. P.;
Fischer, D. A.; Hackney, J. D. (1978) Health effects of ozone exposure in
asthmatics. Am. Rev. Respir. Dis. 117: 835-843.
Linn, W. S.; Shamoo, D. A.; Venet, T. G.; Spier, C. E.; Valencia, L. M.;
Anzar, U. T. ; Hackney, J. D. (1983) Response to ozone in volunteers with
chronic obstructive pulmonary disease. Arch. Environ. Health 38: 278-283.
Linn, W. S. ; Fischer, D. A.; Medway, D. A.; Anzar, U. T.; Spier, C. E. ;
Valencia, L. M.; Venct, T. G.; Hackney, J. D. (1982a) Short-term respira-
tory effects of 0.12 ppm ozone exposure in volunteers with chronic ob-
structive lung disease. Am. Rev. Respir. Dis. 125: 658-663.
0190LG/A 11-92 5/2/84
-------
Linn, W. S.; Jones, M. P.; Bachmayer, E. A.; Clark, K. W.; Karuza, S. K. ;
Hackney, J. D. (1979) Effect of low-level exposure to ozone on arterial
oxygenation in humans. Am. Rev. Respir. Dis. 119: 731-740.
Linn, W. S.; Jones, M. P.; Bachmayer, E. A.; Spier, C. E. ; Mazur, S. F.; Avol,
E. L.; Hackney, J. D. (1980) Short-term respiratory effects of polluted
air: a laboratory study of volunteers in a high-oxidant community. Am.
Rev. Respir. Dis. 121: 243-252.
Linn, W. S.; Medway, D. A.; Anzar, U. T.; Valencia, L. M.; Spier, C. E.; Tsao,
F. S-0.; Fischer, D. A.; Hackney, J. D. (1982b) Persistence of adaptation
to ozone in volunteers exposed repeatedly over six weeks. Am. Rev. Respir.
Dis. 125: 491-495.
McDonnell, W. F. ; Horstmann, D. H.; Hazucha, M. J. ; Seal, E. , Jr.; Haak, E.
D.; Salaam, S. ; House, D. E. (1983) Pulmonary effects of ozone exposure
during exercise: dose-response characteristics. J. Appl. Physiol. Respir.
Environ. Exercise Physiol. 54: 1345-1352.
HcKenzie, W. H.; Knelson, J. H.; Rummo, N. J.; House, D. E. (1977) Cytogenetic
effects of inhaled ozone in man. Mutat. Res. 48: 95-102.
McKenzie, W.H. (1982) Controlled human exposure studies: cytogenetic effects
of ozone inhalation. In: Bridges, B.A.; Butterworth, B.E.; Weinstein,
I.B., eds. Indicators of genotoxic exposure. Spring Harbor, NY:
Cold Spring Harbor Laboratory; pp. 319-324. (Banbury report: no. 13).
Merz, T. ; Bender, M. A.; Kerr, H. D.; Kulle, T. J. (1975) Observations of
aberrations in chromosomes of lymphocytes from human subjects exposed to
ozone at a concentration of 0.5 ppm for 6 and 10 hours. Mutat. Res.
31: 299-302.
Mihevic, P. M.; Gliner, J. A.; Horvath, S. M. (1981) Perception of effort and
respiratory sensitivity during exposure to ozone. Ergonomics 24: 365-374.
Miller, F. J. ; Menzel, D. B.; Coffin, D. L. (1978) Similarity between man and
laboratory animals in regional pulmonary disposition of ozone. Environ.
Res. 17: 84-101.
National Air Pollution Control Administration. (1970) Air quality criteria for
photochemical oxidants. Washington, DC: U.S. Department of Health,
Education, and Welfare, Public Health Service; NAPCA publication no. AP-63.
Available from: NTIS, Springfield, VA; PB 190262.
National Research Council. (1977) Ozone and other photochemical oxidants.
Washington, DC: National Academy of Sciences, Committee on Medical and
Biologic Effects of Environmental Pollutants.
Peterson, M. L. ; Harder, S.; Rummo, N. ; House, D. (1978a) Effect of ozone on
leukocyte function in exposed human subjects. Environ. Res. 15: 485-493.
Peterson, M. L. ; Rummo, N.; House, D. ; Harder, S. (1978b) In vitro responsive-
ness of lymphocytes to phytohemmagglutinin. Arch. Environ. Health 33: 59-63.
0190LG/A 11-93 5/2/84
-------
Peterson, M. L.; Smialowicz, R.; Harder, S.; Ketcham, B.; House, D. (1981) The
effect of controlled ozone exposure on human lymphocyte function. Environ.
Res. 24: 299-308.
Posin, C. I.; Clark, K. W.; Jones, M. P.; Buckley, R. D.; Hackney, J. D.
(1979) Human biochemical response to ozone and vitamin E. J. Toxicol.
Environ. Health 5: 1049-1058.
Raven, P. B. ; Drinkwater, B. L.; Horvath, S. M. ; Ruhling, R. 0.; Gliner, J.
A.; Sutton, J. C.; Bolduan, N. W. (1974a) Age, smoking habits, heat
stress, and their interactive effects with carbon monoxide and peroxyacetyl
nitrate on man's aerobic power. Int. J. Biometeorol. 18: 222-232.
.•..G;en, P. B., Drinkwater, B. L. ; Ruhling, R. 0.; Bolduan, N.; Taguchi, S.;
Gliner, J. A.; Horvath, S. M. (1974b) Effect of carbon monoxide and
peroxyacetyl nitrate on man's maximal aerobic capacity. J. Appl. Physio!.
36: 288-293.
Asven, P. B.; Gliner, J. A.: Sutton, J. C. (1976) Dynamic lung function changes
following long-term work in polluted environments. Environ. Res. 12: 18-25.
Savin, W.; Adams, W. (1979) Effects of ozone inhalation on work performance
and V02|T)ax. J. Appl. Physiol. 46: 309-314.
.,,y-;>)c, A.; Peterson, M. L. ; House, D.; Turner, A. G.; Jeffries, H. E.; Baker,
R, (1978) The effects of ozone on human cellular and humoral immunity:
Characterization of T and B lymphocytes by rosette formation. Environ.
Res. 15: 65-69.
^..cijhard, R. J.; Urch, B.; Silverman, F.; Corey, P. N. (1983) Interaction of
ozone and cigarette smoke exposure. Environ. Res. 31: 125-137.
. .iraeru F. (1979) Asthma and respiratory irritants (ozone). EHP Environ.
,,:•„! th Pevspect. 29: 131-136.
var^c-n, P.; Fo'iinsbee, L. J.; Barnard, J.; Shephard, R. J. (1976) Pulmonary
junction changes in ozone - interaction of concentration and ventilation.
J, Appl. Physiol. 41: 859-864.
.xh. L. E. (1955) Peroxyacetyl nitrate inhalation. Arch. Environ. Health
id: 161-164.
.0 -';- j J.; Hc.zucha, M. J.; Bromberg, P. A. (1982) Acute effects of 0.2 ppm
or-one in patients with chronic obstructive pulmonary disease. Am. Rev.
r. Dis. 125: 664-669.
Stacy, R. W.; Seal, E., Jr.; House, D. E.; Green, J.; Roger, L. J. ; Raggio, L.
(1983) Effects of gaseous and aerosol pollutants on pulmonary function
measurements of normal humans. Arch. Environ. Health 38: 104-115.
Toyama, T.; Tsumoda, T.; Nakaza, M.; Higashi, T.; Nakadato, T. (1981) Airway
response to short-term inhalation of N0?, 0, and their mixture in healthy
men. Sangyo Igaku 23: 285-293.
0190LG/A 11-94 5/2/84
-------
U.S. Department of Health and Human Services. (1981) Current estimates from
the National Health Interview Survey: United States, 1979. Hyattsville,
MD: Public Health Service, Office of Health Research, Statistics and
Technology, National Center for Health Statistics; DHHS publication no.
(PHS) 81-1564. (Vital and health statistics: series 10, no. 136).
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,
Springfield, VA; PB80-124753.
von Nieding, G.; Wagner, H. M.; Krekeler, H.; Lollgen, H.; Fries, W.; Beuthan,
A. (1979) Controlled studies of human exposure to single and combined
action of N0?, 0.,, and S02- Int. Arch. Occup. Environ. Health 43: 195-210.
von Nieding, G. ; Wagner, H. M.; Lollgen, H.; Krekeler, H. (1977) Zur akuten
Wirkung von Ozon auf die Lungenfunktion des Menschen. [Acute effects of
ozone on lung function in men.] In: Ozon und Begleitsubstanzen im
photochemischen Smog [Ozone and other substances in photochemical smog]:
VDI colloquium; 1976; Dusseldorf, West Germany. Dusseldorf, West Germany:
Verein Deutscher Ingenieure (VDI) GmbH; pp. 195-210. (VDI-Berichte:
no. 270).
world Health Organization. (1978) Photochemical oxidants. Geneva, Switzerland:
World Health Organization. (Environmental health criteria: no. 7.)
Young, W. A.; Shaw, D. B.; Bates, D. V. (1964) Effect of low concentrations of
ozone on pulmonary function in man. J. Appl. Physio!. 19: 765-768.
0190LG/A 11-95 5/2/84
-------
12. FIELD AND EPIDEMIOLOGICAL STUDIES OF THE EFFECTS OF OZONE
AND OTHER PHOTOCHEMICAL OXIDANTS
12.1 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 ambient ozone
or photochemical oxidant exposures; (2) attempts to determine quantitative
relationships between exposures to these agents and observed effects; and
(3) identifies population groups at greatest risk for such health effects.
Studies of both acute and chronic exposure effects are discussed.
Many of the available epidemiological studies used exposure data or
health endpoint measurements inadequate or unreliable for quantifying exposure-
effect relationships. Also, results from these studies have often been con-
founded by factors such as variations in activity levels and time spent out of
doors, cigarette smoking, poor hygiene, coexisting pollutants, weather, and
socioeconomic status. Thus, selection of those studies thought to be most
useful in attempting to derive health criteria for ozone or oxidants is of
critical importance. To judge the relative scientific quality of epidemio-
logical studies for standard-setting purposes, the following guidelines (as
modified from U.S. Environmental Protection Agency, 1982) were set forth:
o The aerometric data are adequate to characterize geographic or
temporal differences in pollutant exposures of study popula-
tions in the range(s) of pollutant concentrations evaluated.
o The study populations are well defined and allow for statisti-
cally adequate comparisons between groups or temporal analyses
within groups.
o The health endpoints are scientifically plausible for the
pollutant being studied; and the measurement methods are ade-
quately characterized and implemented.
o The statistical analyses are appropriate and properly per-
formed, using data subjected to adequate quality control.
o Potentially confounding or covarying factors are adequately
controlled for or taken into account.
019DC/A 12-1 6/18/84
-------
o The reported findings are internally coherent and biologically
plausible.
For present purposes, greatest emphasis is placed here on discussion of
studies that provide 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. Some studies not meeting the above guidelines but considered to be
sources of additional supportive information are also summarized below and
their limitations noted.
12.2 FIELD STUDIES OF EFFECTS OF ACUTE EXPOSURE
Field studies of symptoms and pulmonary function combine features of
controlled human exposure studies (Chapter 11) and epidemiological studies.
These studies employ the more rigorous methods and better experimental control
typical of controlled exposure studies with observations made in the field
(Morris, 1970; Mausner and Bahn, 1974; American Thoracic Society, 1978; World
Health Organization, 1983, 1984). Some attempt to mimic chamber conditions
but include exposures of subjects to ambient air containing the pollutant(s)
of interest as well as exposures to clean air as a control. They thus form a
bridge or continuum between studies discussed in Chapter 11 and epidemiological
studies assessed here.
12.2.1 Symptoms and Pulmonary Function in General Field Conditions
Some early studies of symptoms and pulmonary function under field oxidant
exposure conditions were previously reviewed by the Environmental Protection
Agency (1978). For example, Richardson and Middleton (1957, 1958) studied eye
irritation in subjects under both air-filtration and nonfiltration conditions.
They reported increased complaints to be associated with oxidant concentrations
019DC/A 12-2 6/18/84
-------
of 0.1 ppm, measured by the potassium iodide (KI) method, but not with nitrogen
dioxide (N0?) or suspended particles.
Balchum (1973) reported an expansion of a study by Remmers and Balchum
(1965). Pulmonary function changes were observed in 15 patients with moderately
severe chronic obstructive lung disease (COLD), who spent one week in a room
without air filtration and a second week in a room with filtered air. In the
unfiltered room, mean daily oxidants (KI method) averaged 0.11 ppm and ranged
up to 0.2 ppm, but ranged from 0.02 to 0.03 ppm in the filtered room. Decreases
in airway resistance and increases in arterial partial pressure of oxygen
(PaOp) appeared in both smokers and nonsmokers after 48 hours in filtered air,
both when at rest and during exercise in about 75 percent of subjects. Re-
examination of the 1965 data by Ury and Hexter (1969) showed airway resistance
decreases to be more strongly correlated wi^h oxidant concentrations than with
either N02 or nitric oxide (NO) levels.
More recent field studies of pulmonary function have employed pre- and
post-exercise function measurements (often used in controlled human exposure
studies) in comparing the effects of short-term exposures to ambient air
containing ozone and oxidants versus clean air (sham control) exposures. For
example, in a series of studies carried out in a mobile laboratory, Linn and
coworkers have shown pulmonary function decrements to be associated with
exposure of Los Angeles area residents to ambient air containing ozone and
other photochemical oxidants. The subject characteristics and experimental
conditions employed in different studies by Linn and collaborators are sum-
marized in Table 12-1 and associated pollutant levels in Table 12-2.
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 (near
Los Angeles) during two periods separated by 3 weeks. Only 5 subjects were
smokers, and the two groups were similar in age, height, and sex ratio.
Asthmatic subjects had heterogeneous disease characteristics, determined by
questionnaire responses. Of the "normal" group, 25 subjects were considered
allergic based on a history of upper respiratory allergy or reported undiag-
nosed wheeze which they called "allergic." Ozone, nitrogen oxides (NO ),
/\
sulfur dioxide (S0?), sulfates, and total suspended particulate matter (TSP)
were monitored inside and outside the chamber at 5-min intervals, and valida-
tion studies were performed at the mobile laboratory. Measurements of 0,, by
the ultraviolet (UV) method were calibrated against California Air Resources
019DC/A 12-3 6/18/84
-------
TABLE 12-1. SUBJECT CHARACTERISTICS AND EXPERIMENTAL CONDITIONS
• OF THE MOBILE LABORATORY STUDIES
Subjects
Number
%Males
%Asthmatics
%Smokers
Age6
Height, cm
Weight, kg
Exercise
Exposure time
Location
Atmosphere
1978a
64
41
47
8
30110
170110
70114
light intermittent
2 hr. (p.m. )
Duarte
oxidant
1979b
64
41
33
22
34111
170112
69+16
light intermittent
2 hr. (a.m.)
Hawthorne
primary pollutant
1980C
60
75
12
13
30111
173+15
69110
heavy continuous
1 hr. (p.m. )
Duarte
oxidant
1981
98
58
51
7
28±8
172+9
67111
d
heavy continuous
1 hr. (p.m
Duarte
oxidant
. )
Linn et al. (1980, 1983).
bLinn et al. (1982, 1983).
cLinn et al. (1983), Avol et al. (1983).
dLinn et al. (1983).
eMean + standard deviation.
TABLE 12-2. POLLUTANT LEVELS (MEAN 1 S.D.) MONITORED INSIDE A MOBILE LABORATORY
DURING AMBIENT AIR EXPOSURES
Subjects
03 (ppm)e
S02 (ppm)
N02 (ppm)
CO (ppm)
Parti cul ate:
Total (ug/m3)
S04_(Mg/m3)
N03 (tag/m3)
19783
. 174+ . 068
.0121 .003
.069+ .014
2.9
182
1§
1 1.1
+42
1 7
1979b
. 022+ . Oil
. 0181 . 099
.056+ .033
1.6
112
13
19
1 0.9
145
1 6
+10
1980°
.165+ .059
.099+ .005
.050+ .028
3.1
227
17
22
1 2.0
+76
112
1 9
1981d
.156+ .055
.005+ .033
.062+ .023
2.2
166
9
32
1 0.7
±52
1 4
±10
aLinn et al. (1980, 1983).
bLinn et al. (1982, 1983).
cLinn et al. (1983), Avol et al. (1983).
dLinn et al. (1983).
eUltraviolet photometer calibration method.
Measurements unsatisfactory due to artifact nitrate formation on filters.
019DC/A
12-4
6/18/84
-------
Board (CARB) reference standards and corrected to those obtained by the KI
method. The mobile laboratory has been described previously (Avol et al.,
1979), as have the methods for studies of lung function. Lung function
measures before and after exposure were compared by t-tests and nonparametric
methods. Intermittent periods of exercise were combined with the exposure.
Ozone and particulate pollutants predominated in the ambient air mixture,
as shown in Table 12-1 for the 1978 Duarte study. Ozone levels (corrected to
3
the KI method) averaged 427 pg/m (0.22 ppm) inside the mobile laboratory
3
chamber and 509 p.g/m (0.26 ppm) outside the laboratory during ambient air
3
exposures, and 7.8 (jg/m (0.004 ppm) during purified air exposures. Matching
3
peak 0~ concentrations, respectively, were 498 ± 186 pg/m (0.025 ± 0.10 ppm);
597 ± 217 pg/m3 (0.31 ± 0.11 ppm); and 19 ± 17 pg/m3 (0.01 ± 0.009 ppm). TSP
3 3
levels averaged 182 pg/m inside the chamber and 244 pg/m outside the labora-
3
tory during ambient air exposures, but 49 pg/m inside the chamber during
purified-air exposures. Average NOp, S0», CO, and sulfate levels inside the
chamber were uniformly low during ambient-air exposures (as shown in Table 12-1)
and were even lower during purified-air exposures (i.e., 0.015 ppm for NO •
0.009 ppm for S0?; 2.8 ppm for CO; 0.9 ppm for sulfates). Gases were monitored
continuously, alternatively inside and outside the mobile laboratory for 5-min
periods. Particles were measured during testing inside and outside the labora-
tory. 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
masking odors 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), 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 approximately double the respiratory minute
ventilation relative to resting level. The purified-air control study for
each subject took place at least three weeks after the ambient-air exposure
session, with identical procedures except for purified-air in place of the
ambient. Note that Linn et al. (1980, 1983) also separately tested 12 healthy
subjects from the project staff in order to validate various aspects of the
study. The validation tests indicated insignificant variability in the measure-
ment methods for healthy normal subjects.
019DC/A 12-5 6/18/84
-------
In the main set of experiments $ The asthmatic group experienced greater
changes from baseline in residual volume (RV) and 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 NH3, or NO™. Increasing 0_
was correlated with decreasing peak flow and 1-sec forced expiratory volume
(FEV ). No explanation was given for an association of increasing CO with
increasing RV and with the slope of the alveolar plateau (SBNT). Increasing
SQy 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 (V 75%^' as we^ as in
the FEV, normalized for forced vital capacity (FEV.,/FVC%), TLC, and pulmonary
resistance (R ) in the normal/allergic group. Although other pollutant vari-
ables contributed to the observed effects, none did so consistently. Apart
from 0_, 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. Asth-
matics and normals/allergies also had significantly increased symptom scores
during ambient air exposure sessions. This increase appeared to last later
into the day in asthmatics but not in normals/ allergies (Figure 12-1).
Nine of 12 highly reactive subjects (four from the normal/allergic group
and five asthmatics—a similar proportion from each group), who had experience^!
a fall in FEV greater than 200 ml during ambient exposure (compared to purified-
3
air exposure), underwent a controlled 2-hr exposure experiment at 392 ug/m
(0.2 ppm) with intermittent exercise (see Chapter 11). 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. The authors suggested that ambient exposures had greater
effects than chamber exposures. Normal/allergic subjects in the validation
studies 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 al. ,
1980) with 64 different subjects, ages 18 to 55, at a different location
019DC/A 12-6 6/18/84
-------
30
LU
§ 20
g
10
1 I I
AMBIENT AIR
PURIFIED AIR
1 \ T
I I
I
I I
I
PE 1C LO
ALL
PE 1C LD
NORMAL
PE 1C LD
ASTHMATIC
Figure 12-1. Mean symptom score changes with
exposure for all subjects, normal and allergic sub-
jects, and asthmatic subgroup of subjects. PE =
pre-exposure; 1C = in chamber (near end of ex-
posure period); LD = later in day. Circles (Oor®)
indicate total symptom scores; triangles (AorA)
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 non-
significant difference between ambient and
purified air scores.
Source: Adapted from Linn et al. (1980).
019DC/A
12-7
6/18/84
-------
(Hawthorne) with low CL levels (0.04 ± 0.02 ppm, 82 ± 39 pg/m ) but with
elevated levels of other pollutants. They found no meaningful lung-function
or symptom changes, and they concluded that 0~ was primarily responsible for
the effects seen in the original study.
A third experiment (Linn et al . , 1983; Avol et al . , 1983) was conducted
at the original oxidant-polluted location (Duarte) with 60 subjects, ages 18
to 55, exercising heavily (four to five times resting minute ventilation) and
o
continuously for 1 hr. The mean 0- concentration was 314 pg/m (0.16 ppm) in
ambient air (measured by the UV method). Total reported symptoms did not
differ significantly between exposure and control (purif ied-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
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 seemed
to occur more frequently (34 of 47 cases) at 0, exposure concentrations above
3 3
235 pg/m (0.12 ppm), up to 549 jjg/m (0.28 ppm) in the total study group (P =
0.02). The authors stated that the considerable functional losses in this
study were not necessarily accompanied by symptoms, nor were they related to
obvious prior physical or clinical status.
A fourth study in the original location (Duarte) studied 98 subjects,
including 50 asthmatics (Linn et al . , 1983; Avol et al . , 1983). Mean exposure
3 3
was 306 pg/m (0.156 ppm) 0, and 166 pg/m TSP (lower than in 1980). The
3
highest exposure concentration was 431 |jg/m (0.22 ppm), which was lower than
in 1982. The subjects were exposed to heavier, continuous exercise (though
lower exercise ventilation levels than in 1980), and those showing the largest
changes in pulmonary function (positive and negative) were the asthmatics.
The mean decreased values remained depressed for up to 3 hr post ambient
exposure. Maximum mean changes in FVC and FEV, for asthmatics after ambient
exposure were 122 ml and 89 ml, respectively, with the former returning more
quickly to control levels. The value for V 5Qo/ was more variable with a
maximum mean change of 132 L/s after ambient exposure. The only significant
mean changes after exposure were for FVC in normals (P < 0.003). There were
019DC/A 12-8 6/18/84
-------
significant interactions of ambient and purified air after exposure in asthma-
tics for FEV.. and V cr.v.
1 max50%
In summary, the Linn et al. (1980, 1982, 1983) and Avol et al. (1983)
studies have demonstrated respiratory effects in Los Angeles area residents
related to CL concentration and level of exercise. Such effects include
pulmonary function decrements seen at 0~ levels as low as 0.16 ppm and increased
symptoms observed at levels as low as 0.12 ppm 03- The effects are typically
mild and generally do not differ substantially between asthmatics and persons
with normal respiratory health, although symptoms last for a few hours longer
in asthmatics. However, many of the normal subjects had a history of allergy
and appeared to be more sensitive to 0_ than "non-allergic" normal subjects.
O
The relative importance of exercise level, duration of exposure, individual
variations in sensitivity, and effects of coexisting pollutants in producing
the observed effects remains to be more fully investigated.
Lebowitz et al. (1974) demonstrated an association between pulmonary flow
and volume changes (measured by a water-filled spirometer) in exercising
children under ambient exposure conditions. However, no effects of exercise
or diurnal shifts in function during the day were observed under controlled
temperature and humidity conditions in filtered rooms; later, Lebowitz et al.
(1982b) verified the lack of diurnal effect in normal subjects and validated
the use of the Mini-Wright Peak Flow Meter for field use.
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 spirometer at the beginning of
the day or at lunch, both adjusted for age and height. No day-of-week effect
was seen. Ambient air levels of TSP, hydrogen ions, and sulfates were moni-
tored by a high-volume sampler in the day camp building rooftop. Ozone concen-
trations 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 that
yielded 03 estimates within ±16 ug/m (0.008 ppm) on average. Estimated 1-hr
peak 03 levels (early afternoon) varied from 90 to 249 ug/m3 (0.046 to 0.122 ppm),
whereas TSP levels were low (6-hr samples <103 ug/m ), as were sulfuric acid
O
(H2S04) equivalent concentrations (maximums <6.3 ug/m ). Lippman et al.
(1983) reported significant inverse correlations between FVC and FEV-. and
estimated maximum 1-hr 03 levels for 4 or more days covering a twofold
019DC/A 12-9 6/18/84
-------
range in 0,.. Differences in correlations (i.e., slopes) were not related to
other pollutants (TSP, H?SO.) or ambient temperatures. Qualitatively, the
Lippmann et al. (1983) study results suggest low-level 0~ effects; however,
because exposure modeling (rather than on-site monitoring) was used to esti-
mate CL levels, much uncertainty surrounds quantitative interpretation of the
O
study results. The uncertainty about appropriate quantitative interpretation
of these findings may be reduced by consideration of the results from a similar
study conducted the next summer by Lippmann and Lioy (1984).
A similar group of children was studied at a day camp in Mendham, NJ.
Preliminary analyses of the Mendham data, as summarized by Lippmann and Lioy
(1984), indicates a significant association between peak hour CL levels and
decrements in peak expiratory flow rate (PEFR). In order to provide better
air monitoring data, CL concentrations were measured (UV) at the Mendham camp
<3
site, as were concentrations of HUSO,. The highest peak 1-hr CL concentration
measured on a study day was 0.143 ppm; values ranged from 0.02 to 0.18 ppm O^-
Several comparisons can be made between the data reported by Lippmann
et al. (1983) and Lippmann and Lioy (1984). There were 39 children (22 girls,
17 boys) in the follow-up study with sufficient data for analysis; however,
the children were not as physically active as the children studied in the
previous study in Indiana, PA. While marked (^-dependent changes in PEFR were
,-eported, Lippmann and Lioy (1984) did not observe an Q3-dependent change in
FVC, as was found previously. Also, the change in FEv^ Q with 03 was smaller
in girls. However, in both studies, the 03-related decrements were greater in
girls than boys. Both studies also reported low concentrations of acidic
aerosol, suggesting that the response was primarily attributable to 03- A
final analysis of the two studies cannot be made until a complete description
of the results obtained in Mendham, NJ, has been published.
12.2.2 Symptoms and Pulmonary Function Under High-Altitude Conditions
Young et al. (1962) noted high average CL levels in passenger cabins of
aircraft flying between 27,000 and 39,000 feet. In 1973, Bischof reported
that 0,, concentrations (Comhyr ECC meter) during 14 spring polar flights
(1967-71) varied from 0.1 to 0.7 ppm, with 1-hr peaks above 1.0 ppm, 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)
019DC/A 12-10 6/18/84
-------
levels as high as 1.035 ppm. Other reports (House of Representatives, 1980;
Broad, 1979) indicate that 0- concentrations in high-altitude aircraft can
reach excessively high levels; for example, 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.*
Anecdotally, flight attendants and passengers in high-altitude aircraft
have complained of certain symptoms (chest pain, substernal pain, cough) which
were most prevalent during late winter and early spring flights. Similar
symptoms have been observed in more systematic studies of such effects, such
as (1) the study by Reed et al. (1980), which found symptoms among 1,330
flight attendants to be related to aircraft type and altitude duration but not
to sex, medical history, residence, or years of work; and (2) the Taskin
et al. (1983) study, which found increased 0_-related symptoms in flight
attendants on Boeing 747SP (higher-altitude) flights in comparison to attendants
on lower-flying 747 flights. Neither of these two studies, however, measured
03 concentrations in the aircraft studied.
Two recent studies by Lategola and associates attempted more quantitative
evaluation of problems associated with 0- exposures of flight attendants and
passengers. Lategola et al. (1980a) exposed 55 young subjects (29 men and 26
women) to ambient air and to an 0- environment in an altitude chamber maintained
at 1829 m (6000 ft). Subjects served as their own controls in each experiment.
Two major studies were conducted on 27 (15 men and 12 women) and 28 (14 men
and 14 women) subjects.
In the first study, (1) 0_ concentrations were 0 and 315 ng/m (0.0 and
0.2 ppm), (2) exposure time was 4 hr (with four 10-min exercise periods, the
first three being at lower levels of activity and the fourth at a higher
level) and (3) pulmonary function and subjective evaluations were obtained
pre- and post-exposure. These measurements were made near sea level before
and 10 min after the altitude exposures. Other studies, on vision parameters,
*Note that, as ambient pressure decreases at high altitude, 03 concentra-
tions remain the same as expressed in terms of ppm levels, but 0,, mass concen-
trations (in (jg/m ) 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 pg/m 03 concen-
trations under specific measurement conditions.
019DC/A 12-11 6/18/84
-------
hand steadiness, and Wechsler memory tests, were conducted during the high-
altitude exposures. Male subjects exercised with minute ventilations of 20
L/min in the first three exercise periods and 30 L/min for the last period
just prior to descent; for female subjects, exercise ventilations were 13 and
17 L/min, respectively. No alterations in the measured pulmonary functions
were found and although slight discomforts were reported, they were not signi-
ficantly related to 0- exposure. The second study differed from the first in
3
that the 0« exposure was 475 \JQ/n\ (0.3 ppm) and only three exercise periods
were used. Again, men exercised at ventilations of 24.9 L/min for the first
two periods and 38.6 L/min for the last, and the women at 16.4 and 20.9 L/min,
respectively. Significantly greater symptom scores were found after both the
last exercise period and the termination of the study. In this experiment,
differences between the no-0_ and the 0 responses for all spirometry param-
eters [FVC, FEV-p forced expiratory flow (^^25-75°^' and ^^75-957-^ Wltnin
each sex group were statistically significant (P < 0.05). The two lung-volume
measures manifested smaller changes than did flow-rate flow measures. Symptom
scores were greater in men than in women during the last treadmill tests, but
were not statistically significant. The results indicate increased symptoms
and pulmonary function decrements among normal subjects at 0.30 ppm, but not
0.2 ppm under light exercise conditions.
Lategola et al. (1980b) also studied 40 middle-aged men, 20 smokers and
20 nonsmokers, again exposed in an altitude chamber (1829 m), resting for 3 hr
in environments containing 0 or 475 pg/m (0.0 or 0.3 ppm) 0_. Eye discomfort
was the most frequently reported symptom; headache and nose and throat irrita-
cion were also reported. All subjects combined manifested small but statisti-
cally significant spirometric decrements in FVC, FEV and FEF-,5_g5o,» primarily
due to changes within the nonsmoking group. Smokers reported fewer or dimin-
ished symptoms, confirming observations reported by others. The study tends
to confirm small but significant respiratory effects observed at 0.3 ppm among
nonsmoking normal adults under high-altitude conditions. The 0_ levels used
O
in the Lategola studies are, however, generally lower than 0_ concentrations
reported to occur in certain aircraft at high altitudes, as are the simulated
altitudes employed by Lategola and coworkers.
019DC/A 12-12 6/18/84
-------
12.3 EPIDEMIOLOGICAL STUDIES OF EFFECTS OF ACUTE EXPOSURE
Effects of acute exposure to photochemical oxidants are generally assessed
in communities by comparing functional or clinical status during periods of
high and low 0_ or oxidant concentrations. Occasionally, communities with
different concentrations are compared. The concentrations measured have been
24-hr averages, maximum hourly averages, or instantaneous peaks.
12.3.1. Acute Exposure Morbidity Effects
For purposes of this document, indices of acute morbidity associated with
photochemical oxidants include the incidence of acute respiratory illnesses;
symptom aggravation in patients with asthma and other chronic lung diseases;
eye irritation; headache; respiratory irritation; and effects on pulmonary
function, athletic performance, auto accident rates, school absenteeism, and
hospital admissions.
12.3.1.1. Respiratory and Other Symptoms of Irritation. Various symptoms,
including eye irritation, have been reported during ambient air exposure.
However, eye irritation has generally not been associated with 0- exposure in
controlled laboratory studies (Chapter 11). This symptom has been associated
with formaldehyde, acrolein, and other organic photochemical reaction products
such as peroxyacetyl nitrate (PAN) (National Air Pollution Control Association,
1970; Altshuller, 1977; Environmental Protection Agency, 1978; National Research
Council, 1977; Okawada et al., 1979). Of the biological effects caused by or
aggravated by photochemical air pollution, eye irritation appears to have one
of the lowest thresholds; however, it also appears to be a short-term, revers-
ible effect, since damage to conjunctiva and subjacent tissue has not been
reported.
Regression analyses by Renzetti and Gobran (1957), as reviewed previously
(Environmental Protection Agency, 1978), has indicated increases in eye irrita-
tion over a wide range of average oxidant values in the Los Angeles area,
suggesting that severity increased above hourly oxidant concentrations of
about 0.1 ppm.
The U.S. Environmental Protection Agency (1978) also reviewed several
studies on 850 Japanese schoolchildren by Shimizu (1975) and Shimizu et al.
(1976), by the Japanese Environmental Agency (1976), and by Makino and Mizoguchi
(1975) and Mizoguchi et al. (1977). The Shimizu et al. studies did not segre-
gate the effects of oxidants, although they found that acrolein (0.5 ppm,
019DC/A 12-13 6/18/84
-------
5 min) produced eye irritation. The Japanese Environmental Agency (1976)
study reported complaints from a survey conducted at oxidant concentrations
>0.15 ppm, but without denominators. In the studies by Makino and Mizoguchi
(1975) and Mizoguchi et al. (1977), no yearly symptom-pollution correlations
were significant for SO-, N0?, or NO alone, whereas some symptoms were posi-
tively correlated with temperature (alone and with other pollutants). The
highest correlations were reported between symptoms and oxidants. On days
when maximum hourly oxidant levels exceeded 0.10 ppm, significantly higher
rates of eye irritation, cough, headache, and sore throat were reported.
Analyses of further studies, which measured oxidants (KI) and 07 (chemilumines-
O
cence) on a schoolground, yielded similar results. When maximum oxidant
concentrations exceeded 0.15 ppm, eye irritation, sore throat, headache, and
coughing were greater than on lower-oxidant-level days. Infectious illnesses
were not distinguished. Symptom rates in 74 allergic students were generally
higher than rates in nonallergic or all students on days when the maximum
hourly oxidant level was 0.23 ppm or greater. These and other subjective
symptoms were reported during episodes of acute smog in Japan, although rates
(i.e., denominators) were unknown, and other pollutants were present at high
concentrations (Kagawa, 1982; Kabayama, 1971; Fujii, 1972; Mikami and Kudo,
1973a,b; Adachi et al., 1973; Adachi and Nakajima, 1974; Matsumura et al.,
1973; Sugita et al., 1976; Masuda, 1977). Weather variables were not controlled
in the analyses of data from these studies. Effects seen at different times
of the day during episodes in Japan may be due to different pollutant mixes.
In the more recent literature, Okawada et al. (1979) examined the associa-
tions between eye irritation and photochemical oxidants in Tokyo high school
students 7 days during two summer sessions (n = 28 and 43, respectively).
Tests were performed between 1:00 and 4:00 p.m., during periods of daily
maximum oxidant levels (measured by KI method at test site). Tear lysozyme
and pH values were measured, and eyes were examined with a slit-lamp. Tear
lysozyme and pH values decreased on 2 days when the oxidant concentration was
nighest (0.175 and 0.210 ppm), in comparison to 2 days when the concentration
was lowest (0.020 to 0.033 ppm). Eye irritation incidence rates (determined
from questionnaire responses each day) increased proportionately with oxidant
concentrations above 0.1 ppm. The irritation was produced experimentally with
the following pollutants individually: formaldehyde >0.2 ppm, PAN > 0.05 ppm,
and peroxybenzoyl nitrate (PBZN) > 0.01 ppm.
019DC/A 12-14 6/18/84
-------
Several studies have also reported respiratory and other symptoms associ-
ated with photochemical oxidant pollution. One such U.S. study was performed
by Hammer et al. (1974) on similar groups of freshman student nurses at two
hospitals in Los Angeles, as previously reviewed (Environmental Protection
Agency, 1978). Symptom rates from daily diaries (a daily average of 61 students)
were obtained from October 1961 through June 1964. Simultaneous daily measure-
ments of oxidants (KI method) and other pollutants and maximum daily tem-
perature were available on more than 90 percent of the days in the study from
Los Angeles Air Pollution Control District monitoring stations located 1.5 to
3.0 km from both hospitals. Both before and after adjusting the rates by
excluding days on which subjects reported fevers (to minimize effects of
infections), Hammer and coworkers found eye discomfort at oxidant levels
3 3
between 294 and 372 jjg/m (0.15 and 0.19 ppm), cough at 588 to 764 ug/m (0.30
3
to 0.39 ppm), and chest discomfort at 490 to 568 ug/m (0.25 to 0.29 ppm)
maximum hourly oxidant levels. These adjusted rates were related to oxidant
levels more closely than to CO, NO-, or daily temperature. The rates are
shown in Figure 12-2.
Symptoms of cough, chest discomfort, and headache have been both (1) asso-
ciated with occupational exposure to oxidants (see below) and (2) in some
community studies cited above appear to have resulted from exposure to ambient-
air oxidants. Some of these effects may have resulted from interactions
between oxidants and other pollutants (National Research Council, 1977).
Various oxidants may produce irritation at levels found in smog (Dimitriades,
1976; U.S. Environmental Protection Agency, 1978; National Research Council,
1977).
12.3.1.2 Alterecj Performance. To determine the possible effects of photo-
chemical oxidant pollution on athletic performance, Wayne et al. (1967) and
Herman (1972) studied a group of cross-country track runners during meets in
Los Angeles. Their results indicated that NO , CO, and particulate matter
were not related to performance. They did not examine SO,,. The proportion of
runners failing to improve their times during the track season significantly
rose as concentrations of oxidants measured by the Air Pollution Control
District increased to the range of 0.06 to 0.37 ppm in the hour before the
race. Subsequent analysis of this study has yielded estimates of impaired
athletic performance above 0.12 ppm oxidant (Hasselblad et al. , 1976; U.S.
Environmental Protection Agency, 1978; World Health Organization, 1978) or
0.065 ppm (National Research Council, 1977). Analysis of an extended set of
019DC/A 12-15 6/18/84
-------
35
£ 30 h
0
o
-------
data by Herman (1972) showed an inverse association between running speed and
oxidant measured 1 hr before the meet, after correcting for average speeds,
time, season, and temperature.
Some investigators have hypothesized that photochemical oxidant pollution
may create poor daytime driving conditions. Ury (1968) found that concentra-
tions of oxidants monitored by the Air Pollution Control Districts correlated
positively with the frequency of weekday daylight motor vehicle accidents in
Los Angeles during August through October. Accident rates were higher on days
when hourly oxidant levels exceeded 0.15 ppm than on days below 0.10 ppm.
Other pollutants were not evaluated, but are low in summer. As for weather,
only days of rain and fog were excluded from data analyses. In a second
study, Ury et al. (1972) investigated CO concentrations during winter months
with the same analytical methods. A statistically significant difference in
frequency of accidents above and below 0.10 ppm was again noted in relation to
oxidant concentrations, but no consistent relationship was noted with lagged
oxidant or CO concentrations. Morning (9:00 a.m. to 12:00 noon) peaks in
accidents may implicate 0_ precursors or other pollutants, but do not implicate
traffic density. Reduced visual acuity (according to results of Lagerwerff,
1963), increased eye irritation, or reduced visibility may have been partly
responsible (U.S. Environmental Protection Agency, 1978).
12.3.1.3 Acute Effects on Pulmonary Function. Previously reviewed studies
(U.S. Environmental Protection Agency, 1978) showed significant differences in
children's peak flow rates related to oxidants in two Los Angeles communities
(McMillan et al., 1969) but no differences in pulmonary function in office
workers in Los Angeles and San Francisco (Linn et al., 1976). Neither study
measured pollutant exposures sufficiently or accounted for meteorological
variables; also, within-study populations appeared to differ between commu-
nities.
Kagawa and Toyoma (1975) and Kagawa et al. (1976) reported consistent
effects of 0« on the pulmonary function of children in Japan. First, they
studied 21 children 11 years of age (in 1975) for 29 weeks (June-December).
Hourly average concentrations of 0,. (measured by chemiluminescence) at their
3
school ranged from 20 to 294 ug/m (0.01 to 0.15 ppm). Maximum hourly concen-
3 3
trations of NOS N0?, and S0? were approximately 98 ug/m (0.08 ppm), 432 ug/m
3
(0.23 ppm), and 133 ug/m (0.05 ppm), respectively, and particulate matter was
3
350 ug/m . The overall significance of the association between 0. and pulmonary
019DC/A 12-17 6/18/84
-------
function tests was accounted for by 25 percent of the subjects, in whom airway
resistance (R ) was positively correlated with 0_ concentrations during
testing, specific conductance (SG ) was negatively correlated, and maximum
aw
expiratory flow rates (V 5Q^, V 25^) were inconsistent. These measures
also correlated with temperature (more than with any other variable) and SO,,
levels, but not with N0» levels.
The same students were studied during a low-temperature period (November-
March) and a high-temperature period (April-October). Hourly average 0_ con-
3
centrations ranged from about 20 to 588 ug/m (0.01 to 0.30 ppm); NO, N0?, and
3
S0? concentrations were approximately 220, 563, and 418 ug/m (0.18, 0.30, and
0.16 ppm) respectively, and the concentration of particulate matter was approxi-
mately 450 pg/m . Again, concentrations of 0, were positively correlated with
R , V rrio/5 and V OI-o/ and negatively correlated with SG , in both periods,
aw' max50%' max25% y •* aw' K ,
and more consistently in the low-temperature period when 0^ was lowest (<0.10
3
ppm, 196 ug/m ). As in the previous study, associations of function with
pollutants were confounded by temperature, which acted differently in the two
seasons. Excluding the effect of temperature yielded several 0~-R and
o dW
0.,-V r-no/ partial correlations of statistical significance in the low-
3 max50% r a
temperature (low-0,) period. Analysis of multiple correlation coefficients
indicated a few likely pollutant interactions. R and SG correlated with
multiple environmental variables in nine subjects. There were linear rela-
tions of health effects with 03 concentrations occurring up to the maximum
concentrations: 0.15 ppm in the first study, (high-0~ period) and either 0.10
(as the effects were seen in the low-03 period) or 0.30 ppm (in the high-03
period) in the second study. Another Japanese study (Shishido et al. , 1974)
showed similar results, but did not control for other pollutants.
Lebowitz et al. (1982a, 1983) and Lebowitz (1984) studied 24 children and
young adults, ages 8 to 25, from middle-class backgrounds for an 11-month
period in 1973 and 1980 in Tucson, AZ. Every day, in the late afternoon (3:00
to 7:00 p.m., usually 4:00 to 6:00 p.m.) peak flow was measured with a Mini-
Wright® peak flow meter (Wright, 1978; Williams, 1979; van As, 1982; Lebowitz
et al., 1982b). Subsets of the group, chosen randomly, underwent measurements
during different seasons of the year. After age and height correction, no
peak flow differences in baseline data were seen among the subjects by analysis
of variance (ANOVA), and all were within the published normal range (within 1
standard deviation of 100 percent of prediction). Daily peak flows for each
019DC/A 12-18 6/18/84
-------
child were transformed into a standard normal variable (x = 0, s = 1), using
the formula z. = (x. - x)/s. The seasonal mean and standard deviation were
used to generate daily values (z-scores) that were standardized deviations
from seasonal averages, with similar units for all individuals. This procedure
adjusts for seasonal effects and differences between individual means and
variances.
Ozone (measured by chemi1uminescence), CO (infrared), and NO- (chemilu-
minescence) were monitored outdoors at three stations. Daily TSP level (6-day
high-volume samples) was measured at 12 locations, including stations at the
center of each cluster of subjects within a 1/4- to 1/2-mi radius). Previous
inventories by the Pima County Air Quality Control District (1978) showed
significant homogeneity of 0., in the basin. The central station data and the
*J
average basin data were used in the analysis. Comparisons of these data
showed no significant differences in results between the two. In this study,
indoor 0,, (chemiluminescent method) showed very low levels (<0.035 ppm, 69
3
ug/m ) as reported previously (National Research Council, 1981). Indoor and
outdoor CO levels were less than 2.4 ppm (2736 g/m ) and 3.8 to 4.9 ppm (4332
3 3
to 5586 g/m ), respectively, as was N0? (median of 0.03 ppm, 34 ug/m ).
Indoor CO was correlated with gas-stove use only. Outdoor TSP ranged between
3 3
20 and 363 ug/m for all monitoring days and between 27.5 and 129 ug/m on
days of indoor monitoring. Indoor TSP and respirable suspended particle (RSP)
3
ranges for 41 representative houses were 5.7 to 68.5 ug/m and 0.1 to 49.7
3
ug/m , respectively, and were correlated with indoor cigarette smoking but not
gas-stove use (Lebowitz et al., 1983; Lebowitz, 1984).
Initial analysis showed that 0- and TSP levels were negatively correlated
with peak flow, after correcting for season and other pollutants. Multivariate
analysis of variance was conducted to control for person days of observation,
meteorological variables, CO, N02, and TSP, after which the 0- concentration
coefficient was still shown to be independently significant (P < 0.001).
There were significant, independent interactions between 03 and TSP with peak
flow (see Table 12-3).
When the contributions from each of the other factors were removed by
adjustment (using multiple regression), the 0_ concentration correlation with
»j
peak flow was still significantly negative (Lebowitz et al., 1983). The mean
z-score for the person days with a maximum hourly 03 level of 157 ug/m
(0.08 ppm) or greater (21 days) was -0.31 (P < 0.007); it was -0.38 for a mean
3
0- level of 157 ug/m (0.08 ppm) or greater between 3:00 and 7:00 p.m.
019DC/A 12-19 6/18/84
-------
TABLE 12-3. THE RELATIONSHIP BETWEEN AVERAGE STANDARDIZED DEVIATIONS
OF PEAK FLOW AND OUTDOOR CONCENTRATIONS OF OZONE
AND TOTAL SUSPENDED PARTICULATE MATTER3
Maximum hourly
ozone concentration
ug/m3
<75
75-100
102-155
157-235
All
ppm
<0.038
0.038-0.051
0.052-0.079
0.08-0.12
Daily total suspended particulate matter,
(ug/m3)
<56 56-76 >77 All
+0.108,
(167)d
+0.042
(71)
+0.242
(40)
-0.088
(9)
0.115
(298)
+0.239
(53)
-0.162
(39)
-0.021
(94)
-0.196
(31)
-0.027
(244)
+0.156
(61)
-0.061
(39)
-0.474
(67)
-0.804
(27)
-0.227
(223)
0.069
(663)
0.024
(363)
-0.115
(419)
-0.310
(148)
Source: Lebowitz (1983a).
Analysis of variance for total explained effect, for the interaction, and
for each pollutant, P < 0.0001.
Sample size was reduced because total suspended particulate matter (TSP) levels
were not available for all days.
cRepresents all days when data were available for each pollutant.
Person days of observation.
Note: Peak flow decreases with increasing TSP, becoming statistically signifi-
cant only at ozone > 0.052 ppm. Peak flow also decreases with increasing
ozone, becoming significant at TSP > 77 ug/m3 (the decrements at ozone >^ 0.08
ppm are significant for TSP levels of 57-76 ug/m3). There is a very significant
interaction of ozone and TSP. Decrements in peak flow of -0.474, -0.804, and
-0.310 represent 18, 28, and 12% changes respectively, when compared to normal
day-to-day variability in a comparable group of children previously studied by
Lebowitz et al. (1982b).
(P < 0.0001). The z-scores represent decreases in peak flows of 12.2 percent
and 14.8 percent, respectively, and the percent changes are significant
(P < 0.05), based on published data for normal day-to-day variability in
another, comparable group of children (Lebowitz et al., 1982b). This study,
because of the small number of subjects, needs to be repeated to determine the
consistency of the relationships found. Personal monitors, had they been
available, would have provided more accurate exposure estimates. Children are
likely to spend much time outdoors, especially in the afternoon.
019DC/A 12-20 6/18/84
-------
12.3.1.4 Aggravation of Existing Respiratory Diseases. Several studies have
examined photooxidant pollutant effects on symptoms and lung functions of
patients with asthma, chronic bronchitis, or emphysema. Most earlier ones
were evaluated in the predecessor criteria document (U.S. Environmental Protec-
tion Agency, 1978). Schoettlin and Landau (1961) reported increased daily
asthma attacks in 137 subjects from September to December, 1956, on high
oxidant days in Los Angeles, but did not control for age, sex, temperature,
season, or medication use. Schottlin (1962), using regression analyses, found
no relationship between oxidants (KI) and symptoms in 200 chronic lung disease
patients and 200 matched controls from a Los Angeles Veterans Administration
hospital. Rokaw and Massey (1962) performed a pilot study on 31 chronic
pulmonary patients and a control group in Los Angeles over an 18-month period,
using pulmonary function tests four times per week. Only six patients showed
negative changes associated with higher oxidant concentrations (X = 0.06 ppm,
max. =0.42 ppm).
Zagraniski et al. (1979) studied a group of 82 asthmatic and allergic
(i.e., hay fever) patients and a group of 192 normal telephone company employ-
ees in New Haven, CT, from July to September 1976. Of the two groups studied,
57 percent were female, 90 percent white, 61 percent over age 30, 35 percent
current smokers (20 percent more than one pack per day), and 22 percent ex-
smokers. The clinic group (i.e., asthma and allergic patients) had higher
proportions of ex-smokers and persons who had never smoked, whereas the employee
group had significantly more women, persons over 30, and persons who held
clerical or technical jobs. All these variables were controlled in statistical
analyses of data from daily diaries (completed weekly over a 10-week study
period).
Air monitoring occurred at two sites 1.2 km apart and within 0.8 km of
where the subjects were recruited; however, distances from residences and
workplaces were not reported. Concentrations of S0?, TSP, sulfates (from
dried glass-fiber filters), and 0_ (by chemiluminescence) were monitored;
previous monitoring had shown low N02 and CO levels. Meteorological variables,
specifically maximum daily temperature (mean of 27°C, from 19 to 34°C), were
used as covariables. Average daily windspeed varied little and was not used.
Sulfates and 0., often had coincident peaks; few daily sulfate concentrations
3 3
exceeded 24 pg/m . Ozone maximum hourly readings averaged 157 |jg/m (0.08
3
ppm), and the range was 8 to 461 ug/m (0.004 to 0.235 ppm), with maximum
019DC/A 12-21 6/18/84
-------
3
concentrations in the afternoon. Eight-hour mean TSP was 83 ug/m (range: 24
to 169 [jg/m ), and 24-hr mean TSP was 73 ug/m3 (range: 20 to 147 ug/m3).
Reported outdoor exposure, working, and home conditions were judged to be
equivalent for most subjects for most pollutants.
Daily symptom prevalence rates were used as dependent variables. Patients
had higher symptom rates, except for cough, than did controls. Smokers in
both groups reported more episodes of illness and chronic productive cough
than did nonsmokers. Data from participants who returned five or fewer daily
records per week or missed four or more consecutive weeks of the study were
excluded from analysis, and 23 percent of the participants (10 percent controls;
50 percent patients) dropped out of the study. The dropout rate was related
to smoking in both groups and to asthma and allergy exacerbations in the
patients. Symptoms rarely correlated with pollution variables, using paired
and multiple analyses. Maximum hourly 0- levels correlated with cough and
nose irritation in heavy smokers (r = 0.24 and 0.32, respectively, P < 0.05),
and significant positive, pairwise correlations (P < 0.05) of maximum hourly
03 levels were found with cough in hay fever patients (r = 0.22), and with
nose irritation in asthmatics (r = 0.17). When subjects were regrouped by
smoking and illness status for multiple regression analyses, 0, level signifi-
O
cantly (independently) correlated with cough and eye irritation in heavy
smokers, and with cough in hay fever patients (independent of season). Cough
frequency increased linearly with hourly 0_ concentrations in the range of 8
3
to 461 ug/m (0.004 to 0.235 ppm, a mean of 0.08 ppm), especially in smokers
and in those with predisposing illnesses (independent of season). No other
symptoms were associated with 0- in any of the groups, nor were other pollut-
ants associated with symptoms. Negative pH changes of TSP over 8 hr and 24 hr
were positively and independently associated with eye, nose, and throat irrita-
tion in most groups, but not with other symptoms. Pollen was associated
positively only with frequent sneezing in hay fever patients.
A major problem with this study is that daily prevalence data were used,
rather than incidence data, and no correction for auto regression was made
(see below). Misinterpretation and misuse of diaries were limited in frequency,
as determined from comparisons with clinical data, and were not likely to have
substantially influenced symptom data. However, bias may have been induced
(in either direction) by the selective dropout of the more heavy smokers, the
patients with symptoms, and persons who did not report symptoms. These factors
should have been evaluated.
019DC/A 12-22 6/18/84
-------
Whittemore and Korn (1980) reported newly developed statistical methods
by which they evaluated daily asthmatic attack rates recorded in diaries by
asthmatics residing in the Los Angeles area for 34-week periods (May to December)
during 1972 to 1975. The panels were recruited by the U.S. Environmental
Protection Agency (EPA) as part of the Community Health Environmental Surveil-
lance System (CHESS), and participants were asked to complete weekly diaries.
Diaries not received within 16 days after each week were discarded. (The EPA
data sets used have undergone quality control to ensure accurate coding of
health responses.) The 16 location-specific panels were chosen by local
consulting physicians, differed from one another in size and composition, and
were not expected to be representative of the asthmatic population. Information
on demographic variables, smoking, occupational exposures, and other factors
potentially related to asthmatic attacks indicated great interpersonal variabil-
ity. Air pollution measurement (24 hr; midday to midday) periods were derived
from EPA monitors in each of the six communities for all pollutants except
oxidants. Daily maximum hourly averages for oxidants (KI) were used, as mea-
sured by the County Air Pollution Control Districts. Each individual in each
34-week period was considered separately in multiple logistic analyses (without
respect to place). Many individuals were therefore counted in more than one
34-week period. There were 444 such person periods (166 males under 17, and
65 males over 17; 94 females under 17, and 119 females over 17). Homes were
within 1 to 8 mi (average of 3 mi) from the monitoring sites. Since RSP, NO ,
)\
and SO were highly correlated with TSP, TSP was chosen as an index for the
yV
mix of other pollutants. Weather variables, i.e., temperature, relative humi-
dity (rh), and average wind speed, were included in the regressions, as were
day-of-week indicators.
Daily oxidant levels ranged from 0.03 to 0.15 ppm between areas and
between times. Each daily attack rate was regressed by multiple logistic
regression function against the presence or absence of attacks on the preced-
ing day (to correct for an autocorrelation effect), the daily representative
levels of oxidant and TSP, minimum temperature, rh, and average windspeed, as
well as against variables representing time since the start of the study and
day of week. Days with missing attack data, as well as days with missing
pollutant data, were not included in the regressions. The autocorrelations of
asthma were the most significant variables in the logistic regressions. The
other air pollution and weather variables were also independently significant,
019DC/A 12-23 6/18/84
-------
except for windspeed (which was later dropped). Baseline probabilities of
attacks were determined, dependent upon whether or not an attack had occurred
on the previous day. Relative risk probabilities for attacks being associated
with specified increases in oxidant levels were also estimated by the model,
holding all other variables constant. Counts of expected (from the model) and
observed attacks (from the Los Angeles diary data) were then compared to
determine how well the model predicted actual data. Although the panel coef-
ficients obtained for oxidant and TSP indicate a number of consistent effects
(not all panels show such effects), intrapanel variability with respect to
temperature and humidity suggests high individual variability in responses.
Also, days of cool temperature elicited significantly high attack rates. The
relative importance of day of week, day of study, and attack on preceding day
indicate that panel studies should include these factors in the study design.
Results obtained indicated, for example, that panelists having a baseline
attack probability of 0.10 following an attack-free day and an attack probabil-
ity of 0.41 on the day after an attack day, would have the attack probability
on a given day raised to 0.13 or 0.44, respectively, if oxidant levels increased
by 0.2 ppm. Similarly, even smaller increments (<0.01) in relative risk for
attacks were estimated to be associated with increases of 0.10 ppm in oxidant
levels. No consistent departures from the model were noted in examining
deviations of observed from expected values, indicating that the actual data
fit the model quite well. However, caution is demanded before fully accepting
the obtained quantitative findings. Use of daily averages of pollutant concen-
trations from monitors distant from the subjects may not have been sufficient
or appropriate, and the analyses did not use data on medication use, pollen
counts, daily emotional stress, other pollutants, exercise (e.g., in cool
weather), or respiratory infections (because these data were not collected).
The effects of such omissions could not be tested. Also, the ascertainment of
attack was based on subjective appraisal, without clinical validation, leading
to possible biases in reporting. Last, some data on attacks were missing,
and, as with most epidemiological studies, information on actual subject
exposure can only be inferred. Shy and Mueller (1980), commenting on the
study, further indicated that a repeated measure design using analyses of
variance would have allowed an evaluation of the interaction of group and
time, with fewer comparisons necessary, and reduced cases where an individual
occurs in more than one panel.
019DC/A 12-24 6/18/84
-------
In another study of exacerbation of preexisting respiratory disease,
Lebowitz et al. (1982a, 1983) and Lebowitz (1984) studied 117 families (229
subjects) from a stratified sample of families in three geographic clusters in
a community study population. Families were chosen to be representative of
the Anglo-white population, stratified by symptoms, and monitored over a
®
2-year period, using daily symptom and medication diaries and mini-Wright
peak flow meters (Wright, 1978; Williams, 1979; Lebowitz et al. 1982b; van As,
1982). Daily response rates were acceptable for a majority of days in all
seasons. Checks by telephone and visits ensured proper use of diaries, and
visits were made to calibrate peak flow meters. All families provided informa-
tion on their houses, heating, cooling, and appliances, and smoking in the
household.
Twenty three adult asthmatics in one cluster, and a total of 35 adult
asthmatics, provided daily peak flows. There were 353 days with sufficient
information (>5 individuals/day) for analysis. There were additional days
with sufficient information (n > 5) on separate subgroups: 544 days from
adults with reported chronic symptoms of airway obstructive diseases (ADD),
494 days from adults with reported allergies, and 312 days from asymptomatic
adults. For adults, z-score transformation (see above) of peak flows used
sex-, age-, and height specific values. Thus, all peak flows (V ) were
fflclX
adjusted for covariables and were in the same relative units. When the individ-
ual was the unit of study, a person-days dummy variable was used in analysis
to eliminate effects of the different number of individual person days of
observation. Hultivariate analyses of variance and regression methods were
used to examine interactions and to control for colinear variables.
Indoor and outdoor (around the residence) monitoring was conducted in a
random cluster sample of study households (n = 41) for air pollutants, pollen
bacilli, fungi, and algae. Monitoring for pollen and TSP (measured by the
high-volume method) was conducted simultaneously in the center of each cluster,
and pollutants were measured regionally in the basin (see previous discussion
for details). Symptom rates per 100 person days were calculated from daily
diary data for asthmatics and nonasthmatics within exposure groups for compara-
tive purposes. Attempts to estimate concentrations in houses not monitored
yielded a classification based on gas-stove use and smoking in the houses.
Scanning electron microscopy showed that indoor dust differed from outdoor
dust, which was generally almost all silica quartz (mass median aerodynamic
019DC/A 12-25 6/18/84
-------
diameter, MMAD, of ~ 5 pm), and rapid fall -off was observed for outdoor parti-
cles and pollen as participants entered their houses (decreasing 100 to 200-
fold).
For adults, smoking had the biggest effect on V .In adults with AOD
nicix
symptoms, 0- was significantly related to V (P < 0.01) after adjustment was
o nicix
made for smoking and relative humidity as covariables, and TSP and gas-stove
use as other main effects. Concentrations of TSP were also significant
(P < 0.01), and the 03-TSP interaction had a P of 0.104 (n = 258 days). Using
the same variables in multiple regression yielded a regression coefficient of
-5.946 for 0, (P < 0.005 by t-test) and a regression coefficient of + 0.004
(P < 0.0025) for TSP.
In 23 asthmatics in one geographic cluster where indoor monitoring was
most complete, 0., and temperature had a significant interaction in relation to
<5
V ; high temperature had an effect when 0^ was low, and 0., had an associa-
iRSX *3 o
tlon with V . only in low temperatures (Table 12-4). However, 0^ was not
max o
independently related to V after adjustment was made for outside CO, tem-
max
perature, humidity, age, smoking, gas-stove use, indoor TSP, and residential
pollen (fungi were not independently important). There was also an interac-
tion of 0~ and temperature with prevalence rates of acute symptoms in these
asthmatics. Temperature was more important, since 0~ had an effect (though
not statistically significant) only within the high- temperature range. (Since
only 75 incidence days of asthma attacks occurred in 3820 person days, incidence
rates could not be evaluated.) Ozone was associated with prevalence of rhini-
tis, but only in those living in houses using gas stoves (P < 0.015) in this
group, with multivariate analysis of variance controlling for temperature.
Daily medication was correlated highly with exacerbations of symptoms.
The 0_ level at which V effects were seen, although consistent, is
o nicix
lower than expected. After controlling for other variables, the authors
speculated that the effects in asthmatics were occurring primarily at 0^
concentrations > 0.052 ppm, with 0- acting either as a surrogate for other
oxidants or in conjunction with other environmental conditions (i.e., low
temperature, high TSP).
A study of health- related responses to air pollution in persons with
chronic obstructive pulmonary disease was conducted in Houston, TX, by Johnson
et al. (1979). Javitz et al . (1983) recently presented the results of a
reanalysis of this study. Logistic regression of a selected set of self-
reported health symptoms from oxidant exposure revealed that the incidence of
0190C/A 12-26 6/18/84
-------
TABLE 12-4. THE RELATIONSHIP BETWEEN AVERAGE STANDARDIZED DEVIATIONS.
OF PEAK FLOW IN ASTHMATICS AND THE INTERACTION OF OZONE AND TEMPERATURE"
Maximum hourly
ozone concentration Temperature (°F)
ug/m3
<75
75-100
<102
ppm
<0.038
0.038 to 0.051
0.052 to 0.122
<61
-1.94
(217)°
-1.99
(327)
-2.11
(30)
61-80
-1.85
(219)
-1.78
(490)
-1.71
(549)
80-96
-2.17
(174)
-1.75
(388)
-1.57
(794)
Source: Lebowitz et al. (1983b).
Analysis of variance for total explained variation and interaction,
P < 0.0001.
Person days of observation.
chest discomfort, eye irritation, and "feeling worse than usual" increased by
10.1, 7.5, and 2.9 percent, respectively, as PAN concentrations increased from
0 to 0.012 ppm. Incidence of nasal symptoms and respiratory symptoms and use of
medication for respiratory symptoms increased by 6.0, 3.4, and 5.2 percent,
3
respectively, as 0~ increased from 0 to 412 ug/m (0.0 to 0.21 ppm). No
increased incidence of any specific nasal or respiratory symptom or of moderate
or severe nasal or respiratory symptoms were noted. Linear regressions of
spirometry measurements on daily peak 0,, revealed that average FEV-. decreased
o .L
by 1.6 percent and FVC decreased by 2.8 percent as 0_ increased from 0 to 412
3
jjg/m (0.0 to 0.21 ppm). The FEV1 and FVC changes with total oxidants (0 and
PAN) were similar to those found for 0,. alone, but were larger in magnitude
(FVC and FEV1 decreased 4.3 percent and 3.2 percent, respectively). Considering
the relatively small sample sizes and test to test variability of 5 percent,
the magnitude of the effect is small and of questionable significance.
A major shortcoming of this study was that 0- measurements were missing
for about 40 percent of the study's 1026 site days; also, NO , hydrocarbon
(HC), CO, sulfur oxides (SO ), particulate matter, PAN, and aeroallergens were
/\
measured only at some of the sites. Daily maximum hourly concentrations of 0-
were measured at the monitoring station nearest each subject's residence.
However, in two zones, 0- measurements were substituted from the next nearest
019DC/A
12-27
6/18/84
-------
zone and the average reading of six continuous 0~ monitors was substituted in
O
a third zone. Thus, the number of 0- measurements appears insufficient for
appropriate exposure information. Personal exposure information was thought
to be the weakest link in the analyses (Javitz et al., 1983). Other difficulties
arise from the study's design: (1) sample size (286) was not large enough to
allow for sufficient subclassification (Javitz et al., 1983); (2) over one-third
of the subjects (total grouped/ indexed) reported respiratory symptoms on 100
or more of this study's 114 days, and over two-thirds reported nasal symptoms
on 10 or fewer days. This apparent extreme skewing of symptom behavior may
have made such information relatively insensitive to any detected pollution
effect. Also, Finally, the number (114) of monitoring days may have been
insufficient to allow enough variation in exposure variables or effect variables
for relationships between the two to be discerned. A low correlation between
spirometry and questionnaire variables may indicate low validity of one or the
other (Helsing et al., 1979), and the possibility of a differential attack
rate based on lags was not studied. Finally, a number of variables (e.g.,
age, sex, socioeconomic status, migrant pattern, smoking, occupation) may have
been interacting in a colinear or confounding fashion, but were not suffi-
ciently assessed in the analyses.
In regression analyses of questionnaire variables, the health endpoint
was a proportion of subjects reporting symptoms at each site rather than the
presence or absence of symptoms in individual subjects. These analyses were
usually pooled across all sites, although sometimes they were pooled across
only three sites. Site-specific regression of questionnaire variables does
not appear to have been performed. Only in regression analysis of the spiro-
metric variables did the individual serve as his or her own control. Half the
spirometric regression analyses appear to have been limited to only one site.
Therefore, the type of health endpoints and the methods of analyses are incom-
olete and Inappropriate. Furthermore, insufficient information was available
on daily pulmonary function with which to correlate or perform regression
analyses against daily pol'iutant measurements.
12.3.1.5 Incidence of Acute Respiratory Illness. Table 12-5 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.
12.3.1.6 Physician, Emergency Room, and Hospital Visits. Previously reviewed
studies (Environmental Protection Agency, 1978) have indicated that oxidant
019DC/A 12-28 6/18/84
-------
TABLE 12-5. STUDIES OF ACUTE RESPIRATORY ILLNESS
Reference
Subject matter
Findings
Nagata et al. (1979)
Durham (1974)
Pearlman et al. (1971)
ro
ro
to
Wayne and Wehrle (1969)
Cassell et al. (1969)
and Mountain et al.
(1968)
Health insurance records from two locations
in Japan, July-September 1975.
Health service visits for respiratory
illness in students at five Los Angeles
and two San Francisco colleges.
Incidence and duration of influenza-
like illness, December 1968-March 1969,
among elementary school children in five
southern California communities.
Absenteeism in two elementary schools, 1962-
1963.
Frequency of cough, sore throat, colds,
eye irritation, and headaches in a New
York City population near the monitoring
station.
No relationships between oxidant levels
(average hourly max = 0.066 ± 0.041 ppm)
and new acute respiratory diseases. Other
pollutants were not studied.
Pharyngitis, bronchitis, and colds associ-
ated with oxidant levels on same day and on
7 preceding days. Stronger associations
in Los Angeles than in San Francisco.
Oxides were measured about 5 mi away. Other
pollutants and climatic variables were not
control led.
No relationship between photochemical oxi-
dant gradient and illness rates during an
influenza epidemic occurring in a low-
oxidant period; all the communities had
similar levels.
No consistent association between oxidant
level and absenteeism. Other pollutants
were not considered.
In summer, symptoms in children <8 years old
were related to carbon monoxide (surrogate of
ozone and particulate matter). In adult
heavy smokers, eye irritation and headache
were related to carbon monoxide. Maximum
effect often occurred 1 to 2 days after the
peak of pollution. Summer pollution was
associated with symptoms in the total popu-
lation. No ozone or oxidant concentrations
were monitored.
-------
concentrations are insufficient for hospital admissions, with no clear separa-
tion of oxidant effects from effects of other pollutants. The effects of
social factors, which produce day-of-week and weekly cyclical variations, and
holiday and seasonal variations, are rarely removed (and then with possible
loss of sensitivity). Attempts to relate time of visit to time of exposure
are also very difficult. Any visit to medical facilities usually lacks appro-
priate denominators (the number of those at risk), since they are generally
not available, and the catchment area is unknown (Bennett, 1981; Ward and
Moschandreas, 1978). 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. Emergency room data, like
hospital record data, often lack, information on patients' smoking habits,
ethnic group, social class, occupation, and even other medical conditions.
A study by Namekata et al. (1979) of emergency room visits for cardiac
and respiratory diseases in two hospitals in Chicago must be considered in-
adequate because: (1) information collected from the medical records is
insufficient to identify sources of variability in the data and to control for
confounding factors of the types noted above; (2) the 0~ data are insufficient
and incomplete; and (3) the linear models used could not determine effect
levels of the pollutant.
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, GX> CO, NO, N02> S02> sulfate (SO^, and
aldehyde (COH). Catchment areas and air monitoring data from residential 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 associ-
ated 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). Humidity had a positive effect and sulfates a negative
effect when these variables were included in the model. Unfortunately, the
lack of population denominators and characteristics, the lack of admission
019DC/A 12-30 6/18/84
-------
characteristics, and poor characterization of exposures seriously limit the
use of these findings.
Bates and Sizto (1983) studied admissions to all 79 acute-care hospitals
in Southern Ontario (i.e., the whole catchment area) during 4 months (January,
February, July, August) in each year (1974, 1976-1978, and 1979-1980). Air
pollution data for CO, N02> 03> and COH were obtained from 15 stations mostly
along the prevailing wind direction. Temperature was controlled. In July and
August, highly significant associations (Pearson r, 1-tailed, P < 0.001) were
found between excess (percent deviations from day-of-week and seasonal means)
respiratory admissions and average maximum hourly SO- and 0~ (KI method)
concentrations, and temperature (with 24- and 48-hr lags between the variables).
Nonrespiratory admissions showed no relation to pollution. Ozone (maximum
hourly average = 62.8 ppb) was independently related to admissions, as repli-
cated in 1979 when S03 was greatly reduced. Temperature was also 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 effects of sulfates could not be separated from 03 effects. Since
the number of separate people admitted was unknown, a "sensitive" subpopulation
could have affected the results. Improvements in the monitoring data (i.e.,
exposure) would help interpret these findings.
Whether changes in hospital use reflect changes in either illness experi-
ence or illness perception and behavior is still uncertain. A person may
behave differently according to 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,
1981; Ward and Monchandreas, 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, hospital statistics often lack reliability
and validity since determining incidence is difficult, insufficient clinical
data are available to support resolution of diagnostic category in grading
severity, and a number of potential subclassifications of patients may require
separation and attention in the analysis (Ward and Moschandreas, 1978).
019DC/A 12-31 6/18/84
-------
12.3.1.7 Occupational Studies. Studies of acute effects from occupational
exposure are summarized in Table 12-6. These studies did not meet the criteria
necessary for developing quantitative exposure-response relationships for
ambient ozone/oxidant exposures.
12.3.2 Trends in Mortality
The possible association between exposure to 0 and increased mortality
*5
rates has been investigated a number of times, 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). In 1978, the U.S. Environmental Protection Agency published
data on the average number of deaths attributed to cardiac and respiratory
causes among residents of Los Angeles County for different temperature ranges
and days with low and high oxidant concentrations. This report suggested that
a positive relationship might exist between oxidant exposure and mortality
between 70° and 79°F. However, only five of the seven curves plotted from
data in the range of 70° to 79°F have positive slopes. This proportion could
show positive slopes simply by chance, with a probability of P = 0.16 by a
sign test (as recalculated from the data), thus failing to support a relation-
ship between oxidant concentrations and mortality. This failure is especially
probable in light of the inconsistent slopes in the range of 80° to 89°F.
Since high temperature and elevated oxidant concentrations tend to occur
simultaneously in the Los Angeles Basin, Oechsli and Buechley (1970) studied
the effects on mortality of heat waves among the elderly (in 1939, 1955, and
1963). They could not find evidence that high photochemical oxidant concentra-
tions could augment the mortality effect of high temperature. Biersteker and
Evendijk (1976) reached similar conclusions about heat-related mortality in
July and August of 1975 and 1976 in Rotterdam, the Netherlands.
Sensitive subpopulations studied have included elderly residents of
nursing homes and individuals with cardiopulmonary disease. The California
Department of Public Health (1955, 1956, 1957) survey of nursing homes attempted
to correlate daily mortality and patient transfers to the hospital with maximal
daily temperatures and 0.- concentrations (>0.3 ppm). Heat had a significant
effect on mortality, but no correlation could be found between mortality and
high-03 days (Breslow and Goldsmith, 1958; Tucker, 1962).
019DC/A 12-32 6/18/84
-------
TABLE 12-6. STUDIES OF ACUTE EFFECTS FROM OCCUPATIONAL EXPOSURE
Reference
Subject matter
Findings
Fabbri et al. (1979)
Sarto et al. (1979a,b)
Truche (1951)
Kleinfeld et al. (1957)
ro
i
CO
CO
Kudrjavceva (1963)
Poloskaya (1968)
Pulmonary function in workers in a plastic
bag factory (31 exposed and 31 controls
of same age, height, smoking habits).
Reported symptoms in tests of electric
insulators with prolonged exposure to
ozone >0.1 ppm.
Clinical findings and symptoms in welders
using inert gas-shield consumable electrodes
in three plants with ozone measured at
breathing zones.
Symptoms in hydrogen peroxide production
workers employed 7-10 years.
Symptoms in welders and nearby workers
(controls) ages 25-35, with less than
than 5 years employment.
Decreased expiratory flow in 8 of 31 subjects
at ozone levels of 196 to 1803 pg/m3 (0.10 to
0.92 ppm) during workshift. Lower flows in
exposed smokers than control smokers. Acute
changes to acetylchol inesterase, peroxidase,
and lactate dehydrogenase. Other pollutants,
including formaldehyde (0.18 to 0.20 ppm, 220
to 245 pg/m3), were not controlled.
Reports of thoracic cage constriction, in-
spiration difficulty, and laryngeal irritation.
Other pollutants were not controlled.
Increase in chest constriction and throat
irritation at 1-hr concentrations of 588 to
1568 pg/m3 (0.3 to 0.8 ppm); no complaints
or clinical findings below 490 pg/m3 (0.25
ppm). Nitrogen dioxide and total suspended
particulate matter were not measured or
control led.
At 348 to 556 MQ/m3 (0-25 to 0.40 ppm) head-
ache, weakness, increased muscular excitability,
and decreased memory. Other gases were possibly
important.
More frequent complaints of respiratory irri-
tation, headache, fatigue, and nosebleeds in
welders; exams were normal. Ozone averaged
3332 pg/m3 (1.7 ppm), with maximum of
4900 ug/m3 (2.5 ppm); carbon monoxide and
nitrogen dioxide were below permissible levels.
Total suspended particulate matter was not
studied.
-------
TABLE 12-6. STUDIES OF ACUTE EFFECTS FROM OCCUPATIONAL EXPOSURE (continued)
Reference
Subject matter
Findings
von Nieding and Wagner
(1980)
Oxhoj et al. (1979)
Challen et al. (1958)
Young et al. (1963)
Nevskaja and Diterihs
(1975)
Health effects in male German metallurgical
plant workers, as measured by questionnaire,
absenteeism, insurance records, vital capa-
city measures, plethysmographic measures,
blood pressure, and airway resistance.
Ozone nitrogen oxides, and sulfur oxides
were sampled.
Pulmonary function in electric arc
welders (n = 119, 5-38 years exposure)
and clerical controls matched on smoking
and age.
Symptoms in 14 helio-arc welders.
Lung function in seven welders
argon-shield.
using
Illness in hydrogen peroxide production
workers measured by questionnaire and
pulmonary function.
Group exposed to high ozone had more absen-
teeism and more episodes of bronchitis and
pneumonia, more cough and phlegm, and higher
airway resistance than did controls. However,
high total suspended particulate matter levels
and temperature-induced volatilized metals
obscured effects of ozone.
No acute effects found. Chronic pulmonary
function changes thought to be related to par-
ticles only (not controlled).
Upper respiratory symptoms in 11 of 14 welders
exposed daily to ozone (0.8 to 1.7 ppm, 1568
to 3332 (jg/ m3), which disappeared with expo-
sure to 392 |jg/m3 (0.2 ppm). Pulmonary
congestion was seen at 3920 \ig/m3 (2 ppm).
Nitrogen dioxide was present, but not studied.
No changes in function from ozone (0.2 to
0.3 ppm, 392 to 588 pg/m3). Nitrogen dioxide
was probably present, but not controlled.
Increased prevalence of bronchitis and
emphysema and decreased expiratory flow rates
reported. Ozone concentrations were between
78 and 98 pg/m3 (0.04 and 0.05 ppm) Sulfuric
acid was also present.
-------
Massey et al. (1961) compared daily mortality in two areas of Los Angeles
County with similar temperatures but different photochemical pollution levels
by multiple correlation and regression. No statistically significant relation-
ships were observed. Buell et al. (1967) studied lung cancer mortality in
different areas but could draw no meaningful conclusions. Mills (1957a,b)
compared nursing home deaths with an index of photochemical pollution and
found a positive association between the index and excess deaths; other in-
vestigators who analyzed the data observed no associations (California Depart-
ment of Health, 1955, 1956, 1957; Breslow and Goldsmith, 1958). Studying the
effect of pollution concentrations on cardiac and respiratory diseases in Los
Angeles County, Hechter and Goldsmith (1961) found no significant correlation
between pollutants and mortality, either on the same day or after 1 to 4 days
of higher concentrations. Hechter and Goldsmith (1961) also failed to identify
a contribution of oxidant levels to daily mortality in Los Angeles from 1962
to 1965.
12.4 EPIDEMIOLOGICAL STUDIES OF EFFECTS OF CHRONIC EXPOSURE
Only a few prospective studies of the chronic effects of 0., exposure are
available. These studies are usually concerned with symptoms, lung function,
chromosomal effects, and mortality rates. Mortality from chronic respiratory
diseases and lung cancer has not been observed following oxidant exposures and
is not likely to occur given the relatively low levels of oxidants and the
proposed mechanisms of action.
12.4.1 Pulmonary Function and Chronic Lung Disease
Cohen et al. (1972) found no difference in ventilatory function or chronic
respiratory symptoms in nonsmoking adults in the San Gabriel Valley and in San
Diego, but their findings are limited by the similarity of annual average
ambient levels of oxidants in the two areas. From 1963 through 1967 arithmetic
mean oxidant levels were 0.047 ppm in San Gabriel Valley and 0.038 ppm in San
Diego. Average daily maximum hourly oxidant levels during the period of the
study were 0.12 ppm and 0.07 ppm, respectively, and other pollutants (TSP,
S02, and RSP) were equivalent in both areas.
The University of California at Los Angeles (UCLA) population studies of
chronic obstructive respiratory diseases in communities with different air
019DC/A 12-35 6/18/84
-------
pollutant exposures have been reported by Detels and colleagues (Detels et
al., 1979; Rokaw et al., 1980; Detels et a!., 1981). Three areas were exposed
to photochemical oxidants (Burbank, CA); SO , particulates, and HCs (Long
Beach, CA); and low levels of gaseous pollutants (Lancaster, CA). The prevalence
of symptoms was reported to be increased in the residents of polluted areas.
Lung function was generally better among residents of the low-pollution areas
according to measurements of 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
all areas, while the mean AN_ was slightly decreased among residents of the
low-pollution areas. Although the results suggest that adverse effects of
long-term exposure to photochemical oxidant pollutants may occur primarily in
the larger airways, their usefulness is limited by a number of problems. For
example, testing of subjects was not concurrent and occurred over a 4-year
period between areas; 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
79 percent in the three areas. Comparisons of participants with census informa-
tion were fairly close. Analysis of the comparisons of the three communities
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 resi-
dence 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 quite 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
019DC/A 12-36 6/18/84
-------
undeterminable influences that could have affected the results. Also, the
numbers of subjects changed from one report to another and from one analysis
to another.
The major problem in interpreting the pulmonary function data is that the
results do not appear to have been validated, as judged by the poor correlations
between function and chronic symptoms and the fewer than expected smokers with
abnormal lung function. In tests such as interpretation of flows at low lung
volume or the single-breath nitrogen study, there do not appear to be appropri-
ate comparisons for determining observer differences or biases, which are
critical for these difficult tests.
Another major problem is that the investigators used cutoff points to
examine the differences among the areas. Why cutoffs that were three to five
standard deviations below the mean were chosen is unclear, especially since
many of the variables examined were not normally distributed. By performing
the analysis in the manner described, very few people were left with abnormal-
ities in any group. Inconsistencies first surfaced when the authors examined
such variables as total proportions of subjects with symptoms or the mean
percent predicted lung function, and these inconsistencies grew worse. Further-
more, the method was inadequate to determine differences between one case in
one area and two cases in another area. Insufficient numbers of cases were
available, and the trends were in the wrong direction, especially those of the
single-breath nitrogen ANp. Whether the covariables and confounding variables
were sufficiently handled in the analysis is not clear. Thus, this study must
be treated as an insufficiently quantitative study for present purposes.
Additional studies of chronic morbidity are shown in Table 12-7. These
studies also do not provide information useful for quantitative exposure-effect
assessment. Thus, to date, insufficient information is available in the
literature on possible exposure-effect relationships between 0_ and the preva-
lence of chronic lung disease. These relationships need further study.
12.4.2 Chromosomal Effects
The importance of chromosomal damage depends on whether the effect is
mutagenic or cytogenetic, and, thus, whether it occurs in autosomal cells or
peripheral lymphocytes. Translocations and trisomies are important forms of
genetic damage, whereas minor chromosomal breakage (e.g., as associated with
caffeine) are of questionable significance. Interest in chromosomal damage
019DC/A 12-37 6/18/84
-------
TABLE 12-7. ADDITIONAL STUDIES OF CHRONIC MORBIDITY
Reference
Subject matter
Findings
California State Depart-
ment of Public Health
(1955-57)
Hausknecht (1960, 1962)
Deane et al. (1965),
Goldsmith and Deane
(1965)
co Peters et al. (1973)
Linn et al. (1976)
Ulrich et al. (1980)
Illness onsets throughout California in
various age groups, measured by weekly
surveys.
Prevalence of illness in survey of 3445
households throughout California. Chronic
pulmonary disease studied four times, 1957-
1959.
Symptoms, measured by questionnaire and
ventilatory function, in outdoor tele-
phone workers 40-59 years of age in San
Francisco and Los Angeles.
Illness in 61 welders, 63 pipefitters, 61
pipecoverers, and 94 new pipefitters,
measured by questionnaires, pulmonary
function, partial physicals, and X-rays.
Respiratory symptoms and function in office-
workers in Los Angeles and San Francisco,
Summer of 1973.
Immunological values in 30 workers (mean
age 34) exposed for 2 to 9 years (mean of
4.3) to ozone, compared to reference values.
No relationship between incidence of illness
and area in the young. Elderly showed some
increases in Los Angeles. Pollutants other
than ozone were also higher.
Higher prevalence rates in Los Angeles and
San Diego. No quantitative ozone data.
No differences in symptom prevalence between
cities, although particulate concentrations
were about twice as high in Los Angeles. No
aerometric data.
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.
No difference in chronic respiratory symptom
prevalence between cities. More frequent
reports of nonpersistent (<2 years) produc-
tion of cough and sputum by women in the more
polluted community. Different populations
and different aerometric characteristics
complicate the analysis.
Increased immunoglobulins (IgG, IgA, and
IgM), transferrin a, antitrypsin, apparently
associated with 39 to 588 ug/m3 (0.02 to
0.3 ppm). Other pollutants were not
evaluated.
-------
from 0, derives from in vitro and i_n vivo studies (Chapter 10). Findings in
«5 J ———— Mm ,•—«••«.
In v.1vo numan studies are conflicting, but generally negative (Chapter 11).
Four epidemiological studies have investigated chromosomal changes in
humans exposed to 0_. None indicate any evidence that 0- affects peripheral
lymphocytic chromosomes in humans at the reported ambient concentrations. 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, they found
chromosomal changes that were almost entirely of the simple-breakage type and
not more numerous than is usual in a population study.
Magie et al. (1982) studied chromosome aberrations and peripheral lympho-
cytes in college students: 209 nonsmoking freshmen at a campus with higher
3
smog levels (>0.08 ppm 0~; >160 ug/m ) and 206 freshmen at a campus with lower
3
smog levels (<0.08 ppm O^; <160 ug/m ). Both campuses were located in Los
Angeles. Students were enrolled in the study after completing questionnaires,
and were assigned to groups on the basis of campus 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
were found for chromosomal structure of peripheral lymphocytes.
Bloom (1979) studied military recruits before and after welding training.
No effects were seen (03 levels were negligible and N0« was high). Fredga
et al. (1982) studied the incidence of chromosome changes in men occupationally
exposed to automobile fuels and exhaust gases in groups of drivers, automobile
inspectors, and a reference 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 for an occupational effect.
12.5 SUMMARY AND CONCLUSIONS
Field and epidemiological studies, when properly executed, offer a unique
view of health effects research because they involve the real world, i.e., the
study of human populations in their natural setting. However, these studies
also have attendant limitations that must be considered in a critical evaluation
of their results. One major problem in singling out the effects of one pollutant
019DC/A 12-39 6/18/84
-------
in field studies of either morbidity or mortality in populations has been the
interference of other critical variables in the environment. Limitations also
exist for epidemiological research on the health effects of oxidants, including
interference or interaction between oxidants and other pollutants; meteorological
factors such as temperature; proper exposure assessments including individual
activity patterns and location of pollutant monitors; difficulty in identifying
oxidant species responsible for observed effects; and characteristics of the
populations such as hygiene practices, smoking habits, and socioeconomic
status.
Investigative approaches comparing communities with high 0~ concentra-
O
tions and communities with low 0_ concentrations have usually been unsuccess-
ful, often because actual pollutant levels have not differed enough during the
study and other important variables have not been adequately controlled. The
terms "oxidant" and "ozone" and their association with health effects are
often insufficiently clarified. Moreover, our knowledge about the measurement
and calibration methods used is still lacking. Also, as our knowledge and
skills in epidemiology improve, the incorporation of new key variables into
the analyses is required. Thus, the incorporation of individual exposure data
(e.g., from the home and workplace) becomes more of a necessity.
Both acute and chronic exposure situations have been reported in the
literature on photochemical oxidants. Relevant studies providing quantitative
information on effects associated with acute exposure include those on irrita-
tive symptoms, pulmonary function, and aggravation of existing respiratory
disease (Table 12-8). A few studies, of limited quality, have been reported
on morbidity, mortality, and chromosomal effects from chronic exposures.
Studies on the irritative effects of 0, have been complicated by the
presence of other photochemical oxidants and their precursors in the ambient
environment. That 03 causes the eye irritation normally associated with smog
is doubtful. Nevertheless, studies indicate that eye irritation is likely to
occur at oxidant levels of about 0.10 ppm. A shown in Table 12-8, associations
between oxidant levels and symptoms such as eye, nose, 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;
Okawada et al., 1979). Zagraniski et al. (1979) also reported an association
3
of these symptoms with approximately 157 ug/m (0.08 ppm) ozone in adults with
019DC/A 12-40 6/18/84
-------
TABLE 12-8. SUMMARY TABLE: ACUTE EFFECTS OF OZONE AND OTHER PHOTOCHEMICAL OXIOANTS IN POPULATION STUDIES
Lowest
; estimated
ieffect level,
ppm
Average maximum
hourly concentration
range during study,
ppm
Observed effect(s)
Subjects
Reference
jOXIDANTS
ro
I 0.10-0.
0.03-0.15
<0.04-0.50
Daily asthma attack rates increased on days
with high oxidant and particulate levels and
on cool days during a 34-week period in Los
Angeles.
Juvenile and adult
asthmatics
Symptoms of eye irritation, cough, chest
discomfort, and headache related to oxidant
concentration but not carbon monoxide,
nitrogen dioxide, or daily minimum
temperature.
Young adults
Whittemore and Korn, 1980
0.10
0.02-0.21 Eye irritation incidence rates increased with
oxidant concentration.
<0.23 Symptoms of eye irritation, sore throat,
headache, and cough related to oxidant
concentration and temperature but not
S02, N02, or NO.
Adolescents
Children and
adolescents
Okawada et al . , 1979
Makino and Mizoguchi, 1975
Hammer et al., 1974
0.06-0.37
Impaired athletic performance related to
oxidant concentration but not nitrogen
oxide, carbon monoxide, or particulate
levels 1 hr before cross-country track
meets in Los Angeles.
Adolescents
Wayne et al. , 1967
Herman, 1972
-------
TABLE 12-8. SUMMARY TABLE: ACUTE EFFECTS OF OZONE AND OTHER PHOTOCHEMICAL OXIDANTS IN POPULATION STUDIES (continued)
h— >
1
rv>
Lowest Average maximum
estimated hourly concentration
effect level, range during study,
ppm ppm
OZONE
0.08 0.004-0.235
0.08 0.01-0.12
0.08 0.01-0.12
0.15 0.01-0.30
0.166 0.16-0.17
Observed effect(s)
Increased daily prevalence rates for cough,
eye, and nose irritation in smokers and
patients with predisposing illnesses; pH of
parti cul ate was associated with eye, nose, and
throat irritation while suspended sulfates were
not associated with any symptoms.
Daily peak flows decreased 12.2 to 14.8% with
ozone and total suspended parti cul ate matter.
Decreased daily peak flows and increased pre-
valence rate for acute symptoms associated
with ozone, low temperature, and high total
suspended parti cul ate matter.
Increased airway resistance associated with
ozone, sulfur dioxide, and temperature.
Small decrement in forced expiratory function
and increased symptoms with exercise in both
normals and asthmatics.
Subjects
Asthma and allergy
patients; normal
adults
Children and
young adults
Adult asthmatics
Adolescents
Normal and
asthmatic adults
Reference
Zagraniski et al., 1979
Lebowitz et al., 1982a, 1983
Lebowitz, 1984
Lebowitz et al . , 1982a, 1983
Lebowitz, 1984
Kagawa and Toyoma, 1975
Kagawa et al. , 1976;
Kagawa, 1983
Linn et al. , 1980, 1983
Ranked by lowest estimated effect level for oxidant or ozone.
Not determined.
U.S. Environmental Protection Agency, 1978.
dHasselblad et al., 1976.
eDaily mean concentration of ozone was monitored by ultraviolet photometry inside a mobile laboratory; Linn et al., 1980, report concentrations
multiplied by 1.25 that correspond to the neutral buffered potassium iodide (KI) method.
-------
asthma and allergies. Discomfort caused by irritative symptoms may be respon-
sible 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). Although several additional studies have shown respiratory
irritation apparently related to ambient exposure in community populations,
none of these studies provide satisfactory quantitative data on acute respira-
tory illnesses.
Acute epidemiological studies in children and young adults have suggested
that decreased peak flow and increased airway resistance occur over the range
of Oo concentrations from 157 to 294 ug/m (0.08 to 0.15 ppm) (Kagawa and
Toyoma, 1975; Kagawa et al., 1976; Kagawa, 1983; Lebowitz et al., 1982a, 1983;
Lebowitz, 1984). Qualitative studies support this finding (McMillan et al.,
1969; Lebowitz et al. , 1974; Fabbri et al., 1979). No controlled human expo-
sure studies in children are presently available for comparison, although
3
studies in adults appear to show no effect below 235 ug/m (0.12 ppm) 0-
(Chapter 11).
In studies of exacerbation of asthma and chronic lung diseases, the major
problems in most of the studies have been the lack of information on the
possible effects of medications, the absence of records for all days on which
symptoms could have occurred, and the possible concurrence of symptomatic
attacks. Investigators who have been able to control some of these variables
have found consistent effects of 0_ on asthma (TabTe 12-8). Their findings
have been in accordance with those of some of the earlier, more qualitative
studies. Whittemore and Korn (1980) found small increases in the probability
of asthma attacks associated with increases of 0.10 ppm in oxidant levels.
Zagraniski et al. (1979) reported an increased prevalence rate for respiratory
3
symptoms with approximately 157 ug/m (0.08 ppm) 0,, in patients with asthma.
Linn et al. (1980, 1983) found decreased pulmonary function and increased
3
symptoms in lightly exercising asthmatics exposed to 314 to 333 ug/m (0.016
to 0.17 ppm) 0~ or greater, regardless of other pollutants. With increased
3
exercise levels, small effects were found at 235 ug/m (0.12 ppm) 0.,. Lebowitz
et al. (1982a, 1983) and Lebowitz (1984) showed effects in asthmatics, related
also to temperature, at 03 levels of 102 to 235 ug/m (0.052 to 0.12 ppm).
There have been no consistent findings of symptom aggravation or changes in
lung function in patients with other chronic lung diseases besides asthma.
019DC/A 12-43 6/18/84
-------
Apparent adaptations have been observed under controlled conditions with
humans, but this effect would be difficult to demonstrate in community popula-
tions. Recent work with animals suggests that the processes involved in
adaptation may lead to other, perhaps adverse effects, but no implications for
human health can yet be drawn.
Although animal studies indicate that ()„ impairs defenses against infec-
tion (Chapter 10), this impairment has not been examined in clinical studies.
No positive studies of 0, effects on acute respiratory illnesses have been
reported in human populations. In addition, most studies have yet to address
the hypothesis that years or decades of air pollution exposures beginning in
childhood, especially among the sensitive, may increase the risk of developing
chronic illness (U.S. Environmental Protection Agency, 1978).
The lack of quantitative measures of oxidant levels limits the usefulness
of many studies of pollution exposure and mortality. In addition, properly
designed studies have not been conducted to address the effects of oxidants on
the growth and development of the lung or on the progression of chronic diseases,
although the available evidence is consistent with toxicological data indicating
that 0, is not a strong mutagen or a demonstrable carcinogen at ambient concen-
«D
trations. Most long-term studies have employed average annual levels or have
involved broad ranges of pollution; others have used a simple high-oxidant/low-
oxidant dichotomy and compared mortality results. Failure to relate mortality
to specific levels (and types) of oxidant pollutants makes formulation of
exposure-response relationships impossible. Epidemiological identification of
chronic effects of air pollution generally requires well-conducted replicated
studies of large, well-defined populations over long periods of time, which
are not available at this time for 0_ or other photochemical oxidants.
Studies using quantitative measures find that "ozone alerts" occur fre-
quently in association with high temperature. The latter may mask 0, effects
or oy itself produce excess mortality in susceptible elderly cardiopulmonary
patients. When attempts have been made to distinguish the effects of CL, no
positive relationship has been found with mortality; rather, the effect corre-
lates most closely with elevated temperature.
019DC/A 12-44 6/18/84
-------
12.6 REFERENCES
Adachi, T. ; Hasegawa, K. ; Miyamoto, T. ; Inone, H. ; Kamitsuji, H.; Kawa, K.;
Murata, K. ; Hayashida, M. (1973) Clinical findings on photochemical smog
in Osaka. Shonika Shinryo 36: 307-312.
Adachi, T. ; Nakajima, T. (1974) Symptoms and clinical examinations of the
patients seriously injured by photochemical smog. Rinsho Kagaku 3: 257-
267.
Altshuller, A. P. (1977) Eye irritation as an effect of photochemical air
pollution. J. Air Pollut. Control Assoc. 27: 1125-1126.
American Thoracic Society. (1978) Epidemiology standardization project. Am.
Rev. Respir. Dis. 118 (6, pt. 2): 1-20.
Avol, E. L. ; Wightman, L. H. , Linn, W. S. ; Hackney, J. D. (1979) A movable
laboratory for controlled clinical studies of air pollution exposure. J.
Air Pollut. Control Assoc. 29: 743-745.
Avol, E. L. ; Linn, W. S. ; Shamoo, D. A.; Venet, T. G.; Hackney, J. D. (1983)
Acute respiratory effects of Los Angeles smog in continuously exercising
adults. J. Air Pollut. Control Assoc. 33: 1055-1060.
Balchum, 0. J. (1973) Toxicological effects of ozone, oxidant, and hydrocarbons.
In: Proceedings of the conference on health effects of air pollution:
prepared for the Committee on Public Works, U.S. Senate; October; Washington,
DC. Washington, DC: Government Printing Office; pp. 489-505. Available
from: GPO, Washington, DC; S/N 5270-02105.
Bates, D. V.; Sizto, R. (1983) Relationship between air pollution levels and
hospital admissions in Southern Ontario. Can. J. Public Health 74: 117-
133.
Bennett, A. E. (1981) Limitations of the use of hospital statistics as an
index of morbidity in environmental studies. J. Air Pollut. Control
Assoc. 31: 1276-1278.
Biersteker, K. ; Erendijk, J. E. (1976) Ozone, temperature and mortality in
Rotterdam in the summers of 1974 and 1975. Environ. Res. 12: 214-217.
Bischof, W. (1973) Ozone measurements in jet airline cabin air. Water Air
Soil Pollut. 2: 3-14.
Bloom, A. D. (1979) Chromosomal abnormalities among welder trainees. Research
Triangle Park: U.S. Environmental Protection Agency, Health Effects
Research Laboratory; EPA report no. EPA-600/1-79-011. Available from:
NTIS, Springfield, VA; PB295018.
Breslow, L. ; Goldsmith, J. (1958) Health effects of air pollution. Am. J.
Public Health 48: 913-917.
019DC/A 12-45 6/18/84
-------
Broad, W. J. (1979) High anxiety over flights through ozone. Science
(Washington, DC) 205: 767-769.
Buell, P.; Dunn, J. E., Jr.; Breslow, L. (1967) Cancer of the lung and Los
Angeles-type air pollution: prospective study. Cancer (Philadelphia)
20: 2139-2147.
California Department of Public Health, (1955) Clean air for California:
initial report of the Air Pollution Study Project. San Francisco, CA:
State of California, Department of Public Health.
California Department of Public Health. (1956) Clean air for California:
second report of the Air Pollution Study Project. Berkeley, CA: State
of California, Department of Public Health.
California Department of Public Health. (1957) Report III: a progress report
of California's fight against air pollution. Berkeley, CA: State of
California, Department of Public Health.
Cassell, E. J. ; Lebowitz, M. D.; Mountain, I. M.; Lee, H. T.; Thompson, D. J.;
Wolter, 0. W.; McCarrol1, J. R. (1969) Air pollution, weather, and illness
in a New York population. Arch. Environ. Health 18: 523-530.
Challen, P, J, R.; Hickish, D. E.; Bedford, J. (1958) An investigation of some
health hazards in an inert-gas tungsten-arc welding shop. Br. J. Ind.
Med. 15: 276-282.
Cohen, C, A.; Hudson, A. R.; Clausen, J. L. ; Knelson, J. H. (1972) Respiratory
symptoms, spirometry, and oxidant air pollution in nonsmoking adults.
Am. Rev. Respir. Dis. 105: 251-261.
Daubs, J. (1980) Flight crew exposures to ozone concentrations affecting the
visual system. Am. J. Optom. Phys. Opt. 57: 95-105.
Deane, M.; Goldsmith, J. R.; Tuma, D. (1965) Respiratory conditions in outside
workers: report on outside plant telephone workers in San Francisco and
Los Angeles. Arch. Environ. Health 10: 323-331.
Detels, R.; Rokaw, S. N.; Coulson, A. H.; Tashkin, D. P.; Sayre, J. W. ; Massey,
F. J. , Jr. (1979) The UCLA population studies of chronic obstructive
respiratory disease. I. Methodology and comparison of lung function in
areas of high and low pollution. Am. J. Epidemic!. 109: 33-58.
Detels, R. ; Sayre, J. W. ; Coulson, A. H. ; Rokaw, S. N. ; Massey, F. J. , Jr.;
Tashkin, D. P., Wu, M. M. (1981) The UCLA population studies of chronic
obstructive respiratory disease. IV. Respiratory effect of long-term
exposure to photochemical oxidants, nitrogen dioxide, and sulfates on
current and never smokers. Am. Rev. Respir. Dis. 124: 673-680.
Dimitriades, B. , ed. (1976) International conference on photochemical oxidant
pollution and its controls: v. I and II; September 1976; Raleigh, NC.
Research Triangle Park, NC: U.S. Environmental Protection Agency,
Environmental Sciences Research Laboratory; EPA report no. EPA-600/3-77-001a
and b. Available from: NTIS, Springfield, VA; PB 264232 and 233.
019DC/A 12-46 6/18/84
-------
Durham, W. (1974) Air pollution and student health. Arch. Environ. Health
28: 241-254.
Fabbri, L. ; Mapp, C. ; Rossi, A.; Sarto, F.; Trevisan, A.; De Rosa, E. (1979)
Pulmonary function changes due to low level occupational exposure to
ozone. Med. Lav. 70: 307-312.
Ferris, B. G. , Jr. (1978) Health effects of exposure to low levels of regulated
air pollutants: a critical review. J. Air Pollut. Control Assoc. 28:
482-497.
Fredga, K. ; Davring, L. ; Sunner, M.; Bengtsson, B. 0.; Elinder, C. G. ; Sig-
tryggsson, P.; Berlin, M. (1982) Chromosome changes in workers (smokers
and nonsmokers) exposed to automobile fuels and exhaust gases. Scand. J.
Work Environ. Health 8: 203-221.
Fujii, T. (1972) Studies on air pollution by photochemical reaction. I. The
results of field research of photochemical smog in Osaka, 1971. In:
Proceedings of the Research Section; Osaka Environmental Pollution Control
Centre; No. 3; pp. 21-34.
Goldsmith, J. R. ; Deane, M. (1965) Outdoor workers in the United States and
Europe. Mil banks Mem. Fund Q. 43: 107-116.
Goldsmith, J. R.; Friberg, J. (1977) Effects of air pollution on human health.
In: Stein, A. C., ed. Air Pollution. 3rd ed. Volume II: the effects
of air pollution. New York, NY: Academic Press, Inc.; pp. 476-477, 479,
501 ff.
Goldsmith, J. R. ; Griffith, H. L; Detels, R. ; Beeser, S. ; Neumann, L. (1983)
Emergency room admissions, meteorologic variables, and air pollutants: a
path analysis. Am. J. Epidemic!. 118: 759-779.
Hammer, D. I.; Hasselblad, V.; Portnoy, B.; Wehrle, P. F. (1974) Los Angeles
student nurse study. Daily symptom reporting and photochemical oxidants.
Arch. Environ. Health 28: 255-260.
Hasselblad, V.; Creason, J. P.; Nelson, W. C. (1976) Regression using "hockey
stick" functions. Research Triangle Park, NC: U.S. Environmental Protec-
tion Agency, Health Effects Research Laboratory; EPA report no. EPA-600/1-
76-024. Available from: NTIS, Springfield, VA; PB253576.
Hausknecht, R.; Breslow, L. (1960) Air pollution effects reported by California
residents from the California Health Survey. Berkeley, CA: State of
California, Department of Public Health.
Hausknecht, R. (1962) Experiences of a respiratory disease panel selected from
a representative sample of the adult population. Am. Rev. Respir. Dis.
86(6): 858-866.
Hechter, H. H.; Goldsmith, J. R. (1961) Air pollution and daily mortality.
Am. J. Med. Sci. 241: 581-588.
019DC/A 12-47 6/18/84
-------
Helsing, K. J. ; Comstock, G. W. ; Speizer, F. E.; Ferris, B. G.; Lebowitz, M.
D. ; Tockman, M. S. ; Burrows, B. (1979) Comparison of three standardized
questionnaires on respiratory symptoms. Am. Rev. Respir. Dis. 120: 1221-
1231.
Herman, D. R. (1972) The effect of oxidant air pollution on athletic perfor-
mance. Chapel Hill, NC: University of North Carolina. Master's Thesis.
House of Representatives. (1980) Adverse Health Effects on Inflight Exposure
to Atmospheric Ozone. Prepared for hearing before the Subcommittee on
Oversight and Investigations of the Committee on Interstate and Foreign
Commerce; July 18, 1979. Washington, DC: U.S. Government Printing Office;
Serial No. 96-84.
Japanese Environmental Agency. (1976) Health Hazards of Photochemical Air
Pollution (the results of a survey of health hazards of photochemical air
pollution in 1975). Tokyo, Japan: Air Quality Bureau.
Javitz, H. S. ; Kransnow, R. ; Thompson, C.; Patton, K. M.; Berthiaume, D. E.;
Palmer, A. (1983) Ambient oxidant concentrations in Houston and acute
health symptoms in subjects with chronic obstructive pulmonary disease: a
reanalysis of the HAOS health study. In: Lee, S. D. ; Mustafa, M. G. ;
Mehlman, M. A., eds. International symposium on the biomedical effects of
ozone and related photochemical oxidants; March 1982; Pinehurst, NC.
Princeton, NJ: Princeton Scientific Publishers, Inc.; pp. 227-256.
(Advances in modern toxicology: v. 5).
Johnson, D. E. ; Prevost, R. J.; Kimball, K. T. ; Jenkins, D. E.; Bourhofer, E.
(1979) Study of health-related responses to air pollution of persons with
chronic obstructive pulmonary disease in Houston, Texas. Houston, TX:
Southwest Research Institute. SwRI project no. 01-4902.
Kaoayama, H. Ocular symptoms caused by the oxidant pollution that occurred last
summer and the treatment of them. Nihonnoganka No. 110: 8.
Kagawa, J. (1983) Effects of ozone and other pollutants on pulmonary function
in man. In: Lee, S. D. ; Mustafa, M. G.; Mehlman, M. A., eds. Interna-
tional symposium on the biomedical effects of ozone and related photo-
chemical oxidants; March 1982; Pinehurst, NC. Princeton, NJ: Princeton
Scientific Publishers, Inc.; pp. 411-422. (Advances in modern toxicology:
v .5).
Kagawa, J.; Toyama, T. (1975) Photochemical air pollution: its effects on
respiratory function of elementary school children. Arch. Environ.
Health 30: 117-122.
Kagawa, J. ; Toyama, T. ; Nakaza, M. (1976) Pulmonary function test in children
exposed to air pollution. In: Finkel, A. J.; Duel, W. C., eds. Clinical
implications of air pollution research: proceedings of the 1974 air
pollution medical research conference; December 1974; San Francisco, CA.
Acton, MA: Publishing Sciences Group, Inc.; pp. 305-320.
Kleinfeld, M. ; Giel, C. ; Tabershaw, I. R. (1957) Health hazards associated
with inert gas shielded metal arc welding. Arch. Ind. Health 15: 27-31.
019DC/A 12-48 6/18/84
-------
Kudryavtseva, 0. F. (1963) On the possibility of chronic effects of ozone in
working conditions. Gig. Tr. Prof. Zabol. 6: 52-53.
Lagerwerff, J. M. (1963) Prolonged ozone inhalation and its effects on visual
parameters. Aerosp. Med. 34: 479-486.
Lategola, M. T. ; Melton, C. E. ; Higgins, E. A. (1980a) Effects of ozone on
symptoms and cardiopulmonary function in a flight attendant surrogate
population. Aviat. Space Environ. Med. 51: 237-246.
Lategola, M. T. ; Melton, C. E. ; Higgins, E. A. (1980b) Pulmonary and symptom
threshold effects of ozone in airline passengers and cockpit crew surro-
gates. Aviat. Space Environ. Med. 51: 878-884.
Lebowitz, M. D. (1984) The effects of environmental tobacco smoke exposure and
gas stoves on daily peak flow rates in asthmatic and non-asthmatic families.
Eur. J. Respir. Dis. 65 (suppl. 133): 90-97.
Lebowitz, M. D. ; Bendheim, P. ; Cristea, G. ; Markowitz, D. ; Misiaszek, Jr. ;
Staniec, M. ; Van Wyck, D. (1974) The effect of air pollution and weather
on lung function in exercising children and adolescents. Am. Rev. Respir.
Dis. 109: 262-273.
Lebowitz, M. D. ; Holberg, C. J. ; Dodge, R. R. (1983) Respiratory effects on
populations from low level exposures to ozone. Presented at: 34th
annual meeting of the Air Pollution Control Association; June; Atlanta,
GA. Pittsburgh, PA: Air Pollution Control Association; paper no. 83-12.5.
Lebowitz, M. D. ; Knudson, R. J. ; Robertson, G.; Burrows, B. (1982b) Signifi-
cance of intraindividual changes in maximum expiratory flow volume and
peak expiratory flow measurements. Chest 81: 566-570.
Lebowitz, M. D. ; O'Rourke, M. K.; Dodge, R.; Holberg, C. J.; Gorman, G.;
Hoshaw, R. W. ; Pinnas, J. L. ; Barbee, R. A.; Sneller, M. R. (1982a) The
adverse health effects of biological aerosols, other aerosols, and indoor
microclimate on asthmatics and nonasthmatics. Environ. Int. 8: 375-380.
Linn, W. S. ; Hackney, J. D. ; Pedersen, E. E. ; Breisacher, P.; Mulry, C. A.;
Coyle, J. F. (1976) Respiratory function and symptoms in urban office
workers in relation to oxidant air pollution exposure. Am. Rev. Respir.
Dis. 114: 477-483.
Linn, W. S.; Jones, M. P.; Bachmayer, E. A.; Spier, C. E.; Mazur, S. F. ; Avol,
E. L. ; Hackney, J. D. (1980) Short-term respiratory effects of polluted
ambient air: a laboratory study of volunteers in a high-oxidant community.
Am. Rev. Respir. Dis. 121: 243-252.
Linn, W. S.; Chang, Y. T. C.; Julin, D. R.; Spier, C. E.; Anzar, U. T.; Mazur,
S. F. ; Trim, S. C. ; Avol, E. L.; Hackney, J. D. (1982) Short-term human
health effects of ambient air in a pollutant source area. Lung 160:
219-227.
019DC/A 12-49 6/18/84
-------
Linn, W. S. ; Avol, E. L. ; Hackney, J. D. (1983) Effects of ambient oxidant
pollutants on humans: a movable environmental chamber study. In: Lee,
S. D.; Mustafa, M. G. ; Mehlman, M. A., eds. International symposium on
the biomedical effects of ozone and related photochemical oxidants; March
1982; Pinehurst, NC. Princeton, NJ: Princeton Scientific Publishers,
Inc.; pp. 125-137. (Advances in modern toxicology: v. 5).
Lippmann, M.; Lioy, P. J. (1984) Critical issues in air pollution epidemiology.
EHP Environ. Health Perspect. (in press).
Lippmann, M. ; Lioy, P. J.; Leikauf, G. ; Green, K. B.; Baxter, D. ; Morandi, M.;
Pasternack, B. S. (1983) Effects of ozone on the pulmonary function of
children. In: Lee, S. D.; Mustafa, M. G.; Mehlman, M. A., eds. Interna-
tional symposium on the biomedical effects of ozone and related photo-
chemical oxidants; March 1982; Pinehurst, NC. Princeton, NJ: Princeton
Scientific Publishers, Inc.; pp. 423-446. (Advances in modern toxicology:
v. 5).
Magie, A. R. ; Abbey, D. E. ; Centerwall, W. R. (1982) Effect of photochemical
smog on the chromosome aberrations in peripheral lymphocytes of nonsmoking
college students. Environ. Res. 29: 204-219.
Makino, K. ; Mizoguchi, I. (1975) Symptoms caused by photochemical smog.
Nippon Koshu Eisei Zasshi 22: 421-430.
Masuda, R. (1977) Relationship between ozone and damage to human health.
P.P.M. 8(11): 2-19. (Trans.: Okishi danto to ningen acute-kid higui no
kankei).
Matsumura, T. ; Sakamoto, Y. ; Iwase, M. ; Ebina, R.; Koyama, M.; Nishioka, K.;
Sugiyama, M. ; Takeoka, K. ; Yonei, J. ; Nomura, Y. ; Shitagawa, M. ; Kubo,
T. ; Ueno, Y. ; Kawai, Y., (1973) Clinics of injury considered attributable
to a photochemical smog that occurred in Moriguchi City. Nippon Rinsho
31: 154-168.
Mausner, J. S.; Bahn, A. K. (1974) Epidemiology. Philadelphia, PA: Saunders;
pp. 116-123.
McMillan, R. S.; Wiseman, D. H.; Hanes, B.; Wehrle, P. F. (1969) Effect of
oxidant air pollution on peak expiratory flow rates in Los Angeles school
children. Arch. Enviroq, Health 18: 94-99.
Mikami, U.; Kudo, S. (1973a) Air pollution - especially in terms of oxidants
and respiratory organs. Intern. Med. (Japan) 32: 837-844.
Mikami, R.; Kudo, S. (1973b) Acute disturbances by the so-called photochemical
smog in Japan. Nippon Rinsho 31: 123.
Mills, C. A. (1957a) Do smogs threaten community health? Cincinnati J. Med.
38: 259-261.
Mills, C. A. (1957b) Respiratory and cardiac deaths in Los Angeles smogs. Am.
J. Med. Sci. 233: 379-386.
019DC/A 12-50 6/18/84
-------
Mizoguchi, I.; Makino, K.; Kudo, S. ; Mikami, R. (1977) On the relationship of
subjective symptoms to photochemical oxidant. In: Dimitriades, B., ed.
International conference on photochemical oxidant pollution and its
control: proceedings: v. I; September 1976; Raleigh, NC. Research
Triangle Park, NC: U.S. Environmental Protection Agency, Environmental
Sciences Research Laboratory; pp. 477-494; EPA report no. EPA-600/3-77-001a.
Available from: NTIS, Springfield, VA; PB264232.
Morris, J. N. (1970) Uses of Epidemiology. 2nd edition. London, England:
Livingstone; pp. 268-273.
Motley, H. L. ; Smart, R. H. ; Leftwich, C. T. (1959) Effect of polluted Los
Angeles air (smog) on lung volume measurements. J. Am. Med. Assoc. 171:
1469-1477.
Mountain, I. M. ; Cassell, E. J. ; Wolter, D. W.; Mountain, J. D.; Diamond, J.
R. ; McCarroll, J. R. (1968) Health and the urban environment. VII. Air
pollution and disease symptoms in a "normal" population. Arch. Environ.
Health 17: 343-362.
Nagata, H.; Kadowaki, I.; Ishigure, K.; Tokuda, M.; Ohe, T.; Yamashita, T.
(1979) Meteorological conditions, air pollution and daily morbidity in
summer. Nippon Eiseigaku Zasshi 33: 772-777.
Namekata, T. ; Carnow, B. W.; Flournoy-Gill, Z. ; O'Farrell, E. B.; Reda, D. J.
(1979) Model for measuring the health impact from changing levels of
ambient air pollution: morbidity study. Research Triangle Park, NC:
U.S. Environmental Protection Agency, Health Effects Research Laboratory;
EPA report no. EPA-600/1-79-024. Available from: NTIS, Springfield, VA;
PB80-107030.
National Air Pollution Control Administration. (1970) Air quality criteria for
photochemical oxidants. Washington, DC: U.S. Department of Health,
Education, and Welfare, Public Health Service; NAPCA publication no.
AP-63. Available from: NTIS, Springfield, VA; PB190262.
National Research Council. (1977) Ozone and other photochemical oxidants.
Washington, DC: National Academy of Sciences, Committee on Medical and
Biologic Effects of Environmental Pollutants.
National Research Council. (1981) Indoor pollutants. Washington, DC: National
Academy Press; pp. 283-284.
Nevsaya, A. I.; Diterihs, D. D. (1975) Problems of hygiene of labor in H202
production by electrodynamic method. Gig. Tr. Prof. Zabol. (4): 16.
North Atlantic Treaty Organization. (1974) Air quality criteria for photochem-
ical oxidants and related hydrocarbons: a report by the expert panel on
air quality criteria. Brussels, Belgium: NATO, Committee on the Chal-
lenges of Modern Society; NATO/CCMS n. 29.
Oechsli, F. W. ; Buechley, R. W. (1970) Excess mortality associated with three
Los Angeles hot spells. Environ. Res. 3: 277-284.
019DC/A 12-51 6/18/84
-------
Oxhoj, H.; Bake, B.; Wedel, H.; Wilhelmsen, L. (1979) Effects of electric arc
welding on ventilatory lung function. Arch. Environ. Health 34: 211-217.
Okawada, N. ; Mizoguchi, I.; Ishiguro, T. (1979) Effects of photochemical air
pollution on the human eye—concerning eye irritation, tear lysome and
tear pH. Nagoya J. Med. Sci. 41: 9-20.
Pearlman, M. E.; Finklea, J. F. ; Shy, C. M. ; Bruggen, J.; Newill, V. A. (1971)
Chronic oxidant exposure and epidemic influenza. Environ. Res. 4: 129-
140.
Peters, J. M. ; Murphy, R. L. H.; Ferris, B. G.; Burgess, W. A.; Ranadive, M.
V.; Perdergrass, H. P. (1973) Pulmonary function in shipyard welders: an
epidemiologic study. Arch. Environ. Health 26: 28-31.
Pima County Air Quality Control District. (1978) The Geographical Distribution
of Ground Level Ozone in Metropolitan Tucson, Arizona. Summer 1977.
Tucson, AZ: Pima County Health Department; AQ-99.
Polonskaya, F. I. (1968) Hygienic evaluation of working conditions in argon-
arc welding of titanium alloys. Gig. Tr. Prof. Zabol. 12: 46-48.
Reed, D. ; Glaser, S. ; Kaldor, J. (1980) Health problems and ozone exposure
among flight attendants. Am. J. Epidemic!. 112: 444.
Remmers, J. E. ; Balchum, 0. J. (1965) Effects of Los Angeles urban air pollu-
tion upon respiratory function of emphysematous patients: report on
studies done from July 1, 1964 - February 1, 1965. Presented at: 58th
annual meeting of the Air Pollution Control Association; June; Toronto,
Canada. Pittsburgh, PA: Air Pollution Control Association; paper no.
65-43.
Renzetti, N. A.; Gobran, V. (1957) Studies of eye irritation due to Los Angeles
smog 1954-1956. San Marino, CA: Air Pollution Foundation; report no.
29.
Richardson, N. A. ; Middleton, W. C. (1957) Evaluation of filters for removing
irritants from polluted air. Los Angeles, CA: University of California,
Department of Engineering; report no. 57-43.
Richardson, N. A.; Middleton, W. C. (1958) Evaluation of filters for removing
irritants from polluted air. Heat. Piping Air Cond. 30: 147-154.
Rokaw, S. N.; Massey, F. (1962) Air pollution and chronic respiratory disease.
Am. Rev. Respir. Dis. 86: 703-704.
Rokaw, S. N.; Detels, R.; Coulson, A. H.; Syre, J. W.; Tashkin, D. P.; Allwright,
S. S. ; Massey, F. J., Jr. (1980) The UCLA population studies of chronic
obstructive respiratory disease. III. Comparison of pulmonary function
in three communities exposed to photochemical oxidants, multiple primary
pollutants, or minimal pollutants. Chest 78: 252-262.
Sarto, F. ; Carmignotto, F. ; Fabbri, L. (1979a) Osmotic resistance, alkaline
phosphatase and leucocyte peroxidase in markers occupationally exposed to
ozone. G. Ital. Med. Lav. 1: 121-124.
019DC/A 12-52 6/18/84
-------
Sarto, F.; Trevisan, A.; Gasparotto, G.; Rosa, A.; Fabbri, L. (1979b) Study of
some erythrocyte and serum enzyme activities in workers exposed to low
ozone concentrations for a long time. Int. Arch. Occup. Environ. Health
43: 99-105.
Schoettlin, C. E. (1962) The health effects of air pollution on elderly males.
Am. Rev. Respir. Dis. 86: 878-897.
Schoettlin, C. E.: Landau, E. (1961) Air pollution and asthmatic attacks in
the Los Angeles area. Public Health Rep. 76: 545-548.
Scott, C. D. ; Burkart, J. A. (1978) Chromosomal aberrations in peripheral
lymphocytes of students exposed to pollutants. Research Triangle Park,
NC: U.S. Environmental Protection Agency, Health Effects Research Labora-
tory; EPA report no. EPA-600/1-78-054. Available from: NTIS, Springfield,
VA; PB 285594.
Shimizu, K.; Harada, M.; Miyata, M.; Ishikawa, S. ; Mizoguchi, I. (1976) Effect
of photochemical smog on the human eye: epidemiological, biochemical,
ophthalmological and experimental studies. Rinsho Ganka 30: 407-418.
Shimizu, T. (1975) Classification of subjective symptoms of junior high school
students affected by photochemical air pollution. Taiki Osen Kenkyu 9:
734-741.
Shishido, M,; Suguta, K,; Higuchi, F,; Ogihara, A. (1974) Effects of photo-
chemical smog on respiratory function: observation with the flow volume
curve. Kogai to Taisaku 10: 89.
Shy, C. M. ; Muller, K. E. (1980) Evaluating the effects of air pollution on
sensitive subjects. Am. J. Public Health 78: 680-681.
Sugita, K. ; Ogihara, A.; Murabayashi, H. ; Shishido, M. ; Higuchi, F. (1976)
Effects of photochemical smog on human respiratory function. Yokohama
Med. Bull. 27: 99-107.
Tashkin, D. P.; Coulson, A. H.; Simmons, M. S.; Spivey, G. H. (1983) Respira-
tory symptoms of flight attendants during high-altitude flight: possible
relation to cabin ozone exposure. Int. Arch. Occup. Environ. Health 52:
117-137.
Truche, M. R. (1951) The toxicity of ozone. Arch. Mai. Prof. Med. Trav. Secur.
Soc. (12): 55-58.
Tucker, H.G. (1962) Effect of air pollution and temperature on residents of
nursing homes in the Los Angeles area. Berkeley, CA: State of California,
Department of Public Health.
Ulrich, L.; Malik, E.; Hurbankova, M.; Kemka, R. (1980) The effect of low-level
ozone concentrations on the serum levels of immunoglobulins, alpha- -
antitrypsin and transferrin and on the activation of peripheral lymprio-
cytes. J. Hyg. Epidemiol. Microbiol. Immunol. 24: 303-308.
019DC/A 12-53 6/18/84
-------
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.
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.
Ury, H. K. ; Hexter, A. C. (1969) Relating photochemical pollution to human
physiological reactions under controlled conditions. Arch. Environ.
Health 18: 473-479.
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,
Springfield, VA; PB80-124753.
U.S. Environmental Protection Agency. (1982) Air quality criteria for particu-
late matter and sulfur oxides: v. I-III. Research Triangle Park, NC:
U.S. Environmental Protection Agency, Environmental Criteria and Assess-
ment Office; EPA report nos. EPA-600/8-82-029a,b, and c. Available from:
NTIS, Springfield, VA; PB84-156777.
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-
ship between air pollution and chronic respiratory disease. I. Exposure
to inhalative pollutants (dust, S0«, N02, and 0~) in the working area.
In: Environment and quality of life: ^second environmental research
program 1976-1980. Brussels, Belgium: Commission of the European Com-
munities; report no. ECSC-EEC-EAEC.
Ward, J. R.; Moschandreas, D. J. (1978) Use of emergency room patient popula-
tions in air pollution epidemiology. Research Triangle Park, NC: U.S.
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.
Arch. Environ. Health 19: 315-322.
Wayne, W. S. ; Wehrle, P. F. ; Carroll, R. E. (1967) Oxidant air pollution and
athletic performance. J. Am. Med. Assoc. 199: 902-904.
Whittemore, A. S. ; Korn, E. L. (1980) Asthma and air pollution in the Los
Angeles area. Am. J. Public Health 70: 687-696.
Williams, W. H., Jr. (1979) Evaluation of asthma. Chest 76: 3.
World Health Organization. (1978) Photochemical oxidants. Geneva, Switzerland:
World Health Organization; Environmental health criteria; Environmental
Health Criteria: no. 7.
019DC/A 12-54 6/18/84
-------
World Health Organization. (1983) Indoor air pollutants: exposure and health
effects, report on a WHO meeting: 1982; Nordlingen, W. Germany.
Copenhagen, Denmark: World Health Organization, Regional Office for
Europe. (EURO reports and studies: no. 78).
World Health Organization. (1983) Guidelines on studies in environmental
epidemiology. Geneva, Switzerland: World Health Organization.
(Environmental health criteria: no. 27.)
Wright, B. M. (1978) A miniature Wright peak flow meter. Br. Med. J. (2):
1627-1628.
Young, W. A.; Shaw, D. B. ; Bates, D. V. (1962) Presence of ozone in aircraft
flying at 35,000 feet. Aerosp. Med. 33: 311-318.
Young, W.A.; Shaw, D. B. ; Bates, D. V. (1963) Pulmonary function in welders
exposed to ozone. Arch. Environ. Health 7: 337-340.
Zagraniski, R. T.; Leaderer, B. P.; Stolwijk, J. A. J. (1979) Ambient sulfates,
photochemical oxidants, and acute health effects: an epidemiological
study. Environ. Res. 19: 306-320.
019DC/A 12-55 6/18/84
-------
13. EVALUATION OF INTEGRATED HEALTH EFFECTS DATA
FOR OZONE AND OTHER PHOTOCHEMICAL OXIDANTS
13.1 INTRODUCTION
The preceding chapters (chapters 10, 11, and 12) have documented a wide
array of toxicological responses elicited jjn vivo and j_n vitro by 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 effects of ozone
on the respiratory system was reported and discussed in particular detail in
those chapters. The present chapter provides a vehicle for evaluating this
collective body of data for its significance to public health and for assessing
the certainties and uncertainties associated with the data. Since the purpose
of a criteria document is to provide a scientific basis for the derivation and
promulgation of standards, the present chapter addresses specific issues and
questions that are important in standard-setting.
Paramount among the issues considered in standard-setting is the identifi-
cation of the population or subpopulation to be protected by the regulation,
that is, one that is at particular risk from exposure to ozone and other
photochemical oxidants. The identification of such a population or subpopula-
tion presupposes the identification of one or more effects that are in and of
themselves adverse, or that are indicators of other effects that are adverse
but that are not measurable in man because of ethical constraints.
The existing health effects data indicate that the responses to ozone and
other photochemical oxidants that are most clearly linked to the potential
impairment of public health are those changes in pulmonary function and related
respiratory system variables that have been observed in human controlled-
exposure studies and in a limited number of epidemiological studies. As
discussed in the 1978 criteria document for ozone and other photochemical
oxidants (U.S. Environmental Protection Agency, 1978), changes in lung function
associated with exposure to ozone and other photochemical oxidants are viewed
as signalling impairment of public health for several reasons. Decrements in
the mechanical functions of the lung can interfere with normal activity in the
general population and in susceptible subpopulations, depending upon the
activity and the population. Even in the general population, ozone exposure
during exercise can produce significant decrements in lung function (chapter 11).
In certain individuals in the general population, not yet characterized medi-
cally except for their responses to ozone, significant decrements, larger than
019JSA/A 13-1 6/26/84
-------
those seen in the rest of the general population, are elicited by exposure to
ozone during either continuous or intermittent exercise (chapter 11). In
individuals who have respiratory diseases such as asthma or chronic obstructive
lung disease, even small decrements in lung function may interfere with normal
activity and may be deemed clinically significant. Symptoms usually accompany
the observed decrements in lung function and impairments in other respiratory
indicators (chapters 11 and 12). Discomfort produced by the symptoms that
ozone exposure produces have been reported as interfering with experimental
protocols, especially those employing 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 popu-
lations are discussed at length in this chapter. In addition, inherent bio-
logical characteristics or personal habits and activities that may attenuate
or potentiate typical responses to ozone and other oxidants are discussed.
The environmental factors that determine potential or real exposures of popu-
lations or subpopulations 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 and related airway parameters
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 ozone effects.
019JSA/A 13-2 6/26/84
-------
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 on potentially susceptible individuals.
10. Extrapolation to human populations of ozone-oxidant effects observed
in animals.
11. Effects of other photochemical oxidants and the interactions of
ozone and other pollutants.
12. Identification of potentially-at-risk populations or subpopulations.
13. Demographic information on potentially at-risk subpopulations.
13.2 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, both qualitative and
quantitative information is summarized as background for understanding the
relevance for public health of the concentrations at which effects have been
observed in health studies and as background for estimating exposures.
13.2.1 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 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 concentrations of ozone and
other photochemical oxidants occur during the second and third quarters of the
year, i.e., April through September. The months of highest ozone concentrations
depend upon local or regional weather patterns to a considerable degree, such
that the time of occurrence of maximum 1-hour, 1-month, or seasonal ozone
concentrations is 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 to be May through
October in many California cities and conurbations.
019JSA/A 13-3 6/26/84
-------
In nonurban areas, most peaks in ozone concentrations occur during daylight
hours, but peak concentrations at night are not uncommon. The occurrence of
nighttime peaks appears to be the result of combined induction time and trans-
port time for urban plumes, coupled with the lack of nitric oxide (NO) sources
to provide NO for chemical scavenging of ozone in the evening and early morning
hours. In nonurban areas, ozone concentrations are generally lower than in
urban areas, but it is not unusual to encounter concentrations higher than
those found in urban-core source areas or even in the suburbs of urban areas.
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. Early morning ozone concentrations in nonurban areas are higher than
in urban areas and are near background levels (e.g., 0.02 to 0.04 ppm), since
surface scavenging rather than chemical scavenging by NO is the principal
removal mechanism in nonurban areas.
Concentrations of ozone and the patterns of its occurrence are documented
in chapter 6. Major points pertinent to exposure assessment have been de-
scribed qualitatively above. Quantitative data are briefly summarized here.
Figure 13-1 shows the frequency distribution of the three highest ozone concen-
trations for each of 3 years averaged together (1979 through 1981) (U.S.
Environmental Protection Agency, SAROAD data file). The present national
ambient air quality standard for ozone is expressed as a concentration not to
De exceeded on more than one day per year. Thus, the second-highest 1-hour
ozone concentration, rather than the highest, is regarded as a concentration
of potential significance for public health. As demonstrated by this figure,
50 percent of the monitoring stations reported second-highest ozone concentra-
tions, averaged over 3 years, of 0.12 ppm; 25 percent had 3-year-average
second-highest ozone concentrations of 0.15 ppm; and 10 percent had 3-year-
average second-highest ozone concentrations of 0.20 ppm. Since most of the
ozone monitoring stations are located in urban areas (centers of greatest
population density), the data cited above reflect the potential exposures to
ozone of urban populations.
As data in chapter 11 and in section 13.3.4 show, human controlled-
exposure studies have demonstrated that attenuation of responses to ozone
during repeated, consecutive-day exposures of at least 3 to 4 days can occur
in most, though not all, of the individuals studied. Thus, the potential for
019JSA/A 13-4 6/26/84
-------
UD
C-.
(A)
I
CTI
^
ro
en
00
-p.
a
Z
O
oc
z
UJ
o
z
o
o
UJ
Z
o
N
O
99.99
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
99.9 99.8
99 98
95 90
80 70 60 50 40 30 20
10
1 0.5 0.2 0.1 0.05 0.01
I I
I I I I I I I
HIGHEST
2nd-HIGHEST
3rdHIGHEST
J_L1_L_U I I .I
J_J I L_L
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 13-1. Collective distributions of the three highest 1-hour ozone concentrations for
3 years (1979, 1980, and 1981) at valid sites {906 station-years).
Source: U.S. Environmental Protection Agency, SAROAD data files for 1979,1980,1981.
-------
repeated, consecutive-day exposures of that duration to ambient air concentra-
tions of ozone is of interest. Data records from four cities were examined in
chapter 6 for exposures to three different concentrations persisting for
3 consecutive days or longer (see Figures 6-23 through 6-26). Those data
indicate the probabilities of exposures lasting rr-days or longer, as shown in
Table 13-1. As needed for exposure assessment, the consecutive days between
multiple-day occurrences of these concentrations can be estimated from Figures
6-23 through 6-26 (chapter 6). Probabilities given in Table 13-1 are descrip-
tive statistics based on aerometric data from the respective localities for
1979, 1980, and 1981. The data cannot be used to predict concentrations but
indicate only the probable duration once a concentration has been reached.
Potential exposures of nonurban populations, while not easily ascertained
in the absence of a suitable aerometric data base, can be estimated from
aerometric data for selected sites known to represent agriculturally oriented
areas and from aerometric data obtained from special-purpose monitoring networks.
Data from three National Forest (NF) monitoring stations of the National Air
Pollution Background Network (NAPBN) show 2-year averages of mean concentra-
tions (1979 and 1980) of 0.028 ppm at Kisatchie NF, LA; 0.070 ppm at Custer >
NF, MT; and 0.110 ppm at Green Mt. NF, VT (Evans et al. , 1982). (These are
considered "nonurban" rather than remote or rural sites largely because they
are thought to be subject to transport from urban areas at least some of the
time. A documented case of transport for an NF site in Missouri is given in
chapter 6.)
Data from Sulfate Regional Experiment (SURE) sites showed mean concentra-
tions 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,
JH, 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 G.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).
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
019JSA/A 13-6 6/26/84
-------
TABLE 13-1. PROBABILITY THAT SPECIFIED CONCENTRATIONS OF OZONE
WILL PERSIST FOR STATED CONSECUTIVE DAYS OR LONGER
(probability in percent)
Persistence for stated no. of
% Probability for
S concentration of:
Location
Pasadena, CA
Pomona, CA
Washington, DC
Dallas, TX
consecutive days or longer
2
3
4
5
6
7
2
3
4
5
6
7
2
3
4
5
6
7
2
3
4
5
6
7
0.12 ppm
72
56
42
35
28
23
66
50
38
30
24
19
0.06 ppm
49
33
23
16
12
9
77
62
50
40
32
24
0.18 ppm
59
40
29
20
16
12
51
34
22
15
10
7
0.12 ppm
b
—
—
—
—
—
22
7
•v4
~2
<1
<0.05
Cumulative frequency distribution of concentrations by number of consecutive
days of occurrence. Calculated from aerometric data for 1979 through 1981;
not predictive of concentrations but only of probable duration.
Few multiple-day occurrences in Washington and Dallas for higher
concentrations; not plotted.
Source: Figures 6-23 through 6-26, Chapter 6, compiled from SAROAD data
files for 1979 through 1981.
019JSA/A
13-7
6/26/84
-------
with surfaces of such materials as wall board, carpeting, and draperies (chap-
ter 6). Ozone concentrations indoors depend also on those factors that affect
both reactive and nonreactive pollutants: concentrations outdoors, air exchange
rates, presence or absence of air conditioning, and mode of air conditioning
(e.g., 100 percent fresh-air intake versus recirculation of air). Estimates
in the literature on indoor-outdoor ratios (I/O, expressed as percent) of
ozone concentrations range from 10 percent (Berk et al., 1981), for a residence,
to 80 ± 10 percent (Sabersky et al. , 1973), for an office building. Variations
in estimates in the literature are attributable to the diversity of structures
monitored, of their locations, and of their heating, ventilating, and air-
conditioning systems.
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. Latitudinal variations have little effect on potential
exposures within the contiguous United States, however, since the contiguous
states all fall within latitudes where photochemical oxidant formation is
favored (Logan et al. , 1981; U.S. Environmental Protection Agency, 1978).
Ozone concentrations are known to increase with altitude (Viezee et al. ,
1979; Seiler and Fishman, 1981). These gradients have no physiological signi-
ficance for the general population, however, since concentrations are highest
in the free troposphere, well above inhabited elevations. Data presented in
chapter 6 (Table 6-6) for Denver show, in fact, that ozone concentrations are
lower there than in many metropolitan areas of comparable size. These altitu-
dinal gradients are of possible consequence, however, for certain high-altitude
flights, as reported in the field studies documented in chapter 12. (Since
pressure and other changes with altitude affect measurements and calibrations,
care must be taken to ensure that ozone concentrations reported to produce
health effects at real or simulated high altitudes are correct).
Despite the commonly accepted maxim that ozone is a regional pollutant,
intermediate-scale spatial variations in concentrations occur that are of
potential consequence for designing and interpreting epidemiological studies.
For example, a study of ozone formation and transport in the northeast corridor
(Smith, 1981) resulted in data showing 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.
019JSA/A 13-8 6/26/84
-------
13.2.2 Potential Exposures to Other Photochemical Oxidants
13.2.2.1 Concentrations. In chapter 6 of this document the ranges of concen-
trations of four photochemical oxidants other than ozone were presented for
urban and, where possible, for nonurban atmospheres. The data presented in
sections 6.6 and 6.7 are drawn upon here to examine possible ranges 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 concen-
trations of these pollutants with ozone likely to occur in ambient air. The
four photochemical oxidants for which concentrations were given in sections
6.6 and 6.7 are peroxyacetyl nitrate, peroxypropionyl nitrate, hydrogen peroxide,
and formic acid.
Although they co-occur to varying degrees with ozone, aldehydes are not
photochemical oxidants. The concentrations of the low-molecular-weight alde-
hydes in ambient air are given in chapter 3 because these aldehydes are rela-
tively potent precursors to ozone and other photochemical oxidants. Aldehydes
are both primary and secondary pollutants, inasmuch as they are emitted direct-
ly to the atmosphere from certain sources and are also produced by atmospheric
photochemical reactions. 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 comprehen-
sive review by Altshuller (1983) for a treatment of the relationships in
ambient air between ozone and aldehyde concentrations.
Neither health effects data nor sufficient 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 4). More abundant aerometric data
exist for the other three compounds and will be summarized in this section.
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
019JSA/A 13-9 6/26/84
-------
oxidants (U.S. Department of Health, Education, and Welfare, 1970; U.S.
Environmental 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).
The highest concentrations of PAN measured and reported in the past
5 years were 42 ppb at Riverside, California, in 1980 (Temple and Taylor,
1983), and 47 ppb at Claremont, California, 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 concen-
trations 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 outside California in the past 5 years is that of
Lewis et al. (1983) for New Brunswick, New Jersey. The average PAN concentra-
tion 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 concentrations ranging from 0.4 ppb in Houston, Texas,
in 1976 (Westberg et al. , 1978) to 6.3 ppb in St. Louis, Missouri, in 1973
(Lonneman et al., 1976). Maximum PAN concentrations outside California for
the same period ranged from 10 ppb in Dayton, Ohio, in 1974 (Spicer et al. ,
1976) to 25 ppb in St. Louis (Lonneman et al., 1976).
In Chapter 6, data on PPN concentrations from 1963 through the present
were presented. The highest PPN concentration reported in these studies was
6 ppb in Riverside, California (Darley et al. , 1963). The next highest reported
PPN concentration was 5 ppb at St. Louis, Missouri, in 1973 (Lonneman et al.,
1976). Among more recent data, maximum PPN concentrations at respective sites
ranged from 0.07 ppb in Pittsburgh, Pennsylvania, in 1981 (Singh et al., 1982)
to 3.1 ppb at Staten Island, New York (Singh et al., 1982). California concen-
trations 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
019JSA/A 13-10 6/26/84
-------
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 3 to 4).
In urban areas, hydrogen peroxide (hLO_) concentrations have been reported
to range from < 0.5 ppb in Boulder, Colorado (Heikes et al., 1982) to £ 180 ppb
in Riverside, California (Bufalini et al., 1972). In nonurban areas, reported
concentrations ranged from 0.2 ppb near Boulder, Colorado, in 1S78 (Kelly
et al., 1979) to £ 7 ppb 54 km southeast of Tucson, Arizona (Farmer and Dawson,
1982). These nonurban data were obtained by the 1umino! chemiluminescence
technique (see chapter 5). The urban data were obtained by a variety of
methods, including the luminol chemiluminescence, the titanium (IV) sulfate
8-quinol inol, and other wet chemical methods (see chapter 5).
The higher concentrations of H_0_ reported in the literature must be
regarded as especially problematic, since FTIR measurements of ambient air
have not demonstrated unequivocally the presence of f-LCL even in the high-
oxidant atmosphere of the Los Angeles area. The limit of detection for a
1-km-pathlength FTIR system is around 0.04 ppm (chapter 5); FTIR is capable of
measuring concentrations of H_0? if it is present above the limit of detection.
13.2.2.2 Patterns. The patterns of formic acid (HCOOH), PAN, PPN, and H^
may 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, California, demonstrates (see Figures 6-37
and 6-43), ozone concentrations return to baseline levels faster than the
concentrations of PAN, HCOOH, or H~02 (PPN was not measured). The diurnal
patterns of PAN were reported in earlier criteria documents. Newer data
merely confirm those patterns.
Seasonally, winter concentrations (third and fourth quarters) of PAN are
lower than summer concentrations (second and third quarters). The winter
concentrations of PAN are proportionally higher, however, than the winter
concentrations of ozone; i.e., the PAN-to-ozone ratios are higher in winter
than in summer. Data are not readily available on the seasonal patterns of
the other non-ozone oxidants.
019JSA/A 13-11 6/26/84
-------
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 the
other non-ozone oxidants.
13.2.3 Potential Combined Exposures and Relationship of Ozone and Other
Photochemical Oxidants
Data on concentrations of PAN, PPN, and H?0 summarized in this section
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 second-high ozone concentration measured in the United
States in 1982 was 0.32 ppm, in the Los Angeles area. In the presence of that
concentration of ozone, the addition of non-ozone oxidants (0.15 ppm total)
would bring the total oxidant concentration to around 0.47 ppm, provided the
maximum concentrations of ozone and non-ozone oxidants were reached at the
same time.
Data also indicate that at their average concentrations in recent years
in the Los Angeles Basin, PAN and PPN together would add an additional oxidant
burden of 14 ppb (0.014 ppm) (4 to 13 ppb average PAN: Tuazon et al. , 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, however, on the answers to at
least three basic questions:
1. Do PAN, PPN, or H?0?, 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 synergis-
tically in combination with ozone to elicit adverse or potentially
adverse responses in human populations? Do any or all act antagonis-
tically with ozone?
3. Do the time course and magnitude of the concentrations of these
non-ozone oxidants parallel the time course and magnitude of ozone
concentrations in the ambient air?
The first two questions are addressed by health effects data presented in
chapters 10 through 12 and in section 13.7 of the present chapter.
019JSA/A 13-12 6/26/84
-------
Altshuller (1983) has reviewed data pertinent to the third question. His
conclusion is that "the ambient air measurements indicate that CL 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 03 could serve as an abatement surro-
gate for all photochemical products, including those not relevant to effects
data examined in this document. For example, the products be 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 and, indirectly, of PAN-to-PPN ratios presented in the review by
Altshuller (1983) and summarized in Table 13-2 and in chapter 6.
Certain other information presented in chapter 6 bears out the lack of a
strict quantitative relationship between ozone and PAN, in particular. Not
only are ozone-PAN relationships not consistent between different urban areas,
but they are not consistent in urban versus nonurban areas, in summer versus
winter, in indoor versus outdoor environments, or even, as the ratio data
show, in location, timing, or magnitude of diurnal peak concentrations within
the same city. Data obtained in Houston by Jorgen et al. (1978) show variations
in peak concentrations of concurrently measured PAN among three separate
monitoring sites. Temple and Taylor (1983) have shown that PAN concentrations
are a greater percentage of ozone concentrations in winter than in the remainder
of the year in California (see chapter 6). Lonneman et al. (1976) demonstrated
that PAN-to-0~ ratios are considerably lower in nonurban than in urban areas.
Thompson et al. (1973) showed that PAN persists longer than ozone indoors.
(This is to be expected from its lower reactivity with surfaces and its enhanced
stability at cooler-than-ambient temperatures such as found in air-conditioned
buildings.) 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 precursors that give
rise to PAN also give rise to ozone. Not all are equally reactive toward both
products, however, and therefore some precursors preferentially 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).
019JSA/A 13-13 6/26/84
-------
TABLE 13-2. 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,
Claremont,
Riverside,
Riverside,
Riverside,
Riverside,
Houston, TX
New Brunswi
CA
CA
CA
CA
CA
CA
>
ck
, 1978
, 1979
, 1975-1976
, 1976
, 1977
, 1977
1976
, NJ, 1978-1980
PAN/OS, %
Avg. At 03 peak
9
7
4
9
5
4
4
3
4
6
6
4
5
4
4
NA3
3
2
Hanst
Tuazon
1981b)
Tuazon
Pitts
Tuazon
Tuazon
Singh
Reference
et
et
et
and
et
et
et
Westberg
al.
al
al
(1982)
. (1981a,
. (1981a)
Grosjean (1979)
al
al
al.
et
. (1978)
. (1980)
(1979)
al. (1978)
Brennan (1980)
Not available.
Source: Derived from Altshuller (1983).
chapter 6.
For primary references, see
It must be emphasized that information presented in chapter 5 clearly
shows that no one method can quantitatively and reliably measure 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 5 of this document.
13.3 HEALTH EFFECTS IN THE GENERAL HUMAN POPULATION
13.3.1 Clinical Symptoms
A close association has been observed between the occurrence of respira-
tory symptoms and changes in pulmonary function in response to acute exposure
to 0- (Chapter 11). This association holds for both the time-course and
magnitude of effects. In studies of repeated exposure to 0.,, symptoms have
*3
generally increased while pulmonary function has diminished on the second to
019JSA/A
13-14
6/26/84
-------
third day of exposure, followed by partial or complete reversal of these
findings on the fourth or fifth day. Insofar as cough and chest pain or
irritation may interfere with the maximal inspiratory or expiratory efforts
required to perform spirometric maneuvers, such associations between symptoms
and function might be expected. To date, epidemiological studies of the
health effects of photochemical air pollution have not been designed specifi-
cally to test the comparative frequency or magnitude of response of symptoms
versus functional changes. Which type of effect is more likely to occur
within the polluted community is uncertain.
The symptoms found in association with clinical exposure to 0^ alone 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 clinical exposures to 0,., even at concen-
trations 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 (National Air Pollution Control
Association, 1970; Altshuller, 1977; National Research Council, 1977; U.S.
Environmental Protection Agency, 1978; Okawada et al., 1979).
There is also evidence to suggest that for a specified concentration of
0- other symptoms, as well, are more likely to occur in populations exposed to
ambient air pollution than in subjects exposed in chamber studies, especially
if 0_ is the sole pollutant administered in the chamber studies. The symptoms
•j
may be indicative of either upper or lower respiratory tract irritation. In
epidemiological studies, cough has been reported at 0.08 ppm 0,. (Zagraniski
et al., 1979) and at 0.10 ppm oxidants (Hammer et al., 1974; Makino and Mizoguchi,
1975). Some subjects have experienced cough during clinical exposure to
0.12 ppm 03 (McDonnell et al. , 1983). Nose and throat irritation have been
reported in community studies in association with 0.10 ppm oxidants (Okawada
et al. , 1979; Makino and Mizoguchi, 1975), but not at or below 0.15 ppm 0» in
laboratory studies.
Between 0.15 and 0.30 ppm 0-, a variety of both respiratory and non-
respiratory symptoms have been reported in controlled exposures. They include
throat dryness, difficulty or pain in inspiring deeply, chest tightness,
substernal soreness or pain, wheezing, lassitude, malaise, and nausea (DeLucia
and Adams, 1977; Kagawa and Tsuru, 1979b; McDonnell etal., 1983). Most
"symptom scores" have been positive at concentrations of 0.2 ppm 0, and above;
only two studies reported finding no symptoms at 0.3 ppm 0- (Bennett, 1962;
019JSA/A 13-15 6/26/84
-------
von Nieding et al., 1977). Symptoms tend to remit within hours after exposure
is ended. Relatively few subjects have reported persistence of symptoms
beyond 24 hours.
There are several possible explanations for the apparent differences in
symptomatic effects between epidemiological and controlled human studies.
They include differences in subject populations (e.g., children were subjects
in two of the epidemiological studies but have not been studied clinically);
factors affecting the perception of symptoms in one type of study compared to
the other; or differences in the methods used to assess symptoms. Alternative-
ly, the presence of highly reactive chemical species in polluted ambient air
might be chiefly responsible for the symptoms or might interact synergis-
tically with CL to initiate the symptoms.
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
results obtained immediately after exposure have been noteworthy for their
general consistency across studies. Moreover, as noted earlier, the associa-
tion between changes in symptoms and objective functional tests has been
impressive. Symptoms are therefore considered as useful adjuncts in assessing
the effects of 0., and photochemical pollution, particularly if combined with
objective measurements.
*
13.3.2 Pulmonary Function at Rest and with Exercise and Other Stresses
13.3.2.1 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 hours showed no decrements or only very
small (< 10 percent) decrements in FVC (Silverman et al. , 1976; Folinsbee
et al., 1975; Bates et al., 1972), vital capacity (Silverman et al., 1976;
Folinsbee et al., 1975), FEV^ and FRC (Silverman et al., 1976). More discri-
minating flow-derived variables, such as the maximal expiratory flow at 50 per-
cent VC (FEF 50%) and the maximal expiratory flow at 25 percent VC (FEF25%),
were affected to a greater degree, showing decreases of up to 30 percent from
control in sensitive individuals at 0.75 ppm 0- (Bates et al. , 1972; Silverman
019JSA/A 13-16 6/26/84
-------
et al., 1976). Specific tests for bronchoconstriction did not appear to be
more sensitive in detecting ozone-induced changes than the spirometric tests.
Airway resistance (R ) and pulmonary resistance (R. ) increased only minimally
cLW L
following 2-hr exposures to 0.6 to 0.75 ppm 0~ (Golden et al. , 1978 and 0.75
ppm 03 (Silverman et al. , 1976). More specific measures of pulmonary mechanics
exhibited a similar lack of response. Static compliance (C .) remained virtual-
S v
ly unchanged, whereas dynamic compliance (C . ) and the maximum static elastic
recoil pressure of the lung (P. ) showed some borderline effects (Bates
*cp max
et al. , 1972). No consistent effects of ozone were observed in the most
sensitive region of the respiratory system, the gas-exchange zone of the lung.
Breathing 0.6 to 0.8 ppm 0» for 2 hr reduced markedly diffusion capacity
(D. ) across the alveolo-capillary membrane (Young et al. , 1964); however,
the mean fractional 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 in-
creases as the inhomogeneity in the distribution of ventilation increases, was
not significantly altered by 0~ inhalation (Silverman et al., 1976).
More recent studies of at-rest exposures to 0_ lasting 2 to 4 hr have
demonstrated decrements (< 11 percent) in forced expiratory volume and flow
occurring at and above 0.5 ppm of 0- (Folinsbee et al., 1978; Horvath et al.,
1979). Airway resistance was not changed at these 0- concentrations. Breath-
O
ing 0^ at rest at concentrations < 0.5 ppm did not significantly impair pul-
monary function (Folinsbee et al. , 1978), although the occurrence of some
Og-related pulmonary symptoms has been suggested (Konig et al., 1980), indica-
ting that there may be selective sensitivity in some subjects.
13.3.2.2 Exposures With Exercise. Minute ventilation (VV) during exposure is
considered to be one of the principal modifiers of the magnitude of response
to 0_. The most convenient physiological procedure for increasing Vp is to
exercise exposed individuals either on a treadmill or bicycle ergometer.
Adjustment by the respiratory system to an increased work load is characterized
by increased frequency and depth of breathing. Consequent increases in VF not
only increase the overall volume of inhaled pollutant, but such ventilatory
patterns also promote a deeper penetration of ozone into the peripheral lung
structures, which are most sensitive to injury and which favor a greater
absorption of ozone. These processes are further enhanced at higher workloads
019JSA/A 13-17 6/26/84
-------
(Vp > 35 L/min), since the mode of breathing will most likely change from
nasal to oronasal or oral only (Niinimaa et a!., 1980). Such a redistribution
of the respiratory airflow, with an increasingly greater portion of the total
minute volume being inhaled orally as the ventilation increases (Niinimaa
et al., 1981), may proportionally augment the ozone burden of the airways.
The overall amount of inhaled ozone depends on minute ventilation, ozone
concentration, and duration of exposure. The effective dose of Q~., which is a
composite index of these three determinants (Silverman et al., 1976; Folinsbee
et al., 1978; Adams et al., 1981) can be used to predict group mean decrements
in pulmonary function following 0- exposure. However, considering the great
variability in individual responses to 03 exposure, prediction equations that
use some form of effective dose may not be adequate for predicting differences
in responsiveness to 0_ among individuals.
Even in well-controlled experiments on a homogenous group of subjects,
physiological responses to the same work and pollutant loads will vary widely
among individuals (Chapter 11). The nature of the primary mechanisms inducing
such a spectrum of responses is unclear. Despite such large interindividual
variability, the magnitude of (individual) responses, assessed in terms of
decrements in pulmonary function, correlates reasonably well with the severity
and frequency of subjective symptoms; but the positive association with both
GO concentration and exercise stress is much stronger (Folinsbee et al., 1978;
McDonnell et al., 1983; Haak et al., 1984). Generally, within-individual
variations in response, both subjective and objective, appear to be almost an
order of magnitude smaller than the variations observed between subjects.
The post hoc categorization of subjects into "responders/sensitives" and
"nonresponders/nonsensitives" is based on arbitrary criteria that vary from
study to study (Bell et al., 1977; Gliner et al., 1983; Haak et al., 1984) and
is clearly open to criticism. Using this approach, up to 20 percent of subjects
in the studies cited were classified as more reactive to ozone than the rest
»
of the cohorts. Even under very strenuous exposure conditions (Vr - 45-57
L/min at 0.4 ppm), when lung function in the most responsive yet apparently
healthy individuals was severely impaired (FEV =40 percent of control), the
least responsive subjects showed decrements of less than 10 percent; and the
average decrement was 26 percent (Haak et al., 1984; Silverman et al., 1976).
*
Moderate exercise (VV = 34 L/min) in an atmosphere containing 0.4 ppm ozone
may reduce the average FEV-, of healthy subjects by 17 percent (3 to 50 percent).
019JSA/A 13-18 6/26/84
-------
The same level of exercise in 0.24 ppm ozone elicits mean decreases in FVC,
FEV.., and FEF?c-_7c of H» 14, and 12 percent, respectively. Even very low 0,
concentrations (0.12 ppm) will induce measurable changes in lung function of
more responsive individuals; reported decrements in FVC, FEV and FEF?I- 75 did
not exceed 20 percent of control (McDonnell et al., 1983).
The maximum response can be observed within 5 to 10 min following the end
of each exercise period (Folinsbee et al., 1977b; Haak et al., 1984). During
subsequent rest periods, however, the augmented response is not maintained and
partial improvement, but not a return to the preexercise level, in lung function
can be observed even though the subject still inhales ozone (Folinsbee et al.,
1977b). Continuous exercise equivalent in duration to the sum of intermittent
exercise periods at comparable ozone concentrations (0.20 to 0.40 ppm) and
minute ventilations (approximately 60 to 80 L/min) seems to elicit about the
same changes in pulmonary function (Adams et al., 1981; Adams and Schelegle,
1983). 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 hours, pulmonary function improves more than 50 percent (Bates
and Hazucha, 1973); this is followed by a much slower recovery that is usually
completed within 24 hours. There is some indication, however, that recovery
from sequential exposures may take longer than 24 hours (Folinsbee et al.,
1980). In some individuals, despite apparent functional recovery, other
regulatory systems may still exhibit abnormal responses when stimulated; e.g.,
airway hyperreactivity might persist for days (Golden et al., 1978; Kulle et
al., 1982b).
In evaluating group response, the magnitude of lung functional changes is
positively associated with the level of exercise and ozone concentration.
Heavy intermittent exercise (V£ > 44 L/min) at high ozone concentrations (0.4
to 0.6 ppm) significantly reduces FVC by more than 10 percent, FEV by almost
20 percent, and FEF_ ?5 by nearly 30 percent, on the average. The comparable
exercise stress at lower ozone concentrations (0.12 to 0.20) decreases the
above lung function variables between 3 and 7 percent, with these decrements
bordering on statistical significance.
The effects of intermittent exercise and 0 concentration on the magnitude
*5
of average pulmonary function response (e.g., FEV-) during 2-hr exposures are
best illustrated in Figures 13-2 through 13-6. The data base for these concen-
tration-response curves comprises studies published between 1973 and 1983
019JSA/A 13-19 6/26/84
-------
N5
O
CT>
\
r\>
(Ti
oo
120
110
4,6,7,11.14,17
©20
20
50
40
LIGHT EXERCISE
K25 Umin)
r = 0.87
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
OZONE CONCENTRATION, ppm
Figure 13-2. The effects of ozone concentration on 1-sec forced expiratory volume dur-
ing 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 per-
cent confidence limits. Individual means (± standard error) are given in Table 13-3
along with specific references.
-------
c.
c/i
00
(V)
en
\
r\>
en
oo
c
V
o
<5
Q.
HI
O
cc
o
cc
a.
X
o
cc
O
u.
O
LU
(O
120!
110
1001
90
80
70
60
50
3,4,5,7.13,15,18
40
20
MODERATE EXERCISE
(26-43 L/min)
r = 0.85
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
OZONE CONCENTRATION, ppm
Figure 13-3. 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 13-3 along with specific references.
-------
o
M
UD
00
I
ro
ro
CTl
\
ro
en
CO
c
0>
o
-------
o
»->
vo
C-,
in
120
110
CO
i
INJ
CO
cr>
\
l\>
cn
00
• 4
50
40
VERY HEAVY EXERCISE
O64 L/min)
r = 0.94
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
OZONE CONCENTRATION, ppm
Figure 13-5. 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 size, was used to plot a concentration-response curve
with 95 percent confidence limits. Individual means (±standard errorjare given in Table
13-3 along with specific references.
-------
o
M
vD
CO
I
l^U
110
0)
u
1 10°
LU
1 9«
>
cc
0
£ 80
cc
0.
X
LU
FORCED
2
0 60
LU
CO
r-
50
40
_
^**"*
^rs
__
—
ro
CD
VERY HEAVY
EXERCISE
LIGHT
EXERCISE
MODERATE
EXERCISE
' HEAVY \.
EXERCISE \
\
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
OZONE CONCENTRATION, ppm
Figure 13-6. Group mean decrements in 1-sec forced expiratory volume during 2-hr
ozone exposures with different levels of intermittent exercise: light (VE < 25 L/min);
moderate (Vg -26 43 L/min); heavy (Vg = 44-63 L/min); and very heavy (Vg ^ 64 L/min).
Concentration-response curves are taken from Figures 13-2 through 13-5.
-------
(Table 13-3). In order to compile as complete a data base as possible, comple-
mentary data were obtained from published technical reports and from conference
proceedings. The original articles often reported data that were either
incomplete or that were presented only in graphical form. Only those studies
that reported or for which it was possible to calculate, from additional
sources, all five critical variables (minute ventilation, 0., concentration,
exposure duration (90 to 150 min), cohort size, and at least FEV,) were included
in the data base. Calibration methods for ozone measurements differed among
the studies from which these data were obtained, but the curve parameters
proved insensitive to corrections for biases between methods. Thus, the 0-
concentrations as reported in the original articles were used. To minimize
inhomogeneity of data, studies that did not utilize the intermittent exercise
protocol were not included in the calculations.
Despite methodological and protocol differences among various studies, it
was possible to group the reported averaged data by workloads into four cate-
gories of exercise: light (V_ < 25 L/min), moderate (Vp = 26 to 43 L/min),
heavy (V£ = 44 to 63 L/min), and very heavy (V^ > 64 L/min). Subsequent
curve-fitting by means of a quadratic regression equation, weighted by sample
size, produced clearly differentiated response curves (Figures 13-2 through
13-5) with high correlation coefficients (r = 0.85 to 0.97). The 95 percent
confidence limits for any of the curves did not exceed +5 percent of response.
At 0.6 ppm 03, the expected average decrement in FEV, of lightly exercising
subjects is 12 percent (Figure 13-2), while heavy exercise under comparable
conditions may lower the FEV, by 27 percent (Figure 13-4). 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 magni-
tude. For example, the decrements in FVC were smaller, while decrements in
FEF25-75 were Skater, for a given Og concentration, than decrements in FEV .
The Raw shows a similar concentration-dependent, positively correlated response
(r = 0.540).
A comparison of the respective combinations of minute ventilation (V )
and ozone concentration that induce the same amount of functional change,
e.g., a 10 percent decrease in FEV^ further illustrates the interdependence
of these two determinants. From the curves in Figure 13-6 it can be seen that
very heavy exercise at 0.24 ppm, heavy exercise at 0.43 ppm, moderate exercise
at 0.48 ppm, or light exercise at 0.56 ppm 03 can all be expected to reduce
019JSA/A 13-25 6/26/84
-------
TABLE 13-3. EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC FORCED EXPIRATORY VOLUME
VjJ
I
Ozone
concentration
ug/m3
LIGHT
1470
1470
1470
1470
1470
0
196
588
980
0
392
823
0
784
490
725
980
784
784
0
0
725
725
1470
1470
ppm
EXERCISE
0.75
0.75
0.75
0.75
0.75
0.0
0.1
0.3
0.5
0.00
0.20
0.466
0.0
0.4
0.25
0.37
0.50
0.4
0.4
0.00
0.00
0.37
0.37
0.75
0.75
Measurement,
method
MAST, NBKI
CHEM, NBKI
CHEM, NBKI
UV, UV
CHEM, GPT
CHEM, NBKI
CHEM, NBKI
MAST, NBKI
Exposure
duration,
min
90
90
120
120
120
120
120
120
120
125
125
125
120
120
120
120
120
135
135
120
120
120
120
120
120
Number of
subjects
10
10
10
10
11
10
10
10
10
21
21
21
15
15
6
5
7
6
9
6
6
6
6
6
6
Minute
ventilation,
L/m i n
22.5
22.5
22.5
22.5
20.0
11.2
11.2
9.6
11.8
22.6
22.6
22.6
10.0
10.0
20.0
20.0
20.0
20-0
20.0
22.0
22.0
22.0
22.0
22.0
22.0
FEVt.0,d
%
84.6 ±1.8
81.6 ± 2.2
79.3 ± 2.7
76.6 ± 2.7
77.2 ± 4.4
99.0 ± 15.1
98.4 ± 15.7
99.0 ± 16.1
92.6 ± 17.1
100.3 ±0.8
96.9 ± 1.3
81.6 ±2.7
99.4 ± 5.0
100.0 ±5.3
100.3
97.7
95.3
99.5
95.5
101.4 ±1.7
100.5 ±3.3
92.6 ± 2.3
96.1 ±0.7
73.3 ± 6.8
72.4 ± 4.7
Reference
(2) Bates and Hazucha, 1973
(3) Folinsbee et al . , 1977b
(4) Folinsbee et al . , 1978
(6) Gliner et al. , 1983
(7) Haak et al . , 1984
(8) Hackney et al . , 1975c
(9) Hackney et al. , 1976
(11) Hazucha et al. , 1973
-------
TABLE 13-3. EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC FORCED EXPIRATORY VOLUME (continued)
Ozone3
concentration Measurement >c
ug/m3
431
451
470
784
784
784
1215
1235
0
0
490
490
980
980
1470
1470
0
0
392
392
784
941
1509
ppm method
0.22 MAST, NBKI
0.23
0.24
0.40
0.40
0.40
0.62
0.63
0.00 CHEM, NBKI
0.00
0.25
0.25
0.50
0.50
0.75
0.75
0.0 UV, NBKI
0.0
0.2
0.2
0.40
0.48
0.77
Exposure
duration,
min
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
140
140
140
140
120
120
120
Number of
subjects
4
4
4
4
4
4
4
4
8
7
8
7
8
7
8
7
12
12
12
12
5
5
5
Minute
ventilation, FEV^Q,
L/min % Reference
22.5
22.5
22.5
22.5
22.5
22.5
22.5
22.5
8.4
8.4
8.2
8.2
7.8
7.8
7.7
7.7
20.0
20.0
20.0
20.0
11.0
11.0
11.0
101.5 (12) Hazucha et al . , 1977
93.7 ± 1.4
96.0 ± 3.1
93.9 ± 2.5
91.9 ± 5.9
89.5
88.0
86.0
101.0 (14) Horvath et al., 1979
102.3
101.6
98.3
96.9
91.4
89.2
81.0
101.2 (17) Linn et al . , 1979
99.8
101.5
99.5
101.7 + 2.8 (20) Silverman et al . , 1976
101.4 ±8.3
90.4 ± 4.0
-------
TABLE 13-3. EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON I- SEC FORCED EXPIRATORY VOLUME (continued)
Ozone3
concentration Measurement >c
ug/m3
ppm method
Exposure
duration,
min
Number of
subjects
Minute .
ventilation, FEVn.A,
L/min
% Reference
MODERATE EXERCISE
UJ
i
NJ
oo
0
1470
0
0
0
0
0
0
980
980
980
980
980
980
0
196
588
980
0.00 MAST, NBKI
0.75
0.0 CHEM, NBKI
0.0
0.0
0.0
0.0
0.0
0.5
0.5
0.5
0.5
0.5
0.5
0.0 CHEM, NBKI
0.1
0.3
0.5
120
120
100
100
118
118
125
125
100
100
118
118
125
125
120
120
120
120
3
3
8
6
8
6
8
6
8
6
8
6
8
6
10
10
10
10
25.0
25.0
36.0
35.0
36.0
35.0
36.0
35.0
33.3
39.2
33.3
39.2
33.3
39.2
32.6
32.3
31.0
32.1
104.9 (1) Bates et al., 1972
69.7
96.5 ± 4.3 (3) Folinsbee et al . , 197/b
98.7 -•- 6.6
99.4 + 2.7
96.4 ± 5.5
98.6 ±6.5
100.7 ±5.5
89.9 ± 5.9 j
81.1 ± 6.8 |
87.8 ± 6.4
81.9 ± 5.6
92.0 ± 6.6
92.3 ± 5.8
99.4 ± 13.1 (4) Folinsbee et al., 1978
101.9 ± 13.8
95.4 ± 16.0
87.3 ± 16.6
-------
TABLE 13-3. EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC FORCED EXPIRATORY VOLUME (continued)
Ozone3
concentration Measurement 'c
ug/m3
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
392
392
392
392
392
666
666
666
666
666
902
902
902
902
902
ppm method
0.00 CHEM, NBKI
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.20
0.20
0.20
0.20
0.20
0.34
0.34
0.34
0.34
0.34
0.46
0.46
0.46
0.46
0.46
Exposure
duration,
min
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
Number of
subjects
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
Minute .
ventilation, FEVj.Q,
L/min % Reference3
32.0
32.0
32.0
32.0
32.0
32.0
30.0
30.0
30.0
30.0
31.0
31.0
31.0
31.0
31.0
31.0
31.0
31.0
31.0
31.0
32.0
32.0
32.0
32.0
32.0
30.0
30.0
30.0
30.0
30.0
99.2 ±4.9 (5) Folinsbee et al . , 1980
99.7 ±4.5
101.3 ±4.4
101.1 ±4.4
99.6 ± 4.3
100.7 ± 4.8
101.0 ±4.9
100.3 ±4.5
99.8 ± 4.7
100.6 ±4.7
101.4 ± 4.5
101.9 ±5.1
101.9 ±5.3
100.9 ±5.4
100.2 ±5.1
101.8 ±4.8
102.5 ± 4.8
102.8 ± 4.7
102.2 ±4.8
101.3 ±4.8
101.3 ±4.6
100.6 ±4.3
99.7 ±4.6
96.9 ± 4.8
95.5 ± 4.3
99.8 ± 5.1
95.0 ± 4.8
93.3 ± 6.0
87.0 ± 6.0
91.3 ± 5.0
-------
TABLE 13-3. EFFECTS OF INTI
Ozone3
concentration Measurement >c
ug/ms ppm method
0
0
784
725
725
0
0
1176
1176
0
1058
0
921
921
921
921
921
921
784
941
1509
0.0 CHEM, GPT
0.0
0.4
0.37 CHEM, NBKI
0.37
0.0 CHEM, NBKI
0.0
0.6
0.6
0.00 UV, UV
0.54
0.00 UV, NBKI
0.47
0.47
0.47
0.47
0.47
0.47
0.40 MAST, NBKI
0.48
0.77
EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC FORCED EXPIRATORY VOLUME (continued)
Exposure
duration,
min
120
120
120
120
120
120
120
120
120
125
125
120
120
120
120
120
120
120
120
120
120
Number of
subjects
29
15
15
4
4
14
14
14
14
24
24
11
11
11
11
11
11
11
5
5
5
Minute
ventilation,
I/min
35.0
35.0
35.0
25.0
25.0
35.0
35.0
35.0
35.0
30.0
30.0
30.0
30.0
30.0
30.0
30.0
30.0
30.0
27.
27.
27.5
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
99.7 ±1.0
78.9 ±3.0
100.8
88.7
91.4
84.8
87.4
86.6
86.5
94.6 ± 3.5
95.1 ± 1.9
79.8 ± 6.4
Reference
(7) Haak et al. , 1984
(10) Hackney et al., 1977b
(13) Hazucha, 1981
(15) Horvath et al. , 1981
(18) Linn et al., 1982
(20) Silverman et al., 1976
-------
TABLE 13-3. EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC FORCED EXPIRATORY VOLUME (continued)
Ozone
concentration Measurement >c
ug/m3
HEAVY
0
196
588
980
0
0
784
784
0
1176
784
784
941
941
0
784
ppm method
EXERCISE
0.0 CHEM, NBKI
0.1
0.3
0.5
0.0 CHEM, GPT
0.0
0.4
0.4
0.0 CHEM, NBKI
0.6
0.40 MAST, NBKI
0.40
0.48
0.48
0.0 CHEM, NBKI
0.4
Exposure
duration,
min
120
120
120
120
120
120
120
120
120
120
90
120
90
120
120
120
Number of
subjects
10
10
10
10
15
15
15
15
20
20
5
5
5
5
10
12
Minute
ventilation, FEVX
L/min %
50.4
49.8
56.3
51.4
57.0
57.0
57.0
57.0
45.0
45.0
46.5
46.5
44.7
44.7
55.3
55.3
100.8 ±
100.5 ±
93.7 ±
85.8 ±
98.7 ±
101.9 ±
90.6 ±
95.6 ±
102.5
71.6
96.0
94.3
89.3
84.4
98.8 ±
92.3 ±
d
• o»
16.3
16.2
17.5
19.5
4.1
4.3
4.9
5.4
5.6
4.8
Reference
(4) Folinsbee et al., 1978
(7) Haak et al . , 1984
(16) Ketcham et al . , 1977
(20) Silverman et al., 1976
(21) Stacy et al . , 1983
-------
TABLE 13-3. EFFFCTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC FORCED EXPIRATORY VOLUME (continued)
Ozone
concentration
ug/m3 ppm
VERY
0
196
588
980
^ 0
£ 235
353
470
588
784
b Exposure
Measurement ' duration, Number of
method min subjects
Mi nute
ventilation, PLV1.0,
L/mi n %
d
HEAVY EXERCISE
0
0
0
0
0
0
0
0
0
0
.0
.1
.3
.5
.00
.12
.18
.24
.30
.40
CHEM, NBKI 120
120
120
120
CHEM, UV 150
150
150
150
150
150
10
10
10
10
22
22
20
21
21
29
66.
71.
68.
67.
66.
68.
64.
64.
65.
64.
8
2
4
3
?
0
6
9
4
3
99.
97.
92.
76.
98.
95.
93.
85.
83.
83.
7
4
3
1
9
7
6
6
2
0
± 13
± 17
± 12
± 11
•*: ?.
± 3.
± 3.
± 3.
± 3.
± 3.
•
4
2
4
4
8
7
7
6
7
9
Reference
(4) Folinsbee et al., 1978
(19) McDonnell et al., 1983
References are listed alphabetically within each exercise category; reference number refers to data points on
Figures 13-2 through 13-5.
Measurement method: MAST = Kl-coulometric (Mast meter); CHFM = gas-phase chemi1uminescence; 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.
3
"Subjects exposed to 0.42 and 0.50 ppm ozone were treated as the same subject group (Gliner et al., 1983).
-------
FEV by 10 percent, on the average. The curves also indicate that there is no
threshold concentration; i.e., the concentration below which no measurable
effects are induced as assessed by a mean response. Furthermore, the 95
percent confidence limits show that even very low 0_ copcentrations (<0.2 ppm)
will induce some functional decrements. For example, as Figure 13-4 shows,
one may be 95 percent confident that very heavy exercise during exposure to
0.2 ppm ozone will decrease FEV by 5 to 12 percent; and during exposure to
0.1 ppm, by 1 to 7 percent, on the average. Thus, at any ozone concentration
there will presumably be healthy individuals who will show effects of the
exposure.
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., 1979). In one study, very heavy
exercise (V_ > 64 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 inconsis-
tent (Folinsbee et al., 1975). The extent of ventilatory (VT, fR) and respira-
tory metabolic changes (V0?) observed during or following the exposure appears
to have been related to the magnitude of pulmonary 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.
13.3.2.3 Environmental Stresses. Environmental conditions such as heat and
relative humidity (rh) may enhance subjective symptoms and physiological
impairment following 0 exposure. A hot (31 to 40°C) and/or humid (85 percent
<3
rh) environment, combined with exercise in the 0_ atmosphere, has been shown
O
to reduce forced expiratory volume more than similar exposures at normal room
temperature and humidity (25°C, 50 percent rh) (Folinsbee et al. , 1977b;
Gibbons and Adams, 1984). Modification of the effects of 03 by heat or humidi-
ty stress may be attributed to increased ventilation which, like exercise,
increases the overall volume of inhaled pollutant and promotes greater penetra-
tion into the peripheral areas of the lung.
019JSA/A 13-33 6/26/84
-------
13.3.3 Other Factors Affecting Pulmonary Response to Ozone
13.3.3.1 Age. Although changes in growth and development of the lung with
age have been postulated as one of many factors capable of modifying respon-
siveness to 0.>, studies have not been designed to test adequately for effects
of CL in different age groups. An enhanced responsiveness of the young to
ozone exposure has been suggested from field and epidemiology studies in which
decreases in lung function were reported at 0,, concentrations of 0.08 to 0.15
O
ppm (Kagawa and Toyoma, 1975; Kagawa et al. , 1976; Kagawa, 1983; Lebowitz et
al., 1982, 1983; Lebowitz, 1984). Symptoms have also been observed in children
exposed to 0.10 ppm oxidant and above (Okawada et al, 1979; Makino and Mizoguchi,
1975). No comparable data are available, however, from controlled human
studies, since possible age differences in response to 0_ have not been explored
O
systematically in controlled studies.
The influence of age on responsiveness to ozone is also difficult to
assess from animal studies. Very few age comparisons have been made within a
single study. Raub et al. (1983), Barry (1983), and Barry et al. (1983)
studied pulmonary function and morphometry of the proximal alveolar region in
neonatal (1-day-old) and 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 re-
sponses were observed in the neonates and adults, but they were not major.
Generally, neonates and adults were about equally responsive.
The stage of development at initiation of exposure may be an important
determinant of age responsiveness. A rat is generally considered to be adult
(e.g., sexually mature) at about 60 days of age, while alveolarization of the
lungs is complete at roughly 40 days of age. Stephens et al. (1978) exposed
rats of various ages (1 to 40 days old) to 0.85 ppm ozone continuously for 1,
2, or 3 days. Rats exposed prior to weaning (20 days old) had few or no
effects on lung structure. For rats older than 20 days, centriacinar lesions
increased progressively, reached a plateau at 35 days of age, and persisted.
Biochemical studies (antioxidant metabolism and oxygen consumption in the
lung) of similar design have been conducted by Lunan et al. (1977), Tyson et
al. (1982), and Elsayed et al. (1982). In the first two studies, animals
were exposed to 0.9 ppm ozone for 96 hr; in the latter study, subjects were
exposed to 0.8 ppm ozone for 92 hr. Generally, in rats exposed prior to
weaning (about 20 days old), activities of enzymes decreased; in those around
weaning age there was no change; and in more mature young rats (35 to 90 days
019JSA/A 13-34 6/26/84
-------
old), enzyme activities increased. Numerous other studies of adult rats using
similar methods show increases in these activities. Lunan et al. (1977)
observed a peak in the response at 35 days of age, similar to that of Stephens
et al. (1978). In the studies of Elsayed et al. (1982), the 7- and 12-day-old
rats had 60 percent mortality; the older rats had no mortality. Lunan et al.
(1977) used an additional exposure regimen in which rats aged 10, 15, 25, and
32 days were exposed up to 32 to 34 days of age. Thus, the animals had differ-
ent lengths of exposure. Effects were observed only in the animals 25 and
32 days old. The greatest magnitude of the effect was observed at 32 days of
age, regardless of the absolute length of exposure.
Interpretation of these animal studies may be confounded by the exposure
techniques used. In some studies, neonates and mothers were exposed together
and the possibility exists that the ozone concentration was different in the
breathing zone of the neonates. In the Raub et al. (1983) and Barry et al.
(1983) studies, this potentially confounding factor was minimized. In other
studies, neonates were exposed without mothers. It is not known whether their
breathing parameters may have been influenced from the consequent stress.
Even without these factors, the dosimetry of ozone in the different age groups
is unknown. From the reported studies it appears that rats about 35 days of
age respond equivalently to adult animals when exposed to ozone. Responsive-
ness of rats prior to weaning (about 20 days old) is confounded.
13.3.3.2 Sex. Sex differences in responsiveness to ozone have not been
adequately studied. A small number of female subjects have been exposed 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). Lung function of women, as assessed
by changes in FEV, „, appears to be affected more than that of men under
similar exercise and exposure conditions, but the differences have not been
analyzed systematically. Further research is needed to determine whether
differences in lung volumes or differences in exercise capacity during exposure
may lead to sex differences in responses to 0,.
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 of sex sensitivity to ozone from
animal data virtually impossible. The only exception is a study of effects of
ozone in increasing pentobarbital-induced sleeping time (Graham et al., 1981).
019JSA/A 13-35 6/26/84
-------
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.
13.3.3.3 Smoking Status. Differences between smokers and nonsmokers have
been studied often, but the data are not documented well and are often confus-
ing. Published results indicate a discrepancy in findings. Hazucha et al.
(1S73) and Bates and Hazucha (1973) appear to have demonstrated greater responses
(FVC, MMFR) in nonsmokers at 0.37 ppm 0 but the responses were reversed at
O
0.75 ppm (RV, FEVI} Vmax50, and MMFR). Kerr et al. (1975) observed greater
responses (FRC, SG , R, , FEV, and symptoms) in nonsmokers at 0.5 ppm C_ for
dw L, O
6 hr. DeLucia et al. (1983) observed similar results for VC, FEV.. , MMFR, fD,
1 D
and VT at 0.3 ppm 0_ (1 hr, CE). Kagawa and Tsuru (1979a) stated that the
I J
effects of ozone among nonsmokers were greater for the 0.5 than for the 0.3 ppm
0- exposure levels (2 hr); a later study (Kagawa, 1983) showed that nonsmokers
O
had a greater response (SG ) to 0.15 ppm (2 hr, IE). Shephard et al. (1983)
QW
found a slower and smaller change in spirometric variables in smokers at 0.5
and 0.75 ppm (2 hr, IE). None of these controlled studies have examined the
effects of different amounts of smoking. Epidemiological studies have detected
an increase of symptoms (cough, nose, and eye irritation) in heavy smokers
compared to others at 0.08 ppm 0« and above (Zagraniski et al. , 1979). The
general trend, however, is to imply that smokers are less sensitive than
nonsmokers.
13.3.3.4 Nutritional Status. Posin et al. (1979) found that human volunteers
receiving 800 (about 4 times the recommended daily units) or 1,600 (a very high
supplement) IU vitamin E for 9 weeks as a supplement showed no differences in
blood biochemistry from unsupplemented volunteers when exposed to 0.5 ppm ozone
for 2 hours. The biochemical parameters studied included red cell fragility,
hematocrit, hemoglobin, glutathione concentration, acetylcholinesterase,
glucose-6-phosphate dehydrogenase, and lactic acid dehydrogenase activities.
Hamburger and Goldstein (1979) studied the agglutination of rat red cells by
the lectin concanavalin A after jji vivo exposure to 0.5 to 2 ppm ozone for
2 hours or incubation i_n vitro with 1 ppm ozone for 2 hours. Agglutination
019JSA/A 13-36 6/26/84
-------
was decreased by ozone exposure, but the number of concanavalin A binding
sites on red cells was not decreased. Hamburger et al. (1979) also studied
the effects of ozone exposure on the agglutination of human erythrocytes by
concanavalin A. As with rat erythrocytes, pre-incubation with malonaldehyde,
an oxidation product of polyunsaturated fatty acids, decreased concanavalin A
agglutination of red cells exposed i_n vitro to ozone. Red cells obtained from
29 subjects receiving 800 IU vitamin E (a high supplement) or a placebo were
exposed to 0.5 ppm ozone for 2 hours. 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 indices of exposure to < 1 ppm of 0, measured biochemically
because it is involved in antioxidant metabolism. Increases in 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 dietary vitamin E fed to the rats
influenced the ozone-induced increase of this system. For example, when the
diet of rats had 66 ppm of vitamin E, increased glutathione peroxidase activity
was observed at 0.2 ppm of 0_; with 11 ppm of vitamin E, increases occurred at
*5
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).
Morphological studies of ozone-exposed vitamin E-deficient or supplemented
rats have been undertaken to correlate the biochemical findings with morpholog-
ical alterations (Plopper et al. , 1979; Chow et al. , 1981; Schwartz et al. ,
1976; Sato et al. , 1976, 1978, 1980). Scanning and transmission electron
microscopy were clearly shown to be better than light microscopy for visualiza-
tion of the ozone lesions. Lesions were worse in vitamin E-deficient or
marginally supplemented rats than in highly supplemented rats, supporting the
finding from mortality (Donovan et al. , 1977) and biochemical studies that
vitamin E is protective. Despite the presence of vitamin E in the diets of
these animals, the morphological lesion resulting from ozone exposure was
unchanged. Vitamin E thus alters the rate and extent of toxicity, but not the
lesion itself.
019JSA/A 13-37 6/26/84
-------
The difference in response between animals and man with regard to the
protective effects of vitamin E against ozone toxicity may lie in the pharmaco-
kinetics 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 long times. Human
subjects were exposed for shorter times and lower concentrations because of
ethical considerations. Thus, the protective effects of vitamin E might
likewise be demonstrated in man, but might require longer times and higher
ozone exposures. In addition, animal studies are generally conducted with a
deficient diet (0 ppm vitamin E) group for comparison. The respective human
group would very likely not have had a substantial deficiency. Thus, the
antioxidant properties of vitamin E in preventing ozone-initiated peroxidation
j_n vitro are well demonstrated and the protective effects j_n vivo are clearly
demonstrated in rats and mice. No evidence indicates, however, that man would
benefit from increased vitamin E intake relative to ambient ozone exposures.
Further, vitamin E protection is not absolute and can be overcome by continued
ozone exposure. The vitamin E effects do support the general idea, however,
that lipid peroxidation is involved in ozone intoxication.
13.3.3.5 Red Blood Cell Enzyme Deficiencies. The enzyme glucose-6-phosphate
dehydrogenase (G-6-PD) is essential for the function of the glutathione peroxi-
dase system in the red blood cell (RBC), 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 peroxidation (see
Section 13.5.1). Therefore, Calabrese et al. (1977) has postulated that
individuals with a hereditary deficiency of G-6-PD may be at-risk to signifi-
cant hematological effects from CL exposure. However, there have been too few
studies performed 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 and rats.
Although this species comparison is based on a very limited data base, the
authors point out the importance of developing animal models that can accurate-
ly predict the response of G-6-PD-deficient humans to oxidant stressor agents
019JSA/A 13-38 6/26/84
-------
such as 0,. This group has suggested the use of the C57L/J strain of mice and
O
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-deficient patients. The RBCs of Dorset sheep, however, appear
to be no more sensitive to ozone than normal human RBCs even though the G-6-PD
levels are very low. Further i_n vitro studies (Calabrese et al. , 1982, 1983;
Williams et al. , 1983a,b,c) have demonstrated that the responses of sheep and
normal human erythrocytes were very similar when separately incubated with
potentially toxic CL intermediates, but that G-6-PD-deficient human erythrocytes
were considerably more susceptible. Even if 0- or a reactive product of
00-tissue interaction were to penetrate the RBC after in vivo exposure, it is
o
unlikely that decrements in reduced glutathione levels leading to chronic
hemolytic anemia would be of functional significance for the affected individ-
ual. More research may therefore be needed to determine the susceptibility of
these individuals to 0-.-induced hemolysis from near-ambient CL exposures.
13.3.4 Effects of Repeated Exposure to Ozone
13.3.4.1 Introduction. Ozone toxicity may be mitigated through altered
responses that are functional, biochemical, or morphological in type. For
example, in response to 03 there may be an increase in tissue or cellular
levels of antioxidants, which act to quench free radicals and reduce lipid
peroxidation. At present the underlying mechanisms for this response are
unclear and the effectiveness of such mitigating forces in protecting the
long-term health of the individual against 0, is still uncertain (Bromberg and
Hazucha, 1982).
Reduction of responses associated with repeated exposure to 0., 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" (Chapter 10, Section 10.3.5). Other terms,
including "tachyphylaxis," have also been used to describe this phenomenon.
The distinction, if any, among these terms with respect to 0., and its effects
has never been established in a clear, consistent manner.
13.3.4.2 Development of Altered Responsiveness to Ozone. Successive daily
brief exposures to 0_ (< 0.7 ppm for ~ 2 hrs) induce a typical temporal pattern
of response (Chapter 11, Section 11.3). Maximum functional changes that occur
after the first exposure day (airway resistance, bronchial reactivity tests)
019JSA/A 13-39 6/26/84
-------
(Parrel! et al. , 1979; Dimeo et al., 1981) or the second exposure day (spiro-
metric tests) become progressively attenuated on each of the subsequent days
(Horvath et al., 1981; Kulle et al., 1982b; Linn et al., 1982). By the fourth
day of exposure, the effects are, on the average, not different from those
observed following control (air) exposure. Individuals need between 3 and 7
days to develop full attenuation, with more sensitive subjects requiring more
time (Horvath et al., 1981; 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 in most individuals (Horvath et al., 1981;
Kulle et al., 1982b; Linn et al. , 1982), while partial attenuation might
persist for up to 2 weeks (Horvath et al., 1981). Although symptomatic response
is generally related to the magnitude of the functional response, partial
symptomatic attenuation appears to persist longer, for up to 4 weeks (Linn
et al., 1982). Ozone concentrations inducing only minimal functional effects
(< 0.2 ppm) have not elicited altered responsiveness to 03 in either pulmonary
function or airway responsiveness (Folinsbee etal., 1980; Dimeo et al. ,
1981). The last 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 will
modify the response. Most notably, other pollutants may interact with ozone
to modify changes in the host at lower concentrations during generally more
protracted exposures. The evidence suggesting that Los Angeles residents
exhibit functional attenuation of the response to 0, is sparse and requires
confirmation (Hackney et al., 1976, 1977a,b; Linn et al., 1983).
13.3.4.3 Mechanisms of Altered 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 (cholinergic post-ganglionic pathways) in substantially modifying
the development of altered responsiveness to 0- (Dimeo et al., 1981). Post-
exposure inhalation of atropine (a bronchodilator) blocked completely, though
only transiently, the increase in bronchial reactivity (Golden et al., 1978;
019JSA/A 13-40 6/26/84
-------
Holtzman et al., 1979). Similarly, inhalation of isoproterenol (a bronchodila-
tor) relieved all symptoms and normalized functional changes induced by ozone
(Golden et al. , 1978). Since afferent vagal activity is one of the principal
modifiers of bronchomotor tone, any attenuated changes will be reflected in
airway smooth muscle response and thus in altered airway resistance, which is
used as a convenient index of bronchoconstriction. Besides the vagal component,
numerous other mechanisms might play an important role in the development of
altered responsiveness to 0~; e.g., release of mediators (Linn et al., 1982)
or increased airway mucosa permeability (Davis et al., 1980). The relative
importance and the overall contribution of any of these mechanisms is still
unclear.
Whether laboratory animals develop functional attenuation of responses
similar to that observed in human subjects, as measured by airway resistance
or forced expiratory flow rates, is unreported. In this regard, recent experi-
ments by Gertner et al. (1983a,b,c) are noteworthy, since they offer some
clues on possible mechanisms. They demonstrated that even a brief exposure of
the peripheral airways of dogs to ozone triggered functional response that
appeared to be mediated through both reflex and humoral pathways. The reflex-
mediated response was subject to attenuation after repeated exposure, whereas
the response mediated humorally was not.
As noted previously, functional and symptomatic attenuation of responses
to 03 in human subjects is typically preceded by a limited period during which
effects are slightly exaggerated. The latter period corresponds roughly in
time to the period of heightened responsiveness to a provocative aerosol,
response also caused by QS (Dimeo et al., 1981). Recent experimental evidence
in laboratory animals points to an intimate relationship 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 hyperresponsiveness,
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 hydroxyurea (O'Byrne et al., 1983), or
the neutrophilic infiltration found after ozone exposure was depressed (Fabbri
et al., 1983), no increase was seen in airway responsiveness.
Since many proposed mechanisms of altered responsiveness to CL in humans
O
are difficult if not impossible to investigate, animal studies become essential
in providing necessary confirmatory evidence. Numerous basic metabolic proces-
ses in humans and animals appear to be very similar (Mustafa and Tierney, 1978;
019JSA/A 13-41 6/26/84
-------
Boushey et al. , 1980). Some mechanisms underlying these processes at the
cellular and subcellular level studied extensively in animals do provide some
clues on possible mechanisms in humans. It has been shown that human and
animal leukocytes, pulmonary macrophages, and neutrophils produce superoxide
radicals not only as a product of a vital biological reduction of molecular
oxygen but also as a result of stressful stimuli (Pick and Kersari, 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 inflammatory 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 inflamma-
tion and injury. Reported ozone inactivation of human a-.-proteinase inhibitor
(Johnson, 1980) observed HI vitro and perturbation of lung collagen metabolism
seen i_n vivo in animals (Hussain et al., 1976; Mustafa and Tierney, 1978)
could be factors potentially affecting inflammatory response. Furthermore,
the metabolic attenuation of propyl hydroxylase (a key enzyme in collagen
synthesis) activity (Hussain et al., 1976a,b), and concurrent changes in
superoxide dismutase activity, which catalyzes the dismutation of the superoxide
free radical (Bhatnagar et al. , 1983), could be another important pathway to
the development of altered responsiveness to 0~. The glutathione peroxidase
system, which provides another line of defense by protecting cells from lipid
peroxides, also exhibits metabolic attenuation (Chow, 1976; Chow et al. ,
1976).
With time, there is a reduction in intensity and a change in composition
of the inflammatory response. Partial remission occurs with continuous or
intermittent exposure. There are no data 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 at levels of concern is
essentially intermittent. The timing and intensity of exposure within the
community, and consequently its potential 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 varia-
bility.
019JSA/A 13-42 6/26/84
-------
13.3.4.4 Conclusions Relative to Attenuation with Repeated Exposures. Insofar
as different effects of 0» share the same mechanism(s), they may be expected
to follow approximately similar time courses in their development of altered
responsiveness to CL. As a corollary, effects that are not linked mechanisti-
O
cally should follow independent although not necessarily dissimilar time
courses, assuming that they are involved in this process.
The attenuation of acute effects of 0- after repeated exposure, such as
changes in respiratory mechanical behavior, have been well documented in
controlled exposure studies. In contrast, there is no practical means at
present of assessing the role of altered responsiveness to 0, in human popula-
tions chronically exposed to ozone. There have been no epidemiological studies
designed to test whether the modification of changes involving irritative
symptoms, pulmonary function, or morbidity occur in association with photochem-
ical air pollution. It might be added that the proposition would be difficult
to test epidemiologically. Thus, scientists, as well as regulators, must rely
mainly on inferences and extrapolations from animal experimentation.
Altered responsiveness to 0- may be viewed as a process exhibiting concen-
tration/response characteristics. Concentrations of 0, that have no detectable
effect appear not to invoke changes in response to subsequent exposures at
higher 0, concentrations. Insofar as this generalization is valid, it suggests
that photochemical air pollution may induce altered responses only in individ-
uals who previously responded to exposure. Over some higher range (0.4 to
0.8 ppm) of exposure, changes occurring after repeated exposure may be optimal
so that recovery (assessed by pulmonary function tests) after initial damage
is virtually complete. Above this optimal range, persistent or progressive
damage is most likely to accompany protracted exposure. The attenuation,
however, of pulmonary function (and the time course of attenuation) following
repeated exposure to 0- does not necessarily follow the morphological or
biochemical pattern of responses.
Responses to 0_, whether functional, biochemical, or morphological, have
the potential for altering responses during repeated or continuous exposure.
There is an interplay between tissue inflammation, hyperresponsiveness, ensuing
injury (damage), and changes in response. The hyperresponsiveness followed by
attenuation of responses caused by 0_ may be viewed as obverse or sequential
states in a continuing process.
019JSA/A 13-43 6/26/84
-------
13.3.5 Relationship Between Acute and Chronic Ozone Effects
Understanding the relationship between acute effects that follow (L
exposure of man or animals and the effects that follow long-term exposures of
man or animals is crucial to the evaluation of possible human health effects
of oxidant pollutants. Most of the acute responses to 0- described in animals
and man tend to return to control (filtered air) values with time after the
exposure ends. While effects of longer periods of exposure have been documen-
ted in laboratory animals (Chapter 10), long-term exposures of human beings
have not been done because of possible health hazards. In fact, little is
known about the long-term implications of acute damage or about the chronic
effects of prolonged exposure to 0_ in man.
With newer techniques, pulmonary functions 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 0., results in
increased lung volume, especially at high transpulmonary pressures (Bartlett
et al., 1974; Moore and Schwartz, 1981; Raub et al., 1983; Costa et al. ,
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 0, 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 0, 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
0,, 7 hr/day, 5 days/week for 6 weeks.
Wegner (1982) studied pulmonary functions in bonnet monkeys exposed to
0.64 ppm DO 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 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. Following a 3-month postex-
posure period, static lung compliance tended to decrease in both exposed and
019JSA/A 13-44 6/26/84
-------
control monkeys, but the decrease in exposed monkeys was significantly greater
than that for control monkeys. Although values for other parameters studied
in control and exposed monkeys were not significantly different at the end of
the postexposure period, they tended to be substantially different. Wegner
(1982) interpreted these differences as an indication that recovery was not
complete following the 3-month postexposure period. This interpretation
appears reasonable, as fewer monkeys were available for pulmonary function
testing at the end of the postexposure period because monkeys were terminated
for biochemical and morphological evaluation at the end of each experimental
period. To find the same level of statistical significance with fewer animals,
the difference of the means would have to be greater at the end of the postexpo-
sure period than at the end of the exposure.
Morphological alterations in both rats and monkeys tend to decrease with
increasing duration of exposure to 0~, but significant alterations in the
centriacinar region have been reported at the end of long-term exposures of
rats (Boorman et al., 1980; Moore and Schwartz, 1981; Barry et a!., 1983),
monkeys (Eustis et al., 1981), 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 03 for 42 to 90 days includes damage to
ciliated and alveolar type 1 cells; hyperplasia of nonciliated bronchiolar and
alveolar type 2 cells, with extension of nonciliated bronchiolar cells into
more distal structures than in unexposed controls; accumulation of intraluminal
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). Freeman et al. (1973) exposed dogs to 1.0
to 3.0 ppm 03 8 to 24 hr/day for 18 months. Dogs exposed to 1.0 ppm 0~ 8 hr/day
had the mildest changes, including minimal fibrosis of terminal airways and
adjacent alveoli with a few "extra" macrophages in these areas. Epithelial
hyperplasia and metaplasia and increased fibrosis were seen in dogs exposed to
higher concentrations or more hours per day. These investigators also observed
that bronchiolar walls were thickened by both epithelial hyperplasia and
intramural fibrosis, which reduced the caliber of small airways. Lungs from
the bonnet monkeys studied by Wegner (1982) were evaluated morphologically and
morphometrically by Fujinaka (1984). At the end of the 1-year exposure to
019JSA/A 13-45 6/26/84
-------
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 cor-
relates with the results of the pulmonary function tests performed by Wegner
(1982). Cuboidal broncniolar 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 collagen was increased significantly,
but there was more amorphous intercellular material. There was also a signi-
ficant increase in arteriolar media and intima.
Lung collagen content was increased after short-term exposure to less
than 1.0 ppm 0., (Last et al., 1979; Last et al. , 1981). This change continued
during long-term exposure (Last and Greenberg, 1980; Last et al. , 1984).
Exposure to less than 1.0 ppm 0~ resulted in increased lung collagen content
in both weanling and adult rats exposed for 6 and 13 weeks, respectively, and
in young monkeys exposed for I year (Last et al., 1984). Some of tne weanling
rats and their controls were examined after a 6-week postexposure period
following the 6-week 0^ exposure during which all rats breathed filtered air.
During this postexposure 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 postexposure period was one
of continued damage rather than recovery.
A similar observation of continued damage during a postexposure period
was reported by Gillespie (1980) in pulmonary function studies of beagle dogs
exposed for 5 years to a variety of pollutants (see Chapter 10, Section 5.2).
Similar pulmonary function tests were performed during and at the end of the
5-year exposure in a Cincinnati, Ohio, laboratory and repeated in a Davis,
California, laboratory after a 2-year postexposure period. The postexposure
values of the control group were similar to values at the end of the exposure
and to values for other healthy beagle dogs at Davis. All exposed groups had
more functional abnormalities at the end of the 2-year postexposure period
than at the end of the exposure. Thus, the postexposure period was one of
continued damage, as evaluated by pulmonary function tests.
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,
019JSA/A 13-46 6/26/84
-------
1981; Fujinaka, 1984). There is morphometric (Fujinaka, 1984), morphologic
(Freeman et al., 1973), and functional evidence (Costa et al., 1983; Wegner,
1982) of distal airway narrowing. Continuation of the inflammation also
appears to be correlated with increased lung collagen content (Boorman et al. ,
1980; Last et al., 1979; Last et al., 1984).
The distal airway and arteriolar changes described in the above studies
of ozone-exposed animals have many similarities to those reported in lungs
from cigarette smokers (Niewoehner et al., 1974; Cosio et al., 1980; Hale
et al. , 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 0_. The previous criteria document for 0,
(U.S. Environmental Protection Agency, 1978) cited three studies reporting
emphysema in laboratory animals after exposure to <1 ppm 0- 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 (see Chapter 10;
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.
13.3.6 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 pul-
monary defenses and to measure the ability of these systems to function as an
integrated unit in suppressing pulmonary disease. In these studies, short-term
(3 hr) exposure to 0~ at concentrations of 0.08 to 0.10 ppm can increase the
incidence of mortality from lower respiratory bacterial infection (Coffin et
al., 1968; Ehrlich et al. , 1977; Miller et al. , 1978). Subchronic exposure to
0.1 ppm caused similar effects (Aranyi et al. , 1983). Following short-term
exposures to 0^, a number of alterations in vital 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.,
1974, 1977; Ibrahim et al. , 1976; Nakajima et al. , 1972; Ehrlich et al. ,
1979); (2) reduced effectiveness of mucociliary clearance (Phalen et al. ,
019JSA/A 13-47 6/26/84
-------
1980; Frager et al. , 1979; Kenoyer et al. , 1981; Abraham et al. , 1980); (3)
immunosuppression (Campbell and Hilsenroth, 1976; Thomas et al., 1981b); (4) a
significant reduction in number of pulmonary defense cells (Coffin et al. ,
1968; Alpert et al., 1971); and (5) macrophages with less phagocytic activity,
less mobility, more fragility and membrane alterations, and reduced lysosomal
enzymatic activity (Dowell et al., 1970; Hurst et al., 1970; Hurst and Coffin,
1971; Goldstein et al., 1971, 1974, 1977; Hadley et al., 1977; Ehrlich et a1.,
1979; McAllen et al. , 1981; Witz et al. , 1983; Amoruso et al. , 1981). Such
effects have been reported in a variety of species of animals following either
short-term and subchronic exposure to 0- alone or 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 (Tiling et al., 1980).
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 not be mortality, since today few individuals die of bacterial
pneumonias. A better comparison in humans would be the increased prevalence
of respiratory illness in the community. Such a comparison is proper since
both mortality (animals) and morbidity (humans) result from a loss in pul-
monary defenses. Ideally, studies of pulmonary host defenses should be per-
formed in man using epidemiological or volunteer methods of study. Unfortu-
nately, such studies have not yet been reported. Therefore, attention must, be
paid to experiments conducted with animals.
Our 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 mechanisms of action of these defense cells
and systems are similar in both animals and man. The effects seen in animals
represent alterations in basic biological systems. One would not expect to
see an equivalent response (e.g., mortality) in man, but one could assume that
similar alterations in basic defense mechanisms could occur in humans, who
possess equivalent pulmonary defense systems. It is understood, however, that
different exposure levels may be required to produce similar responses in
humans. The concentrations of 0_ at which effects become evident can be
019JSA/A 13-48 6/26/84
-------
influenced by a number of factors, such as preexisting disease, dietary factors,
combinations with other pollutants, and/or the presence of other environmental
stresses. Thus, one could hypothesize that humans exposed to 03 could experi-
ence decrements in host defenses, but at the present time one cannot predict
the exact concentration at which effects may occur in man or the severity of
the effect.
13.3.7 Extrapulmonary Effects of Ozone
Because of the reactivity of 0 with biological tissue, it was not intui-
O
tively obvious that 0. would ever reach the circulation. Several studies
discussed in Chapters 10 and 11 are indicative, however, of either direct or
indirect extrapulmonary effects of ozone exposure. For example, alterations
in red blood cell morphology, deformity, and enzymatic activity, as well as
chromosomal effects in circulating lymphocytes, have been reported in man and
laboratory animals. Other organ systems of the body may also be involved.
Exposure to high concentrations of 0_ may have central nervous system effects,
O
since decrements in performance of exercise and vigilance tasks have been
observed in man and laboratory animals. Cardiovascular, reproductive, and
teratological effects of 0_ have also been reported in laboratory animals,
J
along with changes in endocrine function; but the implications of these findings
for human health are difficult to judge at the present time. More recent
studies in laboratory animals have shown that hepatic metabolism of xenobiotic
compounds may be impaired by 0_ inhalation. While some systemic effects, such
as those associated with exercise performance, may be secondary to pulmonary
damage, the others are more difficult to conceptualize. These effects may
result from direct contact with 0_ or from contact with a reactive product of
0_ that penetrates to the blood and is transported to the other organs.
Chromosomal and mutational effects of ozone are controversial. In 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 al. , 1979). Lymphocytes isolated
from animals were found to have significant increases in the numbers of chromo-
somal (Zelac et al. , 1971a,b) and chromatid (Tice et al., 1978) aberrations,
after 4- to 5-hr exposures to 0.2 and 0.43 ppm ozone ozone, respectively.
Single-strand breaks in DNA of mouse peritoneal exudate cells were measurable
after a 24-hr exposure to I ppm ozone (Chaney, 1981). Gooch et al. (1976)
019JSA/A 13-49 6/26/84
-------
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 transloca-
tions in the primary spermatocytes. An increase (although not significant)
was observed in chromatid lesions in peripheral blood lymphocytes from 6 human
subjects exposed to 0.5 ppm ozone for 6 or 10 hr (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 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 the ambient environment (Scott and Burkart, 1978; Magie
et al., 1982). Clearly, additional evaluation of the human mutagenic potential
of ozone is needed. Evidence now available, however, fails to demonstrate any
mutagenic effect 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 genotoxic effects
of ozone for all of the other body tissues is unknown. It is somewhat puzzling
that in spite of the experimental difficulties that may be encountered no
cytogenetic investigations have been conducted in the respiratory tissues of
animals exposed to ozone. These tissues are exposed to the highest concentra-
tions and are also the target of most of the toxic manifestations of ozone.
Clearly, one cannot extrapolate ozone-induced genotoxicity data from peri-
pheral blood lymphocytes to other organs, such as the lungs.
Ozone exposure produces a number of hematological and serum chemistry
changes both in rodents and man, but the physiological significance of these
studies is unknown. Most of the hematological changes appear 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
019JSA/A 13-50 6/26/84
-------
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 acety1cholinesterase 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 also support the concept of
membrane damage to circulating RBCs. While it is theoretically possible that
species differences in ozone sensitivity may exist because of differences in
G-6-PD (see Section 13.3.3.5), most experiments have reported a close similari-
ty in the responses of animal and normal human RBCs to ozone exposure.
13.4 HEALTH EFFECTS IN POTENTIALLY SUSCEPTIBLE INDIVIDUALS
13.4.1 Patients with Chronic Obstructive Lung Disease (COLD)
Patients with mild COLD have not shown increased sensitivity to 0- in
O
controlled human exposure studies, and the epidemiological findings are incon-
sistent. Linn et al. (1982, 1983) and Hackney et al. (1983) showed no changes
in symptoms or function at 0.12, 0.18, or 0.25 ppm 03 (1 hr, IE). Likewise,
Solic et al. (1982) and Kehrl et al. (1983) found no significant changes in
symptoms or function at 0.2 or 0.3 ppm 0- (2 hr, IE). At higher concentrations,
however, Kulle et al. (1984) found decreased function in a group of 20 smoking
chronic bronchitics at 0.4 ppm (3 hr, IE) on day 1 of exposure and upon reexpo-
sure at day 6. In an epidemiological study, Balchum (1973) found aggravation
of symptoms and decreased function in COLD patients at an oxidant concentration
of 0.11 ppm.
There is suggestive evidence that bronchial reactivity is increased in
some subjects with COLD (two of three) following exposure to 0.1 ppm 0, (Kb'nig
•3
et al., 1980), and that arterial 02 saturation is reduced slightly in these
subjects during exposure to 0.12 ppm 03 combined with exercise (Linn et al. ,
1982; Hackney et al., 1983). The latter observation is consistent with the
occurrence of unequally distributed defects in mechanical function in the
lung.
One difficulty in attempting to characterize the responsiveness of patients
with COLD is that they may exhibit a wide diversity of clinical and functional
states. These range from a history of smoking, cough, and minimal functional
019JSA/A 13-51 6/26/84
-------
defects to chronic disability that is usually combined with severe defects in
blood gases or respiratory mechanical behavior. The chief locus of damage may
also vary: either the bronchi (chronic bronchitis) or parenchyma (emphysema)
may dominate the clinical picture. Finally, the mixture of acute and chronic
inflammatory processes may vary considerably among patients. There has been
no attempt to sort out these manifestations of COLD in the design of these
studies.
13.4.2 Asthmatics
There is yet no laboratory evidence that mild asthmatics are functionally
more sensitive than healthy individuals to 0~. Linn et al. (1978) found no
significant changes in lung function, as indicated by forced expiratory spiro-
metry or the nitrogen washout test, when asthmatic subjects with mild to
moderate bronchial obstruction were exposed to 0.20 ppm 0, for 2 hr with
*5
intermittent light exercise; increased symptom scores were noted, however.
Silverman (1979) found minimal changes in forced expiratory spirometry following
2-hr exposures of asthmatic subjects to 0.25 ppm 0_ while at rest. Although
O
group mean changes were not statistically significant, one third of the subjects
who rested for 2 hr while inhaling 0.25 ppm 0_ demonstrated a greater than
10 percent decrement in lung function, and it is doubtful if this would have
been true for normal subjects. Finally, in ambient air exposures containing
0.17 ppm 0_, Linn et al. (1980) found small but statistically significant
decrements in forced expiratory measures in both normal and asthmatic subjects,
following 2-hr exposures with intermittent light exercise. The magnitude of
functional responses in both groups was practically the same.
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 03 than that of normals. Intake of medication
was not controlled in several of the studies, and some subjects continued to
use oral medication when being tested. Some of the subjects in one study
(Linn et al., 1978) showed evidence of chronic obstructive lung disease in
addition to asthma. Most of the normal subjects 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 0_ 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
019JSA/A 13-52 6/26/84
-------
proportionately with the intensity of exercise, in determining the response to
0_, additional testing at higher levels of exercise should be undertaken.
Finally, it may be that the specific measurements of pulmonary function
and the exposure protocols employed in the above studies were inappropriate
for ascertaining pulmonary effects in asthmatic subjects. Asthma is essential-
ly characterized by bronchoconstriction. Compared to airway resistance, some
measures of forced expiratory spirometry are less sensitive to bronchoconstric-
tion, since fairly severe bronchoconstriction must occur in order to affect
decrements in these measures. McDonnell et al. (1983), reporting on normal
subjects exposed to levels of CL as low as 0.12 ppm with heavy intermittent
exercise, attributed small decrements in forced expiratory spirometry and
increased symptoms to a reduced inspiratory capacity resulting from stimulation
or sensitization of airway receptors by 0_. They also observed that there was
o
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 stand somewhat in contrast to clinical findings
in that they provide some evidence of exacerbation of asthma at ambient concen-
trations of 0» below those generally associated with symptoms or functional
changes in healthy adults. For example, Zagraniski et al. (1979) reported an
increased prevalence of symptoms among clinic asthmatic patients in association
with a mean ambient 0_ concentration of 0.08 ppm; Whittemore and Korn (1980)
reported an increasing risk of asthmatic attack with increasing ambient oxidant
concentrations between 0.04 and 0.15 ppm; and Lebowitz et al. (1982, 1983)
found similar results when 0_ concentrations were above 0.056 ppm (there was
an interaction between 0., and ambient temperature), Lebowitz (1984) also
reported finding a reduction in expiratory peak flow rate in asthmatics at 0,
O
concentrations above 0.056 ppm. The inconsistency of the epidemiological
findings and the controlled human exposure studies with bronchoconstriction
could be the result of several factors: (1) insensitivity of the pulmonary
function tests employed, (2) insufficient clinical information in these studies;
or (3) interactions of the pollutants inducing responses in the epidemiological
studies.
019JSA/A 13-53 6/26/84
-------
13.4.3 Subjects with Allergy, Atopy, and Hyperreactive Airways
These diagnostic categories have generally been established through
hi story-taking in clinical exposures and through skin-testing and other diag-
nostic procedures in epidemiological studies. The information available on
the responsiveness of these individuals, 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 0,. at rest. 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 0.12 ppm. As with asthmatics (see
13.4.2.2), Zagraniski et al. (1979) found that non-asthmatic allergic subjects
experienced an increased prevalence of symptoms in association with ambient CL,
O
concentrations above 0.08 ppm: cough and hay fever were exacerbated. Similar-
ly, Lebowitz et al. (1982, 1983) also reported an increase in eye symptoms
among non-asthmatic allergic subjects in association with CL concentrations
O
above 0.056 ppm. The association was independent of other air pollutants and
weather.
Some normal subjects with no prior history of respiratory symptoms or
allergy demonstrate increased nonspecific airway sensitivity resulting from 0^
O
exposure (Golden et al. , 1978; Holtzman et al. , 1979; Konig et al. , 1S80;
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 nistamine,
administered after 0- exposure. In one study (holtzman et al. , 1979), in
which subjects were classified as atopic or nonatopic based on medical history
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 G--induced increases in airway responsiveness with airway
inflammation has been reported in dogs at high 0., concentrations (1 to 3 ppm)
(Holtzman et al., 1983a,b; Fabbri et al., 1984); and in sheep at 0.5 ppm G,
(Sielczak et al. , 1983). Little is known, however, about this relationship in
animals at lower CL concentrations (<0.5 ppm), and the possible association
between 0.,-induced inflammation and airway hyperresponsiveness in human subjects
has not been explored systematically.
019JSA/A 13-54 6/26/84
-------
13.5 EXTRAPOLATION OF EFFECTS OBSERVED IN ANIMALS TO HUMAN POPULATIONS
13.5.1 Species Comparisons
Comparisons of the effects of ozone on different animal species is of
interest in attempting to understand whether man might experience similar
effects. For example, if only one of several tested species experienced a
given effect of ozone, this effect might be species specific and not occur in
man. Conversely, if several animal species, with all their inherent differ-
ences, shared a given effect of ozone, it is likely that some element present
in all mammalian species, including man, was susceptible to ozone. A commonal-
ity of effects across species would be expected, provided the effect was
related to a mechanism which is 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 amino acids in tissue
proteins or small-molecular-weight peptides. Thus, if 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 delivered doses
or of subsequent processes of toxicity. For example, a likely target site for
0, toxicity is the cellular membrane, particularly the membrane of cells like
the Type 1 and ciliated cell which cover a large surface area of the respira-
tory tract. Since there are no major interspecies differences in cell membranes
and membranes are composed of proteins and lipids, then both proposed molecular
mechanisms of 0- toxicity could occur at the cellular membrane. In fact, the
two proposed hypotheses most likely occur simultaneously. The consequent
toxic impact on the membrane, the cell, and surrounding tissue would be influ-
enced by species differences in antioxidant defenses or repair mechanisms.
Some of the products of ozone oxidation are water-soluble and can diffuse from
the site of oxidation in the membrane into cytosol or the circulation. The
extrapulmonary effects of ozone exposure may be due to such circulating products.
Inflammatory cells appear in the lung after ozone exposure. Peroxides are
active in the inflammatory process as intermediates in the prostaglandin and
leukotriene cascades. Some of the peroxides formed from ozonized arachidonic
acid are active as prostaglandin agonists, but apparently can not be converted
to more complex prostanoids, at least by human platelets. Fatty acid ozonides
could release histamine and cause both local and pulmonary edema. Many of
these substances (histamine, prostaglandins, etc.) will not only enter addi-
tional metabolic reactions, but will also act as local or, if distributed by
019JSA/A 13-55 6/26/84
-------
the pulmonary circulation, as systemic mediators. Depending on the target
site and the amount released, they may be vasoactive, modulate bronchomotor
tone, stimulate receptors, or trigger reflex reactions and thus influence lung
or other organ function. Such functional changes might be transient or become
more permanent if tissue structure was altered as well. The extent of interde-
pendence among biochemical, morphological, immunological, and functional
changes induced by CL remains to be determined. Since current knowledge is
not sufficiently advanced to assess such events quantitatively, only qualitative
hypotheses can be made, based on the available evidence. A commonly accepted
hypothesis is that if ozone causes an effect in several animal species, it can
cause a similar effect in man. It is important to note that this is a qualita-
tive probability; it does not permit assessment of the concentrations at which
man might experience the common effect.
The health data base for ozone consists of hundreds of studies with about
7 species, and even more strains, of animals. Generally, for a given effect,
whether it be on lung morphology, physiology, biochemistry, or host defenses,
all species tested were responsive to ozone, albeit sometimes 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 mammalian species have
been conducted after ozone exposure. Of the groups studied, there are signi-
ficant 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. Addi-
tional differences exist. Nonetheless, a characteristic ozone lesion occurs
at the junction of the conducting airways and the gaseous exchange tissues,
whatever the species specifics of the structure are. The typical effect in
all the species examined is damage to ciliated and Type 1 cells and hyperplas-
ia of nonciliated bronchiolar cells and Type 2 cells. An increase in inflamma-
tory cells is also observed. Such changes were observed after a 7-day inter-
mittent exposure of monkeys to 0.2 ppm (Dungworth et al. , 1975; Castleman
et al., 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
019JSA/A 13-56 6/26/84
-------
comparisons between monkey and rat studies is not possible because of inadequate
data. Nonetheless, a rough equivalency of responses was observed under similar
exposure conditions between species having major structural differences. Since
the monkey lung may be the most representative model of the human lung, the
possibility is enhanced that man would experience similar effects.
Pulmonary function of eight species of animals has been studied after
exposure to ozone. Short-term exposure for 2 hr to 03 concentrations as low
as 0.22 ppm produces rapid, shallow breathing. Similar changes in respiration
have been observed in man during comparable ozone exposure, as shown in
Table 13-7. The onset of these effects is rapid and appears to be related to
the ozone concentration. In a recent 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 decreased and tidal volume increased
with similar patterns 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 0- exposure (Table 13-8). Short-term
exposure to 0., concentrations as low as 0.32 ppm increases airway resistance
following inhalation of the drugs acetylcholine, carbachol, methacholine, or
histamine in sheep, dogs, and humans. However, the time course of this
response differs. 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 10) but there are insuf-
ficient points of identity in the experiments to permit direct comparisons
among animal species or between animals and man.
019JSA/A 13-57 6/26/84
-------
TABLE 13-4. COMPARISON OF THE ACUTE EFFECTS OF OZONE ON BREATHING PATTERNS IN ANIMALS AND MAN
Ozone3
concentration
MQ/m-3
392
686
431
804
1568
470
588
784
588
OJ 588
i
<_n
666
1333
2117
2646
725
980
1470
980
1100
ppm
0.20
0.35
0.22
0.41
0.8
0.24
0.30
0.40
0.3
0.3
0.34
0.68
1.08
1.35
0.37
0.50
0.75
0.5
0.56
Measurement Exposure
method duration
UV 1 hr
(mouthpiece)
CHEM 2 hr
CHEM 2.5 hr
MAST 1 hr
(mouthpiece)
UV 1 hr
(mouthpiece)
NBKI 2 hr
MAST 2 hr
NBKI 2 hr
CHEM 2 hr
Activity0
level (VE)
CE(77.5)
R
IE(65)
CE(34.7, 51)
CE(66)
R
IE(29)
R
R
Observed effects(s)
Increased fp and decreased V,.
Concentration-dependent increase in f_ for
all exposure levels.
Increased fR and decreased V,..
Increased fR and decreased V-,.
Increased fR and decreased VT.
Increased fR and decreased V-, during
exposure to all 03 concentrations.
Dose-dependent increase in fD and decrease
in VT. K
Increased fD.
K
Abnormal, rapid, shallow breathing while
exercising on a treadmill after exposure.
Species Reference
Human Adams and Schelegle, 1983
Guinea pig Amdur et at., 1978
Human McDonnell et al., 1983
Human DeLucia et al., 1983
Human DeLucia and Adams, 1977
Guinea pig Murphy et al., 1964
Human Folinsbee et al., 1975
Guinea pig Yokoyama, 1969
Dog Lee et al . , 1979
Ranked by lowest observed effect level.
Measurement method: MAST = Kl-Coulometric (Mast meter); CHEM = gas phase cheroiluminescence; UV = ultraviolet photometry; NBKI = neutral buffered
potassium iodide.
Minute ventilation reported in L/min or as a multiple of resting ventilation. R = rest; IE = intermittent exercise; CE = continuous exercise.
-------
TABLE 13-5. COMPARISON OF THE ACUTE EFFECTS OF OZONE ON AIRWAY REACTIVITY IN ANIMALS AND MAN
Ozone3
concentration
i — >
GO
i
en
UD
Mg/mJ
627
784
784
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
Activityc
level (V£)
R
IE(4-5xR)
IE(2xR)
R
IE(2xR)
R
R
R
Observed effects(s)
SR increased with ACh challenge.
aw
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
metfiacholine 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 Konig et al. , 1980
Human Kulle et al. , 1982b
Human 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-Coulometric (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.
-------
Species comparisons of host defense against Infection are possible for
alveolar macrophages. After an intermittent (8 hr/day) 7-day exposure to 0.2
ppm ozone, an increased number of alveolar macrophages was observed in the
lungs of both rats and monkeys (Castleman et al., 1977; Dungworth, 1976;
Stephens et al., 1976). Although numerous other macrophage studies have been
conducted, there are insufficient points of identity for species comparison.
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 al., 1975), glucose-6-phosphate dehydrogenase
activity 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 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 to statistically detect
effects in both species. In a few of the reports, the number of animals was
not given. Mustafa et al. (1982) compared mice to 3 strains of rats exposed
to 0.45 ppm ozone continuously for 5 days. Antioxidant 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 statis-
tically greater than the increase in the rats.
For extrapulmonary effects, the only species comparison using identical
methods 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 respon-
sivity cannot be assessed.
An overview of the animal toxicological data for ozone indicates that rats
are the most prevalent species tested. Other species often used include mice,
rabbits, guinea pigs, and monkeys. A few dog and hamster studies exist. As has
been noted above, very few species comparisons can be made due to differences in
019JSA/A 13-60 6/26/84
-------
exposure regimens and measurement techniques. Even when direct comparisons are
possible, interpretation is difficult. Statements regarding responsiveness can
be made. 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, it is remarkable that even with the wide variation in
techniques and experimental designs, acute and subchronic exposures to levels
of ozone less than 0.5 ppm produce similar types of responses in many species
of animals. Thus, it may be hypothesized that man may experience more types
of effects than have been established in human clinical studies. Types of
effects for which substantial animal data bases exist include changes in lung
structure, biochemistry, and host defenses. However, the actual risk to man
breathing ambient levels of ozone cannot be determined until the animal data
can be quantitatively extrapolated to man.
13.5.2 Dosimetry Modeling
The discussion of species comparisons in response to ozone exposure
presented above (Section 13.5.1) assesses the net effects of species differ-
ences in sensitivity and dosimetry. An uncoupling of these two elements is
required to be able to make quantitative interspecies comparisons of toxicolog-
ical results from different experiments. In this context, dosimetry refers to
determination of the amount of ozone which reaches specific sites in animals
and man, while sensitivity relates to the likelihood of equivalency of biologi-
cal response given that the same dose of ozone is delivered to a target site in
different species.
Although additional research is needed on dosimetry and on species sensi-
tivity before quantitative extrapolations of effective 0., concentrations can be
«j
made between species, only dosimetry is sufficiently advanced for discussion
here. Because the factors affecting the transport and absorption of 0_ are
O
general to animals and to man, dosimetry models can be formulated that use
appropriate species anatomical and ventilatory parameters to describe 0^ absorp-
O
tion. Thus far, theoretical modeling efforts (McJilton et al., 1972; Miller
et al., 1978) have focused on the lower respiratory tract.
Largely due to 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 al., 1973), rabbit
019JSA/A 13-61 6/26/84
-------
(Miller et al., 1979), and guinea pig (Miller et al., 1979). To date, infor-
mation on nasopharyngeal removal of 0~ in man is not available. Since naso-
pharyngeal removal of 03 serves to lessen the insult to lower respiratory
tract tissue which is thought to be more sensitive, 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 CL,
with location and intensity dependent upon concentration. When comparisons
are made at the analogous anatomical site, the morphological effects of 03 on
the lungs of a number of animal species are remarkably similar. Despite
inherent differences in anatomy between various experimental animals and man,
the junction between the conducting airways and the gas exchange region is
most affected by CL exposure in animals (See 10.3.1) and most likely will be
•3
the principal site affected in man. Dosimetry model simulations (Miller
et al. , 1978) predict that the maximal tissue dose occurs at the region of
predominant morphological damage in animals. The overall similarity of the
predicted 0~ dose patterns in animal lungs studied thus far (rabbits and
guinea pigs) extends to the simulation of CL uptake in humans (see 10.2.3.1).
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 on animals exposed to 0«. In the past, extrapolations
have usually been qualitative in nature. With additional research in areas
which 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 quantitatively extrapolating animal toxicological results to man.
Since animal studies are the only available approach for investigating the
full array of potential disease states induced by exposure to 0,, quantitative
use of animal data is in the interest of better establishing 03 levels to
which man can safely be exposed.
13.6 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, if not exclusively, because of its
relative abundance compared with other photochemical oxidants. Still, the
coexistence of other reactive oxidants (Section 13.2.2) suggests that the
019JSA/A 13-62 6/26/84
-------
potential effects of these other oxidants should be examined. Not unexpected-
ly, however, animal and clinical research has centered largely on 03; very
limited effort has been devoted to studies of peroxyacetyl nitrate (PAN) and
hydrogen peroxide (HJ),,). Field and epidemiological studies evaluate health
effects associated with exposure to the ambient environment, making it diffi-
cult to single out the oxidant species responsible for the observed effects.
13.6.1 Effects of Peroxyacetyl Nitrate
There have been far too few controlled toxicological studies with the
other oxidants to permit any sound scientific evaluation of their contribution
to the toxic action of photochemical oxidant mixtures. The few animal toxicol-
ogy studies on PAN indicate that it is much less acutely toxic than 0.,. When
the effects seen after exposure to 0- 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,
O
behavior modification, morphology, or significant alterations in host pulmonary
defense system (Campbell et al. , 1967; Dungworth et al. , 1969; Thomas et al. ,
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 exercise on a treadmill
(Drinkwater et al. , 1974; Raven et al. , 1974a,b; Gliner et al., 1975). No
significant effects were observed at PAN concentrations of 0.25 to 0.27 ppm.
Two additional studies at 0.24 ppm (Raven et al., 1976) and 0.30 ppm (Smith,
1965) of PAN suggested a possible limitation on forced expiratory volume and
flow, but not enough data are available to evaluate the significance of this
effect.
Field and epidemiological studies have found very few specific relation-
ships between reported health effects and PAN concentrations. The increased
prevalence of eye irritation reported during ambient air exposures has been
associated with PAN as well as other photochemical reaction products (National
Air Pollution Control Association, 1970; Altshuller, 1977; National Research
Council, 1977; U.S. Environmental Protection Agency, 1978; Okawada et al. ,
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
019JSA/A 13-63 6/26/84
-------
discomfort was reported along with eye irritation as PAN concentrations in-
creased 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 (CL and PAN) were
similar to those found for CL alone.
13.6.2 Effects of Hydrogen Peroxide
Controlled toxicological studies on H^O^ have been performed at concentra-
tions much higher than those found in the ambient air (see Section 13.2), and
the majority have been mechanistic studies using various i_n vitro techniques
for exposure. Very limited information is available on the health significance
of inhalation exposure to gaseous H?0» in laboratory animals. No significant
effects were observed in rats exposed for 7 days to >95 percent hLCL gas with
a concentration of 0.5 ppm in the presence of inhalable ammonium sulfate
particles (Last et al. , 1982). Because I-LO^ 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, there have not been studies 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 HpO~ when using isolated cells or organs (Stewart et al. , 1981;
Bradley et al. , 1979; Bradley and Erickson, 1981; Speit 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.
13.6.3 Interactions with Other Pollutants
Controlled human exposures have not consistently demonstrated any enhance-
ment of respiratory effects for combined exposures of 03 with S02, N02, CO,
and H?SO. 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 03 criteria
document (U.S. Environmental Protection Agency, 1978) suggested that mixtures
of S09 and 0- at a concentration of 0.37 ppm are potentially more active than
L- O
would be expected from the behavior of the gases acting separately (Bates and
Hazucha, 1973; Hazucha and Bates, 1975). High concentrations of inhalable
019JSA/A 13-64 6/26/84
-------
aerosols, particularly H?SO, or ammonium sulfate, could have been responsible
for the results (Bell et al. , 1977); however, subsequent studies of 0., mixtures
with SO,,, 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., 1983).
Combined exposure studies in laboratory animals have produced varied
results, depending upon the pollutant combination evaluated and the measured
variables. Additive and/or possibly synergistic effects of 0, exposure in
combination with N0? have been described for increased susceptibility to
bacterial infection (Ehrlich et al., 1977; Ehrlich, 1980, 1983), morphological
lesions (Freeman et al. , 1974), and increased antioxidant metabolism (Mustafa
et al., 1984). Additive effects from combined exposures to 0., and H?SO. have
also been reported for host defense mechanisms (Gardner et al., 1977; Last and
Cross, 1978; Grose et al. , 1982) but not for morphology (Cavender et al. ,
1977; Moore and Schwartz, 1981).
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 10, 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 0,. alone.
O
A major limitation of field and epidemiological studies includes the
interference or potential interactions between 0_ and other pollutants in the
environment. The lack of quantitative measurements of oxidant concentrations
has limited the usefulness of these studies. Nevertheless, there is still
concern that combinations of oxidant pollutants, including precursors of
oxidants, contribute to the decreased function and exacerbation of symptoms
reported in asthmatics (Zagraniski et al. , 1979; Whittemore and Korn, 1980;
Linn et al., 1980, 1983; Lebowitz et al., 1982, 1983; Lebowitz, 1984) and in
children and young adults (Kagawa and Toyoma, 1975; Kagawa et al. , 1976;
Kagawa, 1983; Lebowitz et al., 1982, 1983). Possible interactions between 03
and total suspended particulate matter have been reported with decreased
expiratory flow in children (Lebowitz et al., 1982, 1983; Lebowitz, 1984) and
019JSA/A 13-65 6/26/84
-------
adults with symptoms of airway obstructive disease (Lebowitz et al., 1982,
1983) and with increased symptom rates in asthmatics (Zagraniski et al. ,
1979).
The effects of interaction between inhaled oxidant gases and other environ-
mental pollutants on the lung have not been systematically studied. In fact,
one of the major problems with the available literature on interaction studies
is the exposure design. Most of the controlled studies have not used concen-
trations of combined pollutants that are found in the ambient environment. It
may be desirable to place greater research emphasis on characterizing sequen-
tial patterns of air pollutant exposure which may have quite different effects
compared with continuous exposure to pollutant mixtures. An alternative
approacn might be to study the interaction of photochemical oxidant species
and/or precursors of photochemical oxidants. However, since these issues are
complex, they must be addressed experimentally using exposure regimens for
combined pollutants that are more representative of ambient ratios of peak
concentrations, frequency, duration, and time intervals between events.
13.7 IDENTIFICATION OF POTENTIALLY AT-RISK POPULATIONS OR SUBPOPULATIONS
13.7.1 Introduction
The identification of a population or subpopulation as the 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 a population should be protected
from; and (2) the identification of those individuals in whom those specific
endpoints are observed (a) at lower concentrations than in other individuals,
(b) with greater frequency than in other individuals, (c) with greater conse-
quences than in other individuals, or (d) at various combinations of "effects
levels," frequency, or consequences. In addition, as discussed in Chapter 2,
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 subpopulations 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 subpopulations to particular risk from exposure
to photochemical oxidants are discussed. It should be noted that these factors
019JSA/A 13-66 6/26/84
-------
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. The
following sections also include estimates of the number of individuals in the
United States that fall into certain categories of potentially at-risk subpopu-
lations.
It must be emphasized that the final identification of those effects that
are considered "adverse" and the final identification of "at-risk" populations
are both the domain of the Administrator.
13.7.2 Potentially At-Risk Individuals
Sensitivity to ozone varies within and among individuals. The factors
suspected of altering sensitivity to ozone are numerous. Those actually known
to alter sensitivity, however, are few, largely because few have been examined
adequately to determine definitively their effects on sensitivity. The discus-
sion 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. Statistical analysis is generally relied upon to establish
the range of normal responses for a particular biological endpoint, and to
distinguish those responses that are indicative of increased sensitivity and
those that are indicative of decreased sensitivity.
Susceptibility may be conferred by some predisposing host factor, such as
immunologies! 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). Sensitivity may
arise from some prior exposure, that is, one that entails a response, as in
"sensitization"; or may result from cross-reactivity to chemicals. Sensitivity
may also be simply an unusual response upon exposure, possibly resulting from
prior challenge with respiratory irritants).
019JSA/A 13-67 6/26/84
-------
Most human studies do not perform the complex diagnostic procedures
needed to classify study subjects properly, nor do they usually determine the
mechanism of response (i.e., underlying immunological, biochemical, or structural
character). Furthermore, even diagnostic labels, such as COLD, asthma, allergy,
and atopy, are not usually based on sufficient clinical evaluation nor standard-
ized 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 other procedures were performed that characterize disease status, let alone
radiograpnic studies. In epidemiological studies, often not even baseline
pulmonary function is determined. Yet, even if these tests are performed, a
relatively large group of apparently healthy subjects, not previously identi-
fied as being susceptible or sensitive to 0,., will respond dramatically to 0,
exposure.
Ultimately, a complex set of mechanisms activated to varying degrees and
acting differently in different individuals will determine susceptibility or
sensitivity. For example, bronchoconstriction induced by several mechanisms
may be blocked accordingly by different agents, such as £„ agonists, anti-
inflammatory agents, methyl-xanthines, membrane or receptor agonists, catecho-
lamine agents, and prostaglandins. Unfortunately, little information on these
aspects of the study population is available so that reliance must be placed
on limited work-ups, non-standard!zed clinical evaluations and definitions,
and theoretical considerations. Thus, estimates of "at-risk" populations are
difficult if not impossible to assess with any precision.
Various anthropomorphic and demographic characteristics have been used to
try to characterize susceptible individuals in the general population. Gender
differences, especially for children; age differences, especially between the
very young and the very old; and possibly racial or ethnic differences, such
as differences in nutritional status, differences in baseline lung function,
or differences in immunological status, may predispose individuals to suscepti-
bility or sensitivity to ozone, since all of these factors have well-known
implications for infectious and chronic diseases and immunological states.
None of these factors, however, has been sufficiently studied in relation to
0- exposure to give definitive answers.
O
The most prominent modifier of response to 0~ in the general population
is minute ventilation, which increases proportionately with increases in
019JSA/A 13-68 6/26/84
-------
exercise workload. Higher levels of exercise enhance the likelihood of increased
frequency of irritative symptoms and decrements in forced expiratory volume
and flow. Unfortunately, even in a well-controlled experiment on a homogeneous
group of subjects, physiological responses to the same exercise levels and the
same CL concentrations will vary widely among individuals.
Exposure history may determine susceptibility or sensitivity. Smokers
may be more or less sensitive. They are more susceptible to impaired defense
against infection, they have some chronic inflammation in the airways, they
have cellular damage, and they may have altered biochemical/cellular responses
(e.g., reduced trypsin inhibitory capacity, neutrophilia, impaired macrophage
activity). Likewise, those with "significant" occupational exposures to
irritants or 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 0~, although data are
available only from a limited number of studies and are inconclusive.
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.
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 prostaglandin function and/or T-cell function) or
cellular function (e.g., eosinophilia), may be potentially more sensitive to
0_. Defining an asthmatic, however, may be difficult. Likewise, allergic
individuals, with a predisposing atopy, have altered immunological responses,
similar to asthmatics, and may have labile bronchomotor tone, such that they
may be considered to be potentially more sensitive. Patients with COLD may or
may not be potentially more sensitive to 0_. Although currently available
O
evidence indicates that individuals with preexisting disease respond to 0«
O
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 ()„ can be adequately determined. Nevertheless, one question
019JSA/A 13-69 6/26/84
-------
that arises is whether or not small functional changes in individuals with
COLD, asthma, or allergy represent equivalent physiological significance
compared to the normal subject.
13.7.3 Potentially At-Risk Subpopulations
As the preceding discussion clearly indicates, definitive data on the
relative susceptibilities to ozone of various kinds of individual subjects are
lacking, both in epidemiological and control 1ed-exposure studies. Notwith-
standing the uncertainties that exist in the data, it is possible to identify
three major subpopulations that may be at particular risk from exposure to
ozone.
In the Clean Air Act, the definition of a "sensitive population" excludes
"individuals who are otherwise dependent on a controlled internal environment"
and 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, occupational, smoking, and other factors to susceptibility to air
pollution agents."
Consonant with the provisions of the Clean Air Act and with its legislative
history, the first major subpopulation that appears to be at particular risk
from exposure to ozone is that subgroup of the general population characterized
as having preexisting disease. Available data on actual differences in sensitiv-
ity between these and healthy, normal members of the general population indicate
that under the exposure regimes used to date, individuals with preexisting
disease may not be more sensitive to ozone than normal individuals. Neverthe-
less, two considerations place these individuals among subpopulations at
potential risk from exposure to ozone. First, it must be noted that concern
with triggering untoward reactions has necessitated the use of low concentra-
tions and low exercise levels in most studies on subjects with preexisting
019JSA/A 13-70 6/26/84
-------
disease. Therefore, few or no data on responses at higher concentrations and
higher exercise levels are available for comparison with responses in normal
subjects. Thus, definitive data on responses in individuals with preexisting
disease are not available and may not even become 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. Such
declines may be expected to 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.
A second major subpopulation at apparent special risk from exposure to
ozone consists of individuals ("responders") in the general population, not
yet characterized medically except for their responses to ozone, who experience
greater decrements in lung function from exposure to ozone than those observed
in the remainder of the general population. As yet no means of determining in
advance those members of the general population who are "responders" has been
devised. It is important to note here what has been discussed previously in
this chapter and in chapter 11; that is, group means presented in chapter 11
and in Figures 13-2 through 13-5 (and Table 13-3) include values for the
"responders" in the respective study cohorts of otherwise healthy, normal
subjects. Although no means of identifying the number or demographic charac-
teristics of "responders" exists, they are clearly a subgroup of the general
population whose individual members appear to be at particular risk from
exposure to ozone.
Data presented in Chapter 11 and in this chapter underscore the importance
of exercise in the potentiation of effects from exposure to ozone. Thus, a
third major subpopulation potentially at risk from exposure to ozone is com-
posed of those individuals (healthy or otherwise) whose activities out of
doors, whether vocational or avocational, result in increases in minute ventila-
tion. As stated in section 13.7.2, "the most prominent modifier of response
to 0_ in the general population is minute ventilation, which increases propor-
tionately with increases in exercise workload." Although many individuals
with preexisting disease would not be expected to exercise at the same levels
019JSA/A 13-71 6/26/84
-------
one would expect in healthy individuals, any increase in activity level would
bring about a commensurate increase in minute ventilation.
As pointed out throughout this chapter, other biological and nonbiological
factors are suspected of influencing responses to ozone. Data remain inconclu-
sive 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 subpopulations are thought to be biologically predisposed to increased
sensitivity to ozone. To the extent that the aged, the young, males, or
females participate in activities out of doors that raise their minute ventila-
tions, all of these subgroups may be considered to be potentially at risk,
depending upon other determinants of total ozone dose, 0., concentration and
exposure duration.
13.7.4 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 each person as an inhabitant of a
usual place where eating and sleeping take place rather than a person's legal
or voting residence. Each residence is, in turn, grouped according to the
official standaro metropolitan statistical areas (SMSA's) and standard consoli-
dated statistical areas (SCSA's) as defined by the Office of Management and
Budget. Briefly, SMSA's represent a large population nucleus together with
adjacent communities which have a high degree of social and economic integra-
tion; SCSA's are large metropolitan complexes consisting of groups of closely
related adjacent SMSA's. Table 13-6 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 U.S. 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 13-7. 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
019JSA/A 13-72 6/26/84
-------
TABLE 13-6. 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
Nonmetropol itan areas
Urbanc
Rural
Population,
mil lions
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).
cComprises 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.
not been published, preliminary results indicated that overall coverage improved
in the 1980 census. Census data presented in Tables 13-6 and 13-7 have not
been adjusted for underenumeration.
13.7.5 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), asthma, and upper
respiratory allergies. 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 is considered
019JSA/A 13-73 6/26/84
-------
TABLE 13-7. 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
Whitelj
BlacIC
h
Other
Population,
mill ions
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.
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.
The estimated prevalence of chronic bronchitis, emphysema, and asthma in
the United States is shown in Table 13-8 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
019JSA/A 13-74 6/26/84
-------
TABLE 13-8. PREVALENCE OF CHRONIC RESPIRATORY CONDITIONS BY SEX AND AGE FOR 1979
Number of persons, in thousands
CO
i
en
Condition
Chronic bronchitis
Emphysema
Asthma
Hay fever and
other upper
respiratory
allergies
Total0
7474
2137
6402
15,620
Male
3289
1364
3113
7027
Female
4175
770
3293
8584
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
b
f
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).
'With or without hay fever.
Without asthma.
-------
with documented and undocumented respiratory conditions in the United States
is estimated to be at least 47 million, which is approximately 20 percent of
the population.
13.8 SUMMARY AND CONCLUSIONS
Controlled human studies of at-rest exposures to 0_ lasting 2 to 4 hr
have demonstrated decrements in forced expiratory volume and flow occurring at
and above 0.5 ppm of 0~. Airway resistance was not changed at these 0~ concen-
trations. Breathing 0- at rest at concentrations < 0.5 ppm did not significantly
impair pulmonary function although the occurrence of some 0--related pulmonary
symptoms has been suggested in a number of studies.
One of the principal modifiers of the magnitude of response to 0., 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
such ventilatory patterns also promote a deeper penetration of ozone into the
peripheral lung, which is the region most sensitive to ozone and where a greater
absorption of ozone will occur. These processes are further enhanced at high
work loads (VF > 35 L/min), since the mode of breathing will most likely change
at that Vp from nasal to oronasal.
Even in wel1-controlled experiments on a homogeneous group of subjects,
physiological responses to the same work and pollutant loads will vary widely
among individuals. Despite such large interindividual variability, the magni-
tude of group mean lung function changes is positively associated with the
level of exercise and ozone concentration. Based on reported studies of 1 to
3 hr duration, significant pulmonary function impairment (decrement) occurs
when exercise is combined with exposure to ozone:
1. Light exercise (VV < 25 L/min) - Effects at > 0.37 ppm 03;
2. Moderate exercise (VV = 26 to 43 L/min) - Effects at > 0.30 ppm 03;
3. Heavy exercise (VV = 44 to 63 L/min) - Effects at > 0.24 ppm 03; and
4. Very heavy exercise (VV > 64 L/min) - Effects at :> 0.18 ppm 03, with
suggestions of decrements at 0.12 ppm 0~.
019JSA/A 13-76 6/26/84
-------
For the majority of the controlled studies, 15-min intermittent exercise
alternated with 15-min rest was employed for the duration of the exposure.
Continuous exercise equivalent in duration to the sum of intermittent exercise
periods at comparable ozone concentrations (0.2 to 0.4 ppm) and minute ventila-
tion (60 to 80 L/min) seems to elicit about the same changes in pulmonary
function. The maximum response to 0., exposure can be observed within 5 to
10 min following the end of each exercise period. 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 within 24 hr. In some individuals, despite apparent
functional recovery, other regulatory systems may still exhibit abnormal
responses when stimulated; e.g., airway hyperreactivity might persist for
days.
A close association has been observed between changes in pulmonary function
and the occurrence of respiratory symptoms in response to acute exposure to
Q~. This association holds for both the time-course and magnitude of effects.
The symptoms found in association with clinical exposure to 0,, alone and with
exposure to photochemical air pollution are similar but not identical. Eye
irritation, one of the most common complaints associated with photochemical
pollution, is not characteristic of clinical exposures to 0~, even at concen-
trations several times higher than any likely to be encountered in ambient
air. There is also evidence to suggest that other symptoms, indicative of
either upper or lower respiratory tract irritation, are more likely to occur
in populations exposed to ambient air pollution than in subjects exposed to 0,,
alone in chamber studies. For example, cough has been reported at 0.08 ppm 0~
and at 0.10 ppm oxidants in epidemiological studies and during clinical exposure
to 0.12 ppm 03; nose and throat irritation have been reported in community
studies in association with 0.10 ppm oxidants but not at or below 0.15 ppm 03
in laboratory studies. Between 0.15 and 0.30 ppm, a variety of both respira-
tory and nonrespiratory symptoms have been reported in controlled exposures.
They include throat dryness, difficulty or pain during deep inspiration, chest
tightness, substernal soreness or pain, wheezing, lassitude, malaise, and
nausea. Symptoms are therefore considered to be useful adjuncts in assessing
the effects of 0^ and photochemical pollution, particularly if combined with
objective measures of lung function.
019JSA/A 13-77 6/26/84
-------
Only a few studies have been designed to examine the effects of 0_ on
exercise performance. In one study, very heavy exercise (V^ > 64 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 inconsistent. 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 enhance
subjective symptoms and physiological impairment following 03 exposure.
Modification of the effects of 0, by these factors may be attributed to in-
creased ventilation which, like exercise, increases the overall volume of
inhaled pollutant and promotes greater penetration into peripheral areas of
the lung.
Additional factors suspected of altering sensitivity to ozone are numerous.
For example, age differences, especially between the very young and the very
old; gender differences, especially for children; personal habits such as
cigarette smoking; and possibly social, cultural, or economic factors such as
differences in nutritional status or differences in immunological status may
predispose individuals to susceptibility to ozone. 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:
1. 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 CL, studies have not been designed to test adequately for effects of
GO in different age groups.
2. Sex. Sex differences in responsiveness to ozone have not been
adequately studied. Lung function of women, as assessed by changes in FEV, Q,
appears to be affected more than that of men under similar exercise and expo-
sure conditions, but the differences have not been analyzed systematically.
Further research is needed to determine whether differences in lung volumes or
differences in exercise capacity during exposure may lead to sex differences
in responses to 0_.
019JSA/A 13-78 6/26/84
-------
3. Smoking Status. Differences between smokers and nonsmokers have
been studied often, but the data are not documented well and are often confusing.
Published results indicate a discrepancy in findings. There is some evidence,
however, to suggest that smokers may be less sensitive to 0~.
4. Nutritional Status. Antioxidant properties of vitamin E in preventing
ozone-initiated peroxidation jj\ vitro are well demonstrated and their protective
effects 2ji 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 hematological
effects from 0_ exposure.
Successive daily brief exposures of healthy human subjects to 0,. (<0.7 ppm
for approximately 2 hr) induce a typical temporal pattern of response. 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 effects are, on the average, not different from those observed
following control (air) exposure. Individuals need between 3 and 7 days to
develop full attenuation, with more sensitive subjects requiring more time.
The magnitude of a peak response to 0~ appears to be directly related to its
concentration. In addition, concentrations of 03 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 in most individuals, while partial
attenuation might persist for up to 2 weeks. Although symptomatic response is
generally related to the magnitude of the functional response, partial sympto-
matic attenuation appears to persist longer, for up to 4 weeks.
Whether populations exposed to photochemical air pollution develop at
least partial attenuation is unknown. No epidemiological studies have been
designed to test this hypothesis. While there is limited information obtained
from controlled laboratory studies to support this hypothesis, additional
information is required.
Responses to 0~, whether functional, biochemical, or morphological, have
the potential for altering responses in both man and laboratory animals during
019JSA/A 13-79 6/26/84
-------
repeated or continuous exposure. At present, the underlying mechanisms for
this response are poorly understood and the effectiveness of such mitigating
forces in protecting the long-term health of the individual against 0- is
still uncertain. Therefore, hyperresponsiveness to 0^, including changes in
bronchial reactivity, and the subsequent attenuation of responsiveness may be
viewed as sequential states in a continuing process.
Several animal experiments have demonstrated increased susceptibility to
respiratory infections following 0~ exposure. Thus, it could be hypothesized
that humans exposed to 03 could experience decrements in their host defenses
against infection. At the present time, however, these effects have not been
described in humans exposed to 0-, so that concentrations at which effects
might occur in man or the severity of such effects are unknown and difficult
to predict.
Animal studies have also reported a number of extrapulmonary responses to
0«, including cardiovascular, reproductive, and teratological effects, along
«J
with changes in endocrine 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 morphology and enzymatic
activity, as well as chromosomal effects on circulating lymphocytes, have been
observed in man and laboratory animals following exposure to high concentra-
tions of 0~. It is unlikely, however, that these changes would have any
functional significance in humans when exposure schedules are used that are
representative of exposures that the population at large might actually expe-
rience.
Currently available evidence indicates that individuals with preexisting
disease respond to 0_ exposure to a similar degree as normal subjects. Patients
•J
with chronic obstructive lung disease and/or asthma have not shown increased
sensitivity to CL in controlled human exposure studies, but there is some
indication from epidemiological studies that asthmatics may be symptomatically
and possibly functionally more sensitive 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 sensitivity to 0^ can be
adequately determined. None of these factors has been sufficiently studied
in relation to 0., exposures to give definitive answers. Thus, estimates of
O
at-risk populations are difficult to assess with any precision.
Despite wide variations in study techniques and experimental designs,
acute and subchronic exposures of animals to levels of ozone < 0.5 ppm produce
019JSA/A 13-80 6/26/84
-------
similar types of responses in all species examined. A characteristic inflamma-
tory lesion occurs at the junction of the conducting airways and the gas-
exchange regions of the lung after acute 0_ 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 0_ exposures is
especially important since it appears to be correlated with increased lung
collagen content and remodeling of the centriacinar airways. There is no
evidence of emphysema, however, in the lungs of animals exposed to 0~ for
prolonged periods of time.
Controlled human and animal exposures have not consistently demonstrated
any enhancement of respiratory effects for combined exposures of 0- with SC- ,
NOp, CO, or HLSO. and other particulate aerosols. Ozone alone is considered
to be responsible for the observed effects of those combinations or of multi-
ple mixtures of these pollutants. In addition, there have been far too few
controlled toxicological studies with other oxidants, such as peroxyacetyl
nitrate or hydrogen peroxide, to permit any sound scientific evaluation of
their contribution to the toxic action of photochemical oxidant mixtures.
Nevertheless, there is still some concern that combinations of oxidant pollu-
tants with other pollutants may contribute to the symptom aggravation and
decreased lung function described in epidemiological studies on individuals
with asthma and in children and young adults. For this reason, the effects of
interaction between inhaled oxidant gases and other 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.
Despite uncertainties that may exist in the data, it is possible to
identify three major subpopulations that may be at particular risk from expo-
sure to ozone, based on known health effects, activity patterns, personal
habits, and actual or potential exposures to ozone.
The first major subpopulation that appears to be at particular risk from
exposure to ozone is that subgroup of the general population characterized as
having preexisting disease. Available data on actual differences in sensiti-
vity between these and healthy, normal members of the general population
indicate that under the exposure regimes used to date individuals with pre-
existing disease may not be more sensitive to ozone than normal individuals.
Nevertheless, two considerations place these individuals among subpopulations
at potential risk from exposure to ozone. First, it must be noted that concern
019JSA/A 13-81 6/26/84
-------
with triggering untoward reactions has necessitated the use of low concentra-
tions and low exercise levels in most studies on subjects with preexisting
disease. Therefore, few or no data on responses at higher concentrations and
higher exercise levels are available for comparison with responses in normal
subjects. Thus, definitive data on responses in individuals with preexisting
disease are not available and may not ever become 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. Such
declines may be expected to impair further the ability to perform normal
activities. In individuals with preexisting diseases such as asthma or aller-
gies, 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.
A second major subpopulation at apparent special risk from exposure to
ozone consists of individuals ("responders") in the general population, not
yet characterized medically except for their responses to ozone, who experience
greater decrements in lung function from exposure to ozone than those observed
in the remainder of the general population. As yet no means of determining in
advance those members of the general population who are "responders" has been
devised.
Data presented in this chapter underscore the importance of exercise in
the potentiation of effects from exposure to ozone. Thus, a third major
subpopulation potentially at risk from exposure to ozone is composed of those
individuals (healthy and otherwise) whose activities out of doors, whether
vocational or avocational, result in increases in minute ventilation. Although
many individuals with preexisting disease would not be expected to exercise at
the same levels one would expect in healthy individuals, any increase in
activity level would bring about a commensurate increase in minute ventilation.
To the extent that the aged, the young, males, or females participate in
activities out of doors that raise their minute ventilations, all of these
subgroups may be considered to be potentially at risk, depending upon other
determinants of total ozone dose, Q-3 concentration, and exposure duration.
Other biological and nonbiological factors are suspected of influencing
responses to ozone. Data remain inconclusive at the present, however, regard-
ing the importance of age, gender, and other factors in influencing response
019JSA/A 13-82 6/26/84
-------
to ozone. Thus, at the present time, no other subpopulations 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" populations are
both the domain of the Administrator.
019JSA/A 13-83 6/26/84
-------
13.9 REFERENCES
Abraham, W. M. ; Januszkiewicz, A. J.; Mingle, M.; Welker, M.; Wanner, A.;
Sackner, M. A. (1980) Sensitivity of bronchoprovocation and tracheal
mucous velocity in detecting airway responses to 0.,. J. Appl. Physiol.
Respir. Environ. Exercise Physiol. 48: 789-793.
Adams, W. C. ; Savin, W. M.; Christo, H.E. (1981) Detection of ozone toxicity
during continuous exercise via the effective dose concept. J. Appl.
Physiol. Respir. Environ. Exercise Physiol. 51: 415-422.
Adams, W. C. ; Schelegle, E. S. (1983) Ozone toxicity effects consequent to
prolonged, high intensity exercise in trained endurance athletes. J.
Appl. Physiol. Respir. Environ. Exercise Physiol. 55: 805-812.
Alpert, S. M. ; Gardner, D. E. ; Hurst, D. J.; Lewis, T. R.; Coffin, D. L.
(1971) Effects of exposure to ozone on defensive mechanisms of the lung.
J. Appl. Physiol. 31: 247-252.
Altshuller, A. P. (1977) Eye irritation as an effect of photochemical air
pollution. J. Air Pollut. Control Assoc. 27: 1125-1126.
Altshuller, A. P. (1983) Measurements of the products of atmospheric photochem-
ical reactions in laboratory studies and in ambient air—relationships
between ozone and other products. Atmos. Environ. 17: 2383-2427.
Amdur, M. 0.; Ugro, V.; Underbill, D. W. (1978) Respiratory response of guinea
pigs to ozone alone and with sulfur dioxide. Am. Ind. Hyg. Assoc. J. 39:
958-961.
Amoruso, M. A.; Witz, G. ; Goldstein, B. D. (1981) Decreased superoxide anion
radical production by rat alveolar macrophages following inhalation of
ozone or nitrogen dioxide. Life Sci. 28: 2215-2221.
Aranyi, C., Vana, S. C.; Thomas, P. T.; Bradof, J. N.; Renters, J. D.; Graham,
J. A.; Miller, F. J. (1983) Effects of subchronic exposure to a mixture
of GO, S0« and (NH.)?SOA on host defenses of mice. J. Toxicol. Environ.
Health 12: 55-71. ^ 4
Balchum, 0. J. (1973) lexicological effects of ozone, oxidant, and hydrocarbons.
In: Proceedings of the conference on health effects of air pollution:
prepared for the Committee on Public Works, U.S. Senate; October; Washing-
ton, DC. Washington, DC: Government Printing Office; pp. 489-505.
Available from: GPO, Washington, DC; S/N 5270-02105.
Barry, B. E. ; Miller, F. J. ; Crapo, J. D. (1983). Alveolar epithelial injury
caused by inhalation of 0.25 ppm of ozone. In: Lee, S. D. ; Mustafa,
M. G.; Mehlman, M. A., eds. International symposium on the biomedical
effects of ozone and related photochemical oxidants; March 1982; Pine-
hurst, NC. Princeton, NJ: Princeton Scientific Publishers, Inc; pp.
299-309. (Advances in modern environmental toxicology: v. 5.)
019GLY/A 13-84 6/26/84
-------
Barry, B. E. (1983) Morphometric and morphologic studies of the effects of
asbestos, oxygen, and ozone on the lung. Durham, NC: Duke University;
Ph.D. thesis.
Bartlett, D.; Faulkner, C. S. II; Cook, K. (1974) Effect of chronic ozone
exposure on lung elasticity in young rats. J. Appl. Physiol. 37: 92-96.
Bates, D. V.; Hazucha, M. (1973) The short-term effects of ozone on the human
lung. In: Proceedings of the conference on health effects of air pollu-
tants: prepared for the Committee on Public Works. U.S. Senate; October;
Washington, D.C. Washington, DC: Government Printing Office; pp. 507-540.
Available from: GPO, Washington, DC; S/N 5270-02105.
Bates, D. V.; Bell, G. M.; Burnham, C. D.; Hazucha, M. ; Mantha, J.; Pengelly,
L. D. ; Silverman, F. (1972) Short-term effects of ozone on the lung. J.
Appl. Physiol. 32: 176-181.
Bedi, J. F. ; Folinsbee, L. J. ; Horvath, S. M. ; Ebenstein, R. S. (1979) Human
exposure to sulfur dioxide and ozone: absence of a synergistic effect.
Arch. Environ. Health 34: 233-239.
Bedi, J. F.; Horvath, S. M.; Folinsbee, L. J. (1982) Human exposure to sulfur
dioxide and ozone in a high temperature-humidity environment. Am. Ind.
Hyg. Assoc. J. 43: 26-30.
Bell, K. A.; Linn, W. S.; Hazucha, M.; Hackney, J. D.; Bates, D. V. (1977)
Respiratory effects of exposure to ozone plus sulfur dioxide in Southern
Californians and Eastern Canadians. Am. Ind. Hyg. Assoc. J. 38: 695-705.
Bennett, G. (1962) Oxygen contamination of high altitude aircraft cabins.
Aerosp. Med. 33: 969-973.
Berk, J. V.; Young, R. A.; Brown, S. R. ; Hollowell, C. D. (1981) Impact of
energy-conserving retrofits on indoor air quality in residential housing.
Presented at the 74th Annual Meeting of the Air Pollution Control Associa-
tion; June; Philadelphia, PA. Berkeley, CA: University of California,
Lawrence Berkeley Laboratory; report no. LBL-12189. Cited in: Yocom, J.
E. (1982).
Bhatnagar, R. S.; Hussain, M. Z. ; Sorensen, K. R.; Mustafa, M. G.; von Dohlen,
F. M.; Lee, S. 0. (1983) Effect of ozone on lung collagen biosynthesis.
In: Lee, S. D.; Mustafa, M. G.; Mehlman, M. A., eds. International
symposium on the biomedical effects of ozone and related photochemical
oxidants; March 1982; Pinehurst, N.C. Princeton, NJ: Princeton Scienti-
fic Publishers, Inc.; pp. 311-321. (Advances in modern environmental
toxicology: vol. 5).
Boatman, E. S.; Sato, S.; Frank, R. (1974) Acute effects of ozone on cat
lungs. II. Structural. Am. Rev. Respir. Dis. 110: 157-169.
Boorman, G. A.; Schwartz, L. W.; Dungworth, D. L. (1980) Pulmonary effects of
prolonged ozone insult in rats. Morphometric evaluation of the central
acinus. Lab. Invest. 43: 108-115.
019GLY/A 13-85 6/26/84
-------
Boushey, H. A.; Holtzman, M. J.; Sheller, J. R.; Nadel, J. A. (1980) State of
the art: bronchial hyperreactivity. Am. Rev. Respir. Dis. 121: 389-413.
Bradley, M. 0. ; Erickson, L. C. (1981) Comparison of the effects of hydrogen
peroxide and x-ray irradiation on toxicity, mutation, and DNA damage/
repair in mammalian cells (V-79). Biochim. Biophys. Acta 654: 135-141.
Bradley, M. 0. ; Hsu, I.C.; Harris, C.C. (1979) Relationships between sister
chromatid exchange and mutagenicity, toxicity, and DNA damage. Nature
(London) 282: 318-320.
Bromberg, P. A.; Hazucha, M. J. (1982) Editorial: Is "adaptation" to ozone
protective? Am. Rev. Respir. Dis. 125: 489-490.
Buckley, R. D. ; Hackney, J. D. ; Clark, K. ; Posin, C. (1975) Ozone and human
blood. Arch. Environ. Health 30: 40-43.
Bufalini, J. J. ; Gay, B. W. , Jr.; Brubaker, K. L. (1972) Hydrogen peroxide
formation from formaldehyde photooxidation and its presence in urban
atmospheres. Environ. Sci. Techno!. 6: 816-821.
Calabrese, E. J.; Moore, G. S. (1980) Does the rodent model adequately predict
the effects of ozone-induced changes to human erythrocytes? Med. Hypothe-
ses 6: 505-507.
Calabrese, E. J.; Kojola, N. H.; Carnow, B. W. (1977) Ozone: a possible cause
of hemolytic anemia in glucose-6-phosphate dehydrogenase deficient in
individuals. J. Toxicol. Environ. Health 2: 709-712.
Calabrese, E. J.; Moore, G. S.; Williams, P. S. (1982) Effect of methyl oleate
ozonide, a possible ozone intermediate, on normal and G-6-PD deficient
erythrocytes. Bull. Environ. Contam. Toxicol. 29: 498-504.
Calabrese, E. J. ; Moore, G. S. ; Williams, P. S. (1983) An evaluation of the
Dorset sheep as a predictive animal model for the response of G-6-PD
deficient human erythrocytes to a proposed systemic toxic ozone interme-
diate, methyl oleate hydroperoxide. Vet. Hum. Toxicol. 25: 241-246.
Campbell, K. I.; Hilsenroth, R. H. (1976) Impaired resistance to toxin in
toxoid-immunized mice exposed to ozone on nitrogen dioxide. Clin.
Toxicol. 9: 943-954.
Campbell, K. I.; Clarke, G. L. ; Emik, L. 0.; Plata, R. L. (1967) The atmos-
pheric contaminant peroxyacetyl nitrate. Arch. Environ. Health 15:
739-744.
Castleman, W. L.; Tyler, W. S.; Dungworth, D. L. (1977) Lesions in respiratory
bronchioles and conducting airways of monkeys exposed to ambient levels
of ozone. Exp. Mol. Pathol. 26: 384-400.
Castleman, W. L.; Dungworth, D. L.; Schwartz, L. W.; Tyler, W. S. (1980) Acute
respiratory bronchiolitis: an ultrastructural and autoradiographic study
of epithelial cell injury and renewal in rhesus monkeys exposed to ozone.
Am. J. Pathol. 98: 811-840.
019GLY/A 13-86 6/26/84
-------
Cavender, F. L. ; Singh, B.; Cockrell, B. Y. (1978) Effects in rats and guinea
pigs of six-month exposures to sulfuric acid mist, ozone and their combi-
nation. J. Toxicol. Environ. Health 4: 845-852.
Cavender, F. L. ; Steinhagen, W. H.; Ulrich, C. E. ; Busey, W. M. ; Cockrell, B.
Y. ; Baseman, 0. K. ; Hogan, M. D.; Drew, R. T. (1977) Effects in rats and
guinea pigs of short-term exposures to sulfuric acid mist, ozone, and
their combination. J. Toxicol. Environ. Health 3: 521-533.
Chaney, S. G. (1981) Effects of ozone on leukocyte DMA. Research Triangle
Park, NC: U.S. Environmental Protection Agency, Health Effects Research
Laboratory; EPA report no. EPA-600/1-81-031. Available from: NTIS,
Springfield, VA; PB81-179277.
Chow, C. K. (1976) Biochemical responses in lungs of ozone-tolerant rats.
Nature (London) 260: 721-722.
Chow, C. K. ; Tappel, A. L. (1972) An enzymatic protective mechanism against
lipid peroxidation damage to lungs of ozone-exposed rats. Lipids 7:
518-524.
Chow, C. K. ; Mustafa, M. G.; Cross, C. E.; Tarkington, B. K. (1975) Effects of
ozone exposure on the lungs and the erythrocytes of rats and monkeys:
relative biochemical changes. Environ. Physiol. Biochem. 5: 142-146.
Chow, C. K. ; Plopper, C. G. ; Chiu, M.; Dungworth, D. L. (1981) Dietary vitamin E
and pulmonary biochemical and morphological alterations of rats exposed
to 0.1 ppm ozone. Environ. Res. 24: 315-324.
Chow, C. K. ; Hussain, M. Z. ; Cross, C. E. ; Dungworth, D. L. ; Mustafa, M. G.
(1976) Effect of low levels of ozone on rat lungs. I. Biochemical respon-
ses during recovery and reexposure. Exp. Mol. Pathol. 25: 182-188.
Clark, K. W. ; Posin, C. I.; Buckley, R. D.. (1978) Biochemical response of
squirrel monkeys to ozone. J. Toxicol. Environ. Health 4: 741-753.
Coffin, D. L. ; Gardner, D. E. (1972) Interaction of biological agents and
chemical air pollutants. Ann. Occup. Hyg. 15: 219-235.
Coffin, D. L. ; Gardner, D. E.; Holzman, R. S. ; Wolock, F. J. (1968) Influence
of ozone on pulmonary cells. Arch. Environ. Health 16: 633-636.
Cosio, M. G. ; Hale, K. A.; Niewoehner, D. E. (1980) Morphologic and morphome-
tric effects of prolonged cigarette smoking on the small airways. Am.
Rev. Respir. Dis. 122: 265-271.
Costa, D. L.; Kutzman, R. S.; Lehmann, J. R.; Popenoe, E. A.; Drew, R. T.
(1983) A subchronic multi-dose ozone study in rats. In: Lee, S. D. ;
Mustafa, M. G. ; Mehlman, M. A., eds. International symposium on the
biomedical effects of ozone and related photochemical oxidants; March
1982; Pinehurst, NC. Princeton, NJ: Princeton Scientific Publishers,
Inc.; pp. 369-393. (Advances in modern environmental toxicology: v. 5).
Darley, E. F. ; Kettner, K. A.; Stevens, E. R. (1963) Analysis of peroxyacyl
nitrates by gas chromatography with electron capture detection. Anal.
Chem. 35: 589-591.
019GLY/A 13-87 6/26/84
-------
Davis, J. D. ; Gallo, J.; Hu, E. P. C.; Boucher, R. C.; Bromberg, P. A. (1980)
The effects of ozone on respiratory epithelial permeability. Am. Rev.
Respir. Dis. 121: 123A.
DeLucia, A. J. ; Mustafa, M. G. ; Cross, C. E. ; Plopper, C. G. ; Dungworth,
D. L. ; Tyler, W. S. (1975) Biochemical and morphological alterations in
the lung following ozone exposure. In: Rai, C.; Spielman, L. A., eds.
Air: I. pollution control and clean energy; 1973; New Orleans, LA;
Detroit, MI; Philadelphia, PA; Vancouver, British Columbia. New York,
NY: American Institute of Chemical Engineers; pp. 93-100. (AIChE sympo-
sium series: no. 147, v. 71).
DeLucia, A. J. ; Adams, W. C. (1977) Effects of 0_ inhalation during exercise
on pulmonary function and blood biochemistry. J. Appl. Physiol. Respir.
Environ. Exercise Physiol. 43: 75-81.
DeLucia, A. J. ; Whitaker, J. A.; Bryant, L. R. (1983) Effects of combined
exposure to ozone and carbon monoxide in humans. In: Mehlman, M. A. ;
Lee, S. D. ; Mustafa, M. G. , eds. International symposium on the bio-
medical effects of ozone and related photochemical oxidants; March 1982;
Pinehurst, NC. Princeton, NJ: Princeton Scientific Publishers, Inc.;
pp. 145-159. (Advances in modern environmental toxicology: v. 5.)
Dimeo, M. J.; Glenn, M. G. ; Holtzman, M. J.; Sheller, J. R.; Nadel, J. A.;
Boushey, H. A. (1981) Threshold concentration of ozone causing an increase
in bronchial reactivity in humans and adaptation with repeated exposures.
Am. Rev. Respir. Dis. 124: 245-248.
Donovan, D. H. ; Williams, S. J.; Charles, J. M.; Menzel, D. B. (1977) Ozone
toxicity: Effect of dietary vitamin E and polyunsaturated fatty acids.
Toxicol. Lett. 1: 135-139.
Dorsey, A. P.; Morgan, D. L. ; Menzel, D. B. (1983) Filterability of erythro-
cytes from ozone-exposed mice. In: Abstracts of the third international
congress on toxicology; September; San Diego, CA. Toxicol. Lett.
18(suppl. 1): 146.
Dowel 1, A. R. ; Lohrbauer, L. A.; Hurst, D.; Lee, S. D. (1970) Rabbit alveolar
macrophage damage caused by i_n vivo ozone inhalation. Arch. Environ.
Health 21: 121-127.
Drinkwater, B. L. ; Raven, P. B. ; Horvath, S. M.; Gliner, J. A.; Ruhling, R.
W. ; Bolduan, N. W. (1974) Air pollution, exercise and heat stress. Arch.
Environ. Health 28: 177-181.
Dungworth, D. L. (1976) Short-term effects of ozone on lungs of rats, mice and
monkeys. EHP Environ. Health Perspect. 16: 179.
Dungworth, D. L.; Clarke, G. L.; Plata, R. L. (1969) Pulmonary lesions produced
in A-strain mice by exposure to peroxyacetylnitrates. Am. Rev. Respir.
Dis. 99: 565-574.
Dungworth, D. L. ; Castleman, W. L. ; Chow, C. K. ; Mellick, P. W. ; Mustafa, M.
G. ; Tarkington, B. ; Tyler, W. S. (1975) Effects of ambient levels of
ozone on monkeys. Fed. Proc. Fed. Am. Soc. Exp. Biol. 34: 1670-1674.
019GLY/A 13-88 6/26/84
-------
Ehrlich, R. (1980) Interaction between environmental pollutants and respiratory
infections. EHP Environ. Health Perspect. 35: 89-100.
Ehrlich, R. (1983) Changes in susceptibility to respiratory infection caused
by exposure to photochemical oxidant pollutants. In: Lee, S. 0.; Mustafa,
M. G. ; Mehlman, M. A. , eds. International symposium on the biomedical
effects of ozone and related photochemical oxidants; March 1982; Pinehurst,
NC. Princeton, NJ: Princeton Scientific Publishers, Inc.; pp. 273-285.
(Advances in modern environmental toxicology: v.5).
Ehrlich, R. ; Findlay, J. C. ; Fenters, J. D. ; Gardner, D. E. (1977) Health
effects of short-term inhalation of nitrogen dioxide and ozone mixtures.
Environ. Res. 14: 223-231.
Ehrlich, R.; Findlay, J. C. ; Gardner, D. E. (1979) Effects of repeated exposures
to peak concentrations of nitrogen dioxide and ozone on resistance to
streptococcal pneumonia. J. Toxicol. Environ. Health 5: 631-642.
Elsayed, N. M.; Mustafa, M. G. ; Postlethwait, E. M. (1982) Age-dependent
pulmonary response of rats to ozone exposure. J. Toxicol. Environ.
Health 9: 835-848.
Eustis, S. L. ; Schwartz, L. W.; Kosch, P. C.; Dungworth, D. L. (1981) Chronic
bronchiolitis in nonhuman primates after prolonged ozone exposure. Am.
J. Pathol. 105: 121-137.
Evans, G. ; Finkelstein, P.; Martin, B. ; Possiel , N. ; Graves, M. (1982) The
National Air Pollution Background Network, 1976-1980. Research Triangle
Park, NC: U.S. Environmental Protection Agency; EPA report no.
EPA-600/4-82-058.
Evans, M. J. ; Johnson, L. V.; Stephens, R. J.; Freeman, G. (1976a) Renewal of
the terminal bronchiolar epithelium in the rat following exposure to N0»
or 03. Lab. Invest. 35: 246-257.
Evans, M. J.; Johnson, L. V.; Stephens, R. J.; Freeman, G. (1976b) Cell renewal
in the lungs of rats exposed to low levels of ozone. Exp. Mol. Pathol.
24: 70-83.
Evans, M. J. ; Stephens, R. J.; Freeman, G. (1976c) Renewal of pulmonary
epithelium following oxidant injury. In: Bouhuys, A., ed. Lung cells
in disease. New York, NY: Elsevier Press; pp. 165-178.
Fabbri, L. M. ; Aizawa, H. ; 0' Byrne, P. M. ; Walters, E. H. ; Holtzman, M. J. ;
Nadel, J. A. (1983) BW755c inhibits airway responsiveness induced by
ozone in dogs. Physiologist 26(4): A-35. Abstract.
Fabbri, L. M.; Aizawa, H.; Alpert, S. E.; Walters, E. H.; O'Byrne, P. M. ;
Gold, B. D. ; Nadel, J. A.; Holtzman, M. J. (1984) Airway hyperresponsive-
ness and changes in cell counts in bronchoalveolar lavage after ozone
exposure in dogs. Am. Rev. Respir. Dis. 129: 288-291.
Farmer, J. C. ; Dawson, G. A. (1982) Condensation sampling of soluble atmos-
pheric trace gases. J. Geophys. Res. 87: 8931-8942.
019GLY/A 13-89 6/26/84
-------
Parrel 1, B. P.; Kerr, H. D. ; Kulle, T. J. ; Saucier, L. R. ; Young, J. L. (1979)
Adaptation in human subjects to the effects of inhaled ozone after
repeated exposure. Am. Rev. Respir. Dis. 119: 725-730.
Folinsbee, L. J. ; Silverman, P.; Shephard, R. J. (1977a) Decrease of maximum
work performance following ozone exposure. J. Appl. Physio!. Respir.
Environ. Exercise Physio!. 42: 531-536.
Folinsbee, L. J. ; Silverman, P.; Shephard, R. J. (1975) Exercise responses
following ozone exposure. J. Appl. Physio!. 38: 996-1001.
Folinsbee, L. J.; Bedi, J. F.; Horvath S. M. (1984) Pulmonary function changes
in trained athletes following 1-hour continuous heavy exercise while
breathing 0.21 ppm ozone. J. Appl. Physiol. Respir. Environ. Exercise
Physiol. (In Press).
Folinsbee, L. J. ; Bedi, J. F.; Horvath, S. M. (1980) Respiratory responses in
humans repeatedly exposed to low concentrations of ozone. Am. Rev. Respir.
Dis. 121: 431-439.
Folinsbee, L. J. ; Drinkwater, B. L. ; Bedi, J. F. ; Horvath, S. M. (1978) The
influence of exercise on the pulmonary changes due to exposure to low
concentrations of ozone. In: Folinsbee, L. J. ; Wagner, J. A.; Borgia, J.
F. ; Drinkwater, B. L.; Gliner, J. A.; Bedi, J. F. , eds. Environmental
stress: individual human adaptations. New York, NY: Academic Press;
pp. 125-145.
Folinsbee, L. J. ; Horvath, S. M. ; Raven, P. B. ; Bedi, J. F. ; Morton, A. R.;
Drinkwater, B. L.; Bolduan, N. W.; Gliner, J. A. (1977b) Influence of
exercise and heat stress on pulmonary function during ozone exposure. J.
Appl. Physiol. Respir. Environ. Exercise Physiol. 43: 409-413.
Frager, N. B. ; Phalen, R. F. ; Kenoyer, J. L. (1979) Adaptations to ozone in
reference to mucociliary clearance. Arch. Environ. Health 34: 51-57.
Freeman, G. ; Stephens, R. J. ; Coffin, D. L. ; Stara, J. F. (1973) Changes in
dog's lungs after long-term exposure to ozone. Arch. Environ. Health
26: 209-216.
Freeman, G. ; Juhos, L. T. ; Furiosi, N. J. ; Mussenden, R. ; Stephens, R. J. ;
Evans, M. J. (1974) Pathology of pulmonary disease from exposure to
interdependent ambient gases (nitrogen dioxide and ozone). Arch. Environ.
Health 29: 203-210.
Fujinaka, L. E. (1984) Respiratory bronchiolitis following "long-term ozone
exposure in Bonnet monkeys: a morphometric study. Davis, CA: University
of California; Master's thesis.
Gardner, D. E. ; Miller, F. J. ; Tiling, J. W. ; Kirtz, J. M. (1977) Increased
infectivity with exposure to ozone and sulfuric acid. Toxicol. Lett. 1:
59-64.
Gertner, A.; Bromberger-Barnea, B.; Traystman, R.; Menkes, H. (1983c) Effects
of ozone in peripheral lung reactivity. J. Appl. Physiol. Respir. Environ.
Exercise Physiol. 55: 777-784.
019GLY/A 13-90 6/26/84
-------
Gertner, A.; Bromberger-Barnea, B. ; Dannenberg, A. M. , Jr.; Traystman, R. ;
Menkes, H. (1983a) Responses of the lung periphery to 1.0 ppm ozone. J.
Appl. Physio!. Respir. Environ. Exercise Physio!. 55: 770-776.
Gertner, A.; Bromberger-Barnea, B. ; Traystman, R. ; Berzon, D. ; Menkes, H.
(1983b) Responses of the lung periphery to ozone and histamine. J. Appl.
Physiol. Respir. Environ. Exercise Physiol. 54: 640-646.
Gibbons, S. I.; Adams, W. C. (1984) Combined effects of ozone exposure and
ambient heat on exercising females. J. Appl. Physiol. In press.
Gillespie, J. R. (1980) Review of the cardiovascular and pulmonary function
studies on beagles exposed for 68 months to auto exhaust and other air
pollutants. In: Stara, J. F. ; Dungworth, D. L.; Orthoefer, J. C.;
Tyler, W. S., eds. Long-term effects of air pollutants in canine species.
Cincinnati, OH: U.S. Environmental Protection Agency; pp. 115-154;
EPA-600/8-80-014.
Gliner, J. A.; Horvath, S. M. ; Folinsbee, L. J. (1983) Pre-exposure to low
ozone concentrations does not diminish the pulmonary function response on
exposure to higher ozone concentration. Am. Rev. Respir. Dis. 127: 51-55.
Gliner, J. A.; Raven, P. B.; Horvath, S. M.; Drinkwater, B. L.; Sutton, J. C.
(1975) Man's physiologic response to long-term work during thermal and
pollutant stress. J. Appl. Physiol. 39: 628-632.
Gliner, J. A.; Matsen-Twisdale, J. A.; Horvath, S. M. (1979) Auditory and
visual sustained attention during ozone exposure. Aviat. Space
Environ. Med. 51: 344-351.
Golden, J. A.; Nadel, J. A.; Boushey, H. A. (1978) Bronchial hyperirritability
in healthy subjects after exposure to ozone. Am. Rev. Respir. Dis. 118:
287-294.
Goldstein, B. D. ; Lai, L. Y.; Cuzzi-Spada, R. (1974) Potentiation of comple-
ment-dependent membrane damage by ozone. Arch. Environ. Health 28:
40-42.
Goldstein, B. D. ; Hamburger, S. J.; Falk, G. W.; Amoruso, M. A. (1977) Effect
of ozone and nitrogen dioxide on the agglutination of rat alveolar macro-
phages by concanavalin A. Life Sci. 21: 1637-1644.
Goldstein, B. D.; Pearson, B.; Lodi, C.; Buckley, R. D.; Balchum, 0. J. (1968)
The effect of ozone on mouse blood i_n vivo. Arch. Environ. Health 16:
648-650.
Goldstein, E.; Tyler, W. S. ; Hoeprich, P. D. ; Eagle, C. (1971) Ozone and the
antibacterial defense mechanisms of the murine lung. Arch. Intern. Med.
128: 1099-1102.
Gooch, P. C. ; Creasia, D. A.; Brewen, J. G. (1976) The cytogenetic effect of
ozone: inhalation and in vitro exposures. Environ. Res. 12: 188-195.
019GLY/A 13-91 6/26/84
-------
Graham, J. A.; Menzel, D. B. ; Miller, F. J. ; Illing, J. W. ; Gardner, B. E.
(1981) Influence of ozone on pentobarbital-induced sleeping time in mice,
rats, and hamsters. Toxicol. Appl. Pharmacol. 61: 64-73.
Grose, E. C. ; Gardner, D. E. ; Miller, F. J. (1980) Response of ciliated epi-
theluim to ozone and sulfuric acid. Environ. Res. 22: 377-385.
Grose, E. C. ; Richards, J. H. ; Illing, J. W. ; Miller, F. J. ; Davies, D. W. ;
Graham, J. A. ; Gardner, D. E. (1982) Pulmonary host defense responses to
inhalation of sulfuric acid and ozone. J. Toxicol. Environ. Health 10:
351-362.
Grosjean, D. (1983) Distribution of atmospheric nitrogenous pollutants at a
Los Angeles area smog receptor site. Environ. Sci. Technol. 17: 13-19.
Guerrero, R. R. ; Rounds, D. E.; Olson, R. S. ; Hackney, J. D. (1979) Mutagenic
effects of ozone on human cells exposed i_n vivo and j_n vitro based on
sister chromatid exchange analysis. Environ. Res. 18: 336-346.
Haak, E. D.; Hazucha, M. J.; Stacy, R. W.; House, D. E.; Ketcham, B. T.; Seal,
E., Jr.; Roger, L. J. ; Knelson, J. R. (1984) Pulmonary effects in healthy
young men of four sequential exposures to ozone. Research Triangle Park,
NC: U.S. Environmental Protection Agency, Health Effects Research Labora-
tory; EPA report no. EPA-600/1-84-033. Available from National Technical
Information Service, Springfield, VA.
Hackney, J. D. ; Linn, W. S. ; Buckley, R. D.; Pedersen, E. E.; Karuza, S. K.;
Law, D. C. ; Fischer, D. A. (1975a) Experimental studies on human health
effects of air pollutants. I. Design considerations. Arch. Environ.
Health 30: 373-378.
Hackney, J. D. ; Linn, W. S. ; Mohler, J. G. ; Pedersen, E. E. ; Breisacher, P.;
Russo, A. (1975b) Experimental studies on human health effects of air
pollutants. II. Four-hour exposure to ozone and in combination with
other pollutant gases. Arch. Environ. Health 30: 379-384.
Hackney, J. D.; Linn, W. S.; Law, D. C.; Karuza, S. K.; Greenberg, H.; Buckley,
R. D. ; Pedersen, E. E. (1975c) Experimental studies on human health
effects of air pollutants. III. Two-hour exposure to ozone alone and in
combination with other pollutant gases. Arch. Environ. Health 30: 385-
390.
Hackney, J. D.; Linn, W. S.; Karuza, S. K.; Buckley, R. D.; Law, D. C.; Bates,
D. V.; Hazucha, M. ; Pengelly, L. D. ; Silverman, F. (1977b) Effects of
ozone exposure in Canadians and Southern Californians. Evidence for
adaptation? Arch. Environ. Health 32: 110-116.
Hackney, J. D. ; Linn, W. S. ; Buckley, R. D.; Hislop, H. J. (1976) Studies in
adaptation to ambient oxidant air pollution: effects of ozone exposure in
Los Angeles residents vs. new arrivals. EHP Environ. Health Perspect.
18: 141-146.
019GLY/A 13-92 6/26/84
-------
Hackney, J. D.; Linn, W. S. ; Fischer, D. A.; Shamoo, D. A.; Anzar, U. T. ;
Spier, C. E. ; Valencia, L. M. ; Veneto, T. G. (1983) Effect of ozone in
people with chronic obstructive lung disease. In: Mehlman, M. A.; Lee,
S. D.; Mustafa, M. G., eds. In: International symposium on the biomedical
effects of ozone and related photochemical oxidants; March 1982; Pinehurst,
NC. Princeton, NJ: Princeton Scientific Publishers, Inc.; pp. 145-159.
(Advances in modern environmental toxicology: v. 5.)
Hackney, J. D. ; Linn, W. S. ; Mohler, J. G.; Collier, C. R. (1977a) Adaptation
to short-term respiratory effects of ozone in men exposed repeatedly. J.
Appl. Physiol. Respir. Environ. Exercise Physiol. 43: 82-85.
Hadley, J. G. ; Gardner, D. E. ; Coffin D. L. ; Menzel, D. B. (1977) Enhanced
binding of autologous cells to the macrophage plasma membrane as a sensi-
tive indicator of pollutant damage. In: Sanders, C. L. ; Schneider, R.
P.; Dagle G. E. ; Ragan, H. A., eds. Pulmonary macrophage and epithelial
cells: proceedings of the sixteenth annual Hanford biology symposium;
September 1976; Richland, WA. Washington, DC: Energy Research and
Development Administration; pp. 1-21. (ERDA symposium series: 43).
Hale, K. A.; Niewoehner, D. E. ; Cosio, M. G. (1980) Morphologic changes in
muscular pulmonary arteries: relationship to cigarette smoking, airway
disease, and emphysema. Am. Rev. Respir. Dis. 122: 273-280.
Hamburger, S. J. ; Goldstein, B. D. ; Buckley, R. D. ; Hackney, J. D. ; Amoruso,
M. A. (1979) Effect of ozone on the agglutination of erythrocytes by
concanavalin A. Environ. Res. 19: 299-305.
Hamburger, S. J.; Goldstein, B. D. (1979) Effect of ozone on the agglutination
of erythrocytes by concanavalin A. Part I: studies in rats. Environ.
Res. 19: 292-298.
Hammer, D. I.; Hasselblad, V.; Portnoy, B.; Wehrle, P. F. (1974) Los Angeles
student nurse study. Daily symptom reporting and photochemical oxidants.
Arch. Environ. Health 28: 255-260.
Hazucha, M. (1981) Assessment of ozone-induced hyperreactivity by histamine in
normal healthy subjects. In: Proceedings of the research planning work-
shop on health effects of oxidants. Research Triangle Park, NC: U.S.
Environmental Protection Agency; EPA report no. EPA-600/9-81-001; pp. 314-
327. Available from National Technical Information Service, Springfield,
VA.
Hazucha, M. ; Bates, D. V. (1975) Combined effect of ozone and sulfur dioxide
on human pulmonary function. Nature (London) 257: 50-51.
Hazucha, M.; Parent, C.; Bates, D. V. (1977) Development of ozone tolerance in
man. In: Dimitriades, B., ed. International conference on photochemical
oxidant pollution and its control: proceedings: v. II; September 1976;
Raleigh, NC. Research Triangle Park, NC: U.S. Environmental Protection
Agency, Environmental Sciences Research Laboratory; pp. 527-541; EPA
report no. £PA-600/3-77-001a. Available from: National Technical Infor-
mation Service, Springfield, VA; PB 264232.
019GLY/A 13-93 6/26/84
-------
Hazucha, M.; Silverman, F.; Parent, C. ; Field, S.; Bates, D. V. (1973) Pulmonary
function in man after short-term exposure to ozone. Arch. Environ. Health
27: 183-188.
Heikes, B. G. ; Lazrus, A. L. ; Kok, G. L. ; Kunen, S. M. ; Gandrud, B. W. ;
Gitlin, S. N. ; Sperry, P. D. (1982) Evidence of aqueous phase hydrogen
peroxide synthesis in the troposphere. J. Geophys. Res. 87: 3045-3051.
Holtzman, M. I.; Cunningham, J. H.; Sheller, J. R.; Irsigler, G. B.; Nadel, J.
A. ; Boushey, H. A. (1979) Effect of ozone on bronchial reactivity in
atopic ana nonatopic subjects. Am. Rev. Respir. Dis. 120: 1059-1067.
Holtzman, M. J.; Fabbri, L. M.; Skoogh, B.-E.; O'Byrne, P. M.; Walters, E. H.;
Aizawa, H.; Nadel, J. A. (1983a) Time course of airway hyperresponsiveness
induced by ozone in dogs. J. Appl. Physio!. Respir. Environ. Exercise
Physiol. 55: 1232-1236.
Holtzman, M. J. ; Fabbri, L. M.; O'Byrne, P. M.; Gold, B. D.; Aizawa, H.;
Walters, S. E.; Alpert, S. E. ; Nadel, J. A. (1983b) Importance of airway
inflammation for hyperresponsiveness induced by ozone. Am. Rev. Respir.
Dis. 127: 686-690.
Horvath, S. M. ; Gliner, J. A.; Folinsbee, L. J. (1981) Adaptation to ozone:
duration of effect. Am. Rev. Respir. Dis. 123: 496-499.
Horvath, S. H.; Gliner, J. A.; Matsen-Twisdale, J. A. (1979) Pulmonary function
and maximum exercise responses following acute ozone exposure. Aviat.
Space Environ. Med. 40: 901-905.
Hurst, D. J. ; Coffin, D. L. (1971) Ozone effect on lysosomal hydrolases of
alveolar macrophages ijn vitro. Arch. Intern. Med. 127: 1059-1063.
Hurst, D. J. ; Gardner, D. E. ; Coffin, D. L. (1970) Effect of ozone on acid
hydrolases of the pulmonary alveolar macrophage. Res. J. Reticuloendothel.
Soc. 8: 288-300.
Hussain, M. Z. ; Cross, C. E. ; Mustafa, M. G.; Bhatnagar, R. S. (1976b) Hydroxy-
proline contents and prolyl hydroxylase activities in lungs of rats
exposed to low levels of ozone. Life Sci. 18: 897-904.
Hussain, M. Z. ; Mustafa, M. G.; Chow, C. K.; Cross, C. E. (1976a) Ozone-induced
increase of lung proline hydroxylase activity and hydroxyproline content.
Chest 69 (Suppl. 2): 273-275.
Ibrahim, A. L.; Zee, Y. C.; Osebold, J. W. (1976) The effects of ozone on the
respiratory epithelium and alveolar macrophages of mice. I. Interferon
production. Proc. Soc. Exp. Biol. Med. 152: 483-488.
Illing, J. W. ; Miller, F. J. ; Gardner, D. E. (1980) Decreased resistance to
infection in exercised mice exposed to N0? and 0_. J. Toxicol. Environ.
Health 6: 843-851.
019GLY/A 13-94 6/26/84
-------
Javitz, H. S. ; Kransnow, R. ; Thompson, C.; Patton, K. M.; Berthiaume, D. E.;
Palmer, A. (1983) Ambient oxidant concentrations in Houston and acute
health symptoms in subjects with chronic obstructive pulmonary disease: a
reanalysis of the HAOS health study. In: Lee, S. D. ; Mustafa, M. G. ;
Mehlman, M. A., eds. International symposium on the biomedical effects of
ozone and related photochemical oxidants; March 1982; Pinehurst, NC.
Princeton, NJ: Princeton Scientific Publishers, Inc.; pp. 227-256.
(Advances in modern toxicology: v. 5).
Johnson, D. A. (1980) Ozone inactivation of human alpha 1-proteinase inhibitor.
Am. Rev. Respir. Dis. 121: 1031-1038.
Jorgen, R. T.; Meyer, R. A.; Hughes, R. A. (1978) Routine peroxyacetyl nitrate
(PAN) monitoring applied to the Houston Area Oxidant Study. Presented at
71st Annual Meeting of the Air Pollution Control Association; June;
Houston, TX. Paper No. 78-50.1.
Kagawa, J. (1983) Effects of ozone and other pollutants on pulmonary function
in man. In: Lee, S. D.; Mustafa, M. G.; Mehlman, M. A., eds. Interna-
tional symposium on the biomedical effects of ozone and related photo-
chemical oxidants; March 1982; Pinehurst, NC. Princeton, NJ: Princeton
Scientific Publishers, Inc.; pp. 411-422. (Advances in modern toxicology:
v .5).
Kagawa, J.; Toyama, T. (1975) Photochemical air pollution: its effects on
respiratory function of elementary school children. Arch. Environ.
Health 30: 117-122.
Kagawa, J. ; Toyama, T.; Nakaza, M. (1976) Pulmonary function test in children
exposed to air pollution. In: Finkel, A. J.; Duel, W. C., eds. Clinical
implications of air pollution research: proceedings of the 1974 air
pollution medical research conference; December 1974; San Francisco, CA.
Acton, MA: Publishing Sciences Group, Inc.; pp. 305-320.
Kagawa, J.; Tsuru, K. (1979a) Effects of ozone and smoking alone and in combina-
tion on bronchial reactivity to inhaled acetylcholine. Nippon Kyobu
Shikkan Gakkai Zasshi 17: 703-709.
Kagawa, J. ; Tsuru, K. (1979b) Respiratory effects of 2-hour exposure to ozone
and nitrogen dioxide alone and in combination in normal subjects perform-
ing intermittent exercise. Nippon Kyobu Shikkan Gakkai Zasshi 17: 765-774.
Kagawa, J. ; Tsuru, K. (1979c) Respiratory effect of 2-hour exposure with
intermittent exercise to ozone and sulfur dioxide alone and in combina-
tion in normal subjects. Nippon Eiseigaku Zasshi 34: 690-696.
Kehrl , H. R. ; Hazucha, M. J. ; Solic, J. ; Bromberg, P. A. (1983) Effects of
ozone exposure on humans with moderate irreversible chronic obstructive
lung disease. In: Mehlman, M. A.; Lee, S. D.; Mustafa, M. G., eds.
International symposium on the biomedical effects of ozone and related
photochemical oxidants; March 1982; Pinehurst, NC. Princeton, NJ:
Princeton Scientific Publishers, Inc.; pp. 213-225. (Advances in modern
environmental toxicology: v. 5.)
019GLY/A 13-95 6/26/84
-------
Kelly, T. V.; Stedman, D. H.; Kok, G. L. (1979) Measurements of H?0 and HNO
in rural air. Geophys. Res. Lett. 6: 375-378.
Kenoyer, J. L.; Phalen, R. F.; Davis, J. R. (1981) Particle clearance from the
respiratory tract as a test of toxicity: effect of ozone on short and
long term clearance. Exp. Lung Respir. 2: 111-120.
Kerr, H. D. ; Kulle, T. J. ; Mcllhany, M. L. ; Swidersky, P. (1975) Effects of
ozone on pulmonary function in normal subjects. Am. Rev. Respir. Dis.
Ill: 763-773.
Ketcham, B. ; Lassiter, S.; Haak, E. D., Jr.; Knelson, J. H. (1977) Effects of
ozone plus moderate exercise on pulmonary function in healthy young men.
In: Proceedings of the international conference on photochemical oxidant
pollution and its control. Research Triangle Park, NC: U.S. Environmental
Protection Agency; EPA report no. EPA-600/3-77-001a; pp. 495-504. Avail-
able from National Technical Information Service, Springfield, VA.
Kleinman, M. T. ; Bailey, R. M. ; Chung, C. Y-T. ; Clark, K. W. ; Jones, M. P.;
Linn, W. S.; Hackney, J. D. (1981) Exposures of human volunteers to a
controlled atmospheric mixture of ozone, sulfur dioxide and sulfuric
acid. Am. Ind. Hyg. Assoc. J. 42: 61-69.
Ko'nig, G. ; Rommelt, H. ; Kienele, H. ; Dirnagl, K. ; Polke, H. ; Fruhmann, G.
(1980) Changes in the bronchial reactivity of humans caused by the influ-
ence of ozone. Arbeitsmed. Sozialmed. Praeventivmed. 151: 261-263.
Kulle, T. J.; Kerr, H. D.; Farrell, B. P.; Sauder, L. R.; Bermel, M. S. (1982a)
Pulmonary function and bronchial reactivity in human subjects with expo-
sure to ozone and respirable sulfuric acid aerosol. Am. Rev. Respir. Dis.
126: 996-1000.
Kulle, T. J. ; Milman, J. H.; Sauder, L. R.; Kerr, H. D.; Parrel 1, B. P.;
Miller, W. R. (1984) Pulmonary function adaptation to ozone in subjects
with chronic bronchitis. Environ. Res. (In Press).
Kulle, T. J. ; Sauder, L. R.; Kerr, H. D.; Parrel 1, B. P.; Bermel, M. S.;
Smith, D. M. (1982b) Duration of pulmonary function adaptation to ozone
in humans. Am. Ind. Hyg. Assoc. J. 43: 832-837.
Last, J. A.; Cross, C. E. (1978) A new model for health effects of air pol-
lutants: evidence for synergistic effects of mixtures of ozone and sulfuric
acid aerosols on rat lungs. J. Lab. Clin. Med. 91: 328-339.
Last, J. A.; Greenberg, D. B. (1980) Ozone-induced alterations in collagen
metabolism of rat lungs. II. Long-term exposure. Toxicol. Appl. Pharmacol
55: 108-114.
Last, J. A.; Greenberg, D. B. ; Castleman, W. L. (1979) Ozone-induced altera-
tions in collagen metabolism of rat lungs. Toxicol. Appl. Pharmacol. 51:
247-258.
Last, J. A.; Dasgupta, P. K.; DeCesare, K.; Tarkington, B.K. (1982) Inhalation
toxicology of ammonium persulfate, an oxidant aerosol, in rats. Toxicol.
Appl. Pharmacol. 63: 257-263.
019GLY/A 13-96 6/26/84
-------
Last, J. A.; Hesterberg, T. W.; Reiser, K. M.; Cross, C. E.; Amis, T. C. ;
Gunn, C.; Steffey, E. P.; Grandy, J.; Henrickson, R. (1981) Ozone-induced
alterations in collagen metabolism of monkey lungs: use of biopsy-obtained
lung tissue. Toxicol. Appl. Pharmacol. 60: 579-585.
Last, J. A.; Reiser, K. M.; Tyler, W. S. ; Rucker, R. B. (1984) Long-term con-
sequences of exposure to ozone. I. Lung collagen content. Toxicol.
Appl. Pharmacol. 72: 111-118.
Lebowitz, M. D. (1984) The effects of environmental tobacco smoke exposure and
gas stoves on daily peak flow rates in asthmatic and non-asthmatic families.
Eur. J. Respir. Dis. 65 (suppl. 133): 90-97.
Lebowitz, M. D. ; Holberg, C. J. ; Dodge, R. R. (1983) Respiratory effects on
populations from low level exposures to ozone. Presented at: 34th
annual meeting of the Air Pollution Control Association; June; Atlanta,
GA. Pittsburgh, PA: Air Pollution Control Association; paper no. 83-12.5.
Lebowitz, M. D. ; O'Rourke, M. K.; Dodge, R.; Holberg, C. J.; Gorman, G.;
Hoshaw, R. W. ; Pinnas, J. L. ; Barbee, R. A.; Sneller, M. R. (1982) The
adverse health effects of biological aerosols, other aerosols, and indoor
microclimate on asthmatics and nonasthmatics. Environ. Int. 8: 375-380.
Lee, L.-Y. ; Bleecker, E. R.; Nadel, J. A. (1977) Effect of ozone on bronchomotor
response to inhaled histamine aerosol in dogs. J. Appl. Physiol. Respir.
Environ. Exercise Physiol. 43: 626-631.
Lee, L.-Y.; Dumont, C.; Djokic, T. D.; Menzel, T. E.; Nadel, J. A. (1979)
Mechanism of rapid shallow breathing after ozone exposure in conscious
dog. J. Appl. Physiol. Respir. Environ. Exercise Physiol. 46: 1108-1109.
Lewis, T. E. ; Brennan, E.; Lonneman, W. A. (1983) PAN concentrations in ambient
air in New Jersey. J. Air Pollut. Control Assoc. 33: 885-887.
Linn, W. S.; Buckley, R. D.; Spier, C. E.; Blessey, R. L.; Jones, M. P.;
Fischer, D. A.; Hackney, J. D. (1978) Health effects of ozone exposure in
asthmatics. Am. Rev. Respir. Dis. 117: 835-843.
Linn, W. S.; Shamoo, D. A.; Venet, T. G.; Spier, C. E.; Valencia, L. M.;
Anzar, U. T. ; Hackney, J. D. (1983) Response to ozone in volunteers with
chronic obstructive pulmonary disease. Arch. Environ. Health 38: 278-283.
Linn, W. S. ; Avol, E. L. ; Hackney, J. D. (1983) Effects of ambient oxidant
pollutants on humans: a movable environmental chamber study. In: Lee,
S. D. ; Mustafa, M. G. ; Mehlman, M. A., eds. International symposium on
the biomedical effects of ozone and related photochemical oxidants; March
1982; Pinehurst, NC. Princeton, NJ: Princeton Scientific Publishers,
Inc.; pp. 125-137. (Advances in modern toxicology: v. 5).
Linn, W. S.; Jones, M. P.; Bachmayer, E. A.; Clark, K. W.; Karuza, S. K. ;
Hackney, J. D. (1979) Effect of low-level exposure to ozone on arterial
oxygenation in humans. Am. Rev. Respir. Dis. 119: 731-740.
019GLY/A 13-97 6/26/84
-------
Linn, W. S.; Jones, M. P.; Bachmayer, E. A.; Spier, C. E. ; Mazur, S. F.; Avol,
E. L. ; Hackney, J. D. (1980) Short-term respiratory effects of polluted
air: a laboratory study of volunteers in a high-oxidant community. Am.
Rev. Respir. Dis. 121: 243-252.
Linn, W. S.; Medway, D. A.; Anzar, U. T.; Valencia, L. M.; Spier, C. E.; Tsao,
F. S-0.; Fischer, D. A.; Hackney, J. D. (1982) Persistence of adaptation
to ozone in volunteers exposed repeatedly over six weeks. Am. Rev. Respir.
Dis. 125: 491-495.
Linn, W. S. ; Avol, E. L. ; Hackney, J. D. (1983) Effects of ambient oxidant
pollutants on humans: a movable environmental chamber study. In: Lee,
S. D. ; Mustafa, M. G. ; Mehlman, M. A. , eds. International symposium on
the biomedical effects of ozone and related photochemical oxidants; March
1982; Pinehurst, NC. Princeton, NJ: Princeton Scientific Publishers,
Inc.; pp. 125-137. (Advances in modern toxicology: v. 5).
Logan, J. A.; Prather, M. J. ; Wofsy, S. C.; McElroy, M. B. (1981) Troposheric
chemistry: a global perspective. J. Geophys. Res. 86: 7210-7254.
Lonneman, W. A.; Bufalini, J. J.; Seila, R. L. (1976) PAN and oxidant measure-
ment in ambient atmosphere. Environ. Sci. Techno!. 10: 347-380.
Lum, H. ; Schwartz, L. W.; Dungworth, D. L.; Tyler, W. S. (1978) A comparative
study of cell renewal after exposure to ozone or oxygen. Response of
terminal bronchiolar epithelium in the rat. Am. Rev. Respir. Dis. 118:
335-345.
Lunan, K. D. ; Short, P.; Negi, D.; Stephens, R. L. (1977) Glucose-6-phosphate
dehydrogenase response of postnatal lungs to N0« and 0~. In: Sanders,
C. L.; Schneider, R. P.; Dagle, G. E.; Ragan, ff. A., eds. Pulmonary
macrophage and epithelial cells: proceedings of the sixteenth annual
Hanford biology symposium; September 1976; Richland, WA. Washington, DC:
Energy Research and Development Administration; pp. 236-247. (ERDA
symposium series: 43).
MacRae, W. D. ; Stich, H. F. (1979) Induction of sister chromatid exchanges in
Chinese hamster ovary cells by Thiol and hydrazene compounds. Mutat.
Res. 68: 351-365.
Magie, A. R. ; Abbey, D. E. ; Centerwall, W. R. (1982) Effect of photochemical
smog on the chromosome aberrations in peripheral lymphocytes of nonsmoking
college students. Environ. Res. 29: 204-219.
Makino, K. ; Mizoguchi, I. (1975) Symptoms caused by photochemical smog.
Nippon Koshu Eisei Zasshi 22: 421-430.
Martin, C. J. ; Boatman, E. S.; Ward, G. (1983) Mechanical properties of alveo-
lar wall after pneumonectomy and ozone exposure. J. Appl. Physiol. Respir.
Environ. Exercise Physiol. 54: 785-788.
Martinez, J. R. ; Singh, H. B. (1979) Survey of the role of NO in nonurban
ozone formation. Prepared by SRI International for U.S. (Environmental
Protection Agency, Research Triangle Park, NC. EPA report no.
EPA-450/4-79-035.
019GLY/A 13-98 6/26/84
-------
Mauderly, J. L. (1984) Respiratory function responses of animals and man to
oxidant gases and with pulmonary emphysema. J. Toxicol. Environ. Health
(In press).
Mayrsohn, H. ; Brooks, C. (1965) The analysis of PAN by electron capture gas
chromatography. Presented at the Western Regional Meeting of the American
Chemical Society, Los Angeles, CA.
McAllen, S. J. ; Chiu, S. P.; Phalen, R. F.; Rasmussen, R. E. (1981) Effect of
i_n vivo ozone exposure on i_n vitro pulmonary alveolar macrophage mobility.
J. Toxicol. Environ. Health 7: 373-381.
McDonnell, W. F. ; Horstmann, D. H.; Hazucha, M. J. ; Seal, E. , Jr.; Haak, E.
D. ; Salaam, S. ; House, D. E. (1983) Pulmonary effects of ozone exposure
during exercise: dose-response characteristics. J. Appl. Physiol. Respir.
Environ. Exercise Physiol. 54: 1345-1352.
McJilton, C.; Thielke, J.; Frank, R. (1972) Ozone uptake model for the respira-
tory system. In: Abstracts of technical papers: American industrial
hygiene conference; May 1972; San Francisco, CA. Am. Ind. Hyg. Assoc. J.
33(2): paper no. 45.
McKenzie, W. H.; Knelson, J. H.; Rummo, N. J.; House, D. E. (1977) Cytogenetic
effects of inhaled ozone in man. Mutat. Res. 48: 95-102.
McKenzie, W.H. (1982) Controlled human exposure studies: cytogenetic effects
of ozone inhalation. In: Bridges, B.A.; Butterworth, 8.E.; Weinstein,
I.B. , eds. Indicators of genotoxic exposure. Spring Harbor, NY: Cold
Spring Harbor Laboratory; pp. 319-324. (Banbury report: no. 13).
Menzel, D. B. ; Slaughter, R. J. ; Bryant, A. M.; Jauregui, H. 0. (1975) Heinz
bodies formed in erythrocytes by fatty acid ozonides and ozone. Arch.
Environ. Health 30: 296-301.
Merz, T. ; Bender, M. A.; Kerr, H. D. ; Kulle, T. J. (1975) Observations of
aberrations in chromosomes of lymphocytes from human subjects exposed to
ozone at a concentration of 0.5 ppm for 6 and 10 hours. Mutat. Res.
31: 299-302.
Miller, F. J. ; Illing, J. W. ; Gardner, D. E. (1978) Effect of urban ozone
levels on laboratory-induced respiratory infections. Toxicol. Lett
2: 163-169.
Miller, F. J.; McNeal, C. A.; Kirtz, J. M.; Gardner, D. E. ; Coffin, D. L. ;
Menzel, D. B. (1979) Nasopharyngeal removal of ozone in rabbits and
guinea pigs. Toxicology 14: 273-281.
Moore, G. S. ; Calabrese, E. J. ; Schulz, E. (1981b) Effect of in vivo ozone
exposure to dorset sheep, an animal model with low levels of erythrocyte
glucose-6-phosphate dehydrogenase activity. Bull. Environ. Contam. Toxicol
26: 273-280.
Moore, P. F.; Schwartz, L. W. (1981) Morphological effects of prolonged exposure
to ozone and sulfuric acid aerosol on the rat lung. Exp Mol Pathol
35: 108-123.
019GLY/A 13-99 6/26/84
-------
Moorman, W. J. ; Chmiel, J. J. ; Stara, J. F.; Lewis, T. R. (1973) Comparative
decomposition of ozone in the nasopharynx of beagles. Acute vs. chronic
exposure. Arch. Environ. Health 26: 153-155.
Murphy, S. D. ; Ulrich, C. E. ; Frankowitz, S. H.; Xintaras, C. (1964) Altered
function in animals inhaling low concentrations of ozone and nitrogen
dioxide. Am. Ind. Hyg. Assoc. J. 25: 246-253.
Mustafa, M. G. (1975) Influence of dietary vitamin E on lung cellular sensiti-
vity to ozone in rats. Nutr. Rep. Int. 11: 473-476.
Mustafa, M. G. ; Lee, S. D. (1976) Pulmonary biochemical alterations resulting
from ozone exposure. Ann. Occup. Hyg. 19: 17-26.
Mustafa, M. G.; Tierney, D. F. (1978) Biochemical and metabolic changes in the
lung with oxygen, ozone, and nitrogen dioxide toxicity. Am. Rev. Respir.
Dis. 118: 1061-1090.
Mustafa, M. G.; Elsayed, N. M.; Quinn, C. L. ; Postlethwait, E. M.; Gardner, D.
E. ; Graham, J. A. (1982) Comparison of pulmonary biochemical effects of
low level ozone exposure on mice and rats. J. Toxicol. Environ. Health
9: 857-865.
Mustafa, M. G.; Elsayed, N. M.; von Dohlen, F. M.; Hassett, C. M.; Postlethwait,
E. M.; Quinn, C. L.; Graham, J. A.; Gardner, D. E. (1984) A comparison of
biochemical effects of nitrogen dioxide, ozone, and their combination in
mouse lung. Toxicol. Appl. Pharmacol. 72: (in press).
Nakajima, T. ; Kusumoto, S.; Tsubota, Y.; Yonekawa, E.; Yoshida, R.; Motomiya,
K. ; Ito, K.; Ide, G.; Ostu, H. (1972). Histopathological changes in the
respiratory organs of mice exposed to photochemical oxidants and automo-
bile exhaust gas. Osaka-Furitsu Koshu Eisei Kenkyusho Kenkyu Hokoku Rodo
Eisei Hen 10:35-42.
National Air Pollution Control Administration. (1970) Air quality criteria for
photochemical oxidants. Washington, DC: U.S. Department of Health,
Education, and Welfare, Public Health Service; NAPCA publication no.
AP-63. Available from: NTIS, Springfield, VA; PB190262.
National Research Council. (1977) Ozone and other photochemical oxidants.
Washington, DC: National Academy of Sciences, Committee on Medical and
Biologic Effects of Environmental Pollutants.
Niewoehner, D. E. ; Kleinerman, J. ; Rice, D. 8. (1974) Pathologic changes in
the peripheral airways of young cigarette smokers. N. Engl. J. Med.
291: 755-758.
Niinimaa, V.; Cole, P.; Mintz, S.; Shephard, R. J. (1980) The switching point
from nasal to oronasal breathing. Respir. Physio!. 42: 61-71.
Niinimaa, V.; Cole, P.; Mintz, S. ; Shephard, R. J. (1981) Oronasal distribu-
tions of respiratory airflow. Respir. Physiol. 43: 69-75.
019GLY/A 13-100 6/26/84
-------
0'Byrne, P.; Walters, E.; Gold, B.; Aizawa, H.; Fabbri, L.; Alpert, S.; Nadel,
J. A.; Holtzman, M. (1983) Neutrophil depletion inhibits airway respon-
siveness induced by ozone. Physiologist 26(4): A-35. Abstract.
Okawada, N. ; Mizoguchi, I.; Ishiguro, T. (1979) Effects of photochemical air
pollution on the human eye—concerning eye irritation, tear lysome and
tear pH. Nagoya J. Med. Sci. 41: 9-20.
P'an, A. Y. S. ; Beland, J.; Jegier, Z. (1972) Ozone-induced arterial lesions.
Arch. Environ. Health 24: 229-232.
Phalen, R. F. ; Kenoyer, J. L. ; Crocker, T. T.; McClure, T. R. (1980) Effects
of sulfate aerosols in combination with ozone on elimination of tracer
particles inhaled by rats. J. Toxicol. Environ. Health 6: 797-810.
Pick, E. ; Kersari, Y. (1981) Superoxide and hydrogen peroxide production by
chemically elicited peritoneal macrophages - induction by multiple non-
phagocytic stimuli. Cell Immunol. 59: 301-318.
Plopper, C. G. ; Chow, C. K. ; Dungworth, D. L.; Tyler, W. S. (1979) Pulmonary
alterations in rats exposed to 0.2 and 0.1 ppm ozone: a correlated morpho-
logical and biochemical study. Arch. Environ. Health 34: 390-395.
Posin, C. I.; Clark, K. W.; Jones, M. P.; Buckley, R. D. ; Hackney, J. D.
(1979) Human biochemical response to ozone and vitamin E. J. Toxicol.
Environ. Health 5: 1049-1058.
Raub, J. A.; Miller, F. J. ; Graham, J. A. (1983) Effects of low-level ozone
exposure on pulmonary function in adult and neonatal rats. In: Lee,
S. D. ; Mustafa, M. G. ; Mehlman, M. A., eds. International symposium on
the biomedical effects of ozone and related photochemical oxidants; March
1982; Pinehurst, NC Princeton, NJ: Princeton Scientific Publishers,
Inc.; pp. 363-367. (Advances in modern environmental toxicology: v. 5).
Raven, P. B.; Drinkwater, B. L.; Horvath, S. M.; Ruhling, R. 0.; Gliner, J.
A.; Sutton, J. C.; Bolduan, N. W. (1974a) Age, smoking habits, heat
stress, and their interactive effects with carbon monoxide and peroxyacetyl
nitrate on man's aerobic power. Int. J. Biometeorol. 18: 222-232.
Raven, P. B., Drinkwater, B. L.; Ruhling, R. 0.; Bolduan, N.; Taguchi, S. ;
Gliner, J. A.; Horvath, S. M. (1974b) Effect of carbon monoxide and
peroxyacetyl nitrate on man's maximal aerobic capacity. J. Appl. Physiol.
36: 288-293.
Raven, P. B.; Gliner, J. A.: Sutton, J. C. (1976) Dynamic lung function changes
following long-term work in polluted environments. Environ. Res. 12: 18-25.
Renzetti, N. A.; Bryan, R. J. (1961) Atmospheric sampling for aldehydes and
eye irritation in Los Angeles smog - 1960. J. Air Pollut. Control
Assoc. 11: 421-424.
Sabersky, R. H. ; Sinema, D. A.; Shair, F. H. (1973) Concentrations, decay
rates, and removal of ozone and their relation to establishing clean
indoor air. Environ. Sci. Technol. 1: 347-353.
019GLY/A 13-101 6/26/84
-------
Sato, S.; Kawakami, M.; Maeda, S. ; Takishima, T. (1976) Scanning electron
microscopy of the lungs of vitamin E-deficient rats exposed to a low
concentration of ozone. Am. Rev. Respir. Dis. 113: 809-821.
Sato, S. ; Shimura, S. ; Hirosa, T. ; Maeda, S. ; Kawakami, M. ; Takishima, T. ;
Kimura, S. (1980) Effects of long-term ozone exposure and dietary vitamin
E in rats. Tohoku J. Exp. Med. 130: 117-128.
Sato, S.; Shimura, S.; Kawakami, M. ; Hirosa, T.; Maeda, S.; Takishima, T. ;
Kimura, S. ; Yashiro, M.; Okazaki, S. ; Ito, M. (1978) Biochemical and
ultrastructural studies on the effects of long-term exposure of ozone on
vitamin E-depleted rats. Nippon Kyobu Shikkan Gakkai Zasshi 16: 260-268.
Schwartz, L. W. ; Dungworth, D. L.; Mustafa, M. G.; Tarkington, B. K. ; Tyler,
W. S. (1976) Pulmonary responses of rats to ambient levels of ozone:
effects of 7-day intermittent or continuous exposure. Lab. Invest. 34:
565-578.
Scott, C. D. ; Burkart, J. A. (1978) Chromosomal aberrations in peripheral
lymphocytes of students exposed to pollutants. Research Triangle Park,
NC: U.S. Environmental Protection Agency, Health Effects Research Labora-
tory; EPA report no. EPA-600/1-78-054. Available from: NTIS, Springfield,
VA; PB 285594.
Seiler, W. ; Fishman, J. (1981) The distribution of carbon monoxide and ozone
in the free troposphere. J. Geophys. Res. 86: 7255-7265.
Shephard, R. J. ; Urch, B. ; Silverman, F. ; Corey, P. N. (1983) Interaction of
ozone and cigarette smoke exposure. Environ. Res. 31: 125-137.
Sielczak, M. W. ; Denas, S. M. ; Abraham, W. M. (1983) Airway cell changes in
trachea! lavage of sheep after ozone exposure. J. Toxicol. Environ.
Health 11: 545-553.
Silverman, F. (1979) Asthma and respiratory irritants (ozone). EHP Environ.
Health Perspect. 29: 131-136.
Silverman, F.; Folinsbee, L. J.; Barnard, J.; Shephard, R. J. (1976) Pulmonary
function changes in ozone - interaction of concentration and ventilation.
J. Appl. Physio!. 41: 859-864.
Singh, H. B. ; Salas, L. J. ; Smith, A. J. ; Shigeishi, H. (1981) Measurements
of some potentially hazardous organic chemicals in urban atmospheres.
Atmos. Environ. 15: 601-612.
Singh, H. B. ; Salas, L. J. ; Stiles, R. ; Shigeishi, H. (1982) Measurements of
hazardous organic chemicals in the ambient atmosphere. Report on EPA
Cooperative Agreement 805990. Research Triangle Park, NC: U.S. Environ-
mental Protection Agency, Environmental Sciences Research Laboratory.
Smith, L. E. (1965) Peroxyacetyl nitrate inhalation. Arch. Environ. Health
10: 161-164.
019GLY/A 13-102 6/26/84
-------
Smith, W. J. (1981) New York State Air Monitoring Data Report for the Northeast
Corridor Regional Modeling Project. Albany, NY: New York State Department
of Environment and Conservation.
Solic, J. J. ; Hazucha, M. J.; Bromberg, P. A. (1982) Acute effects of 0.2 ppm
ozone in patients with chronic obstructive pulmonary disease. Am. Rev.
Respir. Dis. 125: 664-669.
Speit, G. ; Vogel, W. ; Wolf, M. (1982) Characterization of sister chromatid
exchange induction by hydrogen peroxide. Environ. Mutagen. 4: 135-142.
Spicer, C. W.; Gemma, J. L.; Joseph, D. W.; Sticksel, P. R.; Ward, G. F. (1976)
The transport of oxidant beyond urban areas. Prepared for U.S. Environ-
metnal Protection Agency, Research Triangle Park, NC. Publication No.
EPA-600/3-76-018.
Stacy, R. W.; Seal, E., Jr.; House, D. E. ; Green, J.; Roger, L. J.; Raggio, L.
(1983) Effects of gaseous and aerosol pollutants on pulmonary function
measurements of normal humans. Arch. Environ. Health 38: 104-115.
Stephens, R. J. ; Sloan, M. F. ; Groth, D. G. (1976) Effects of long-term, low
level exposure of N0? or 0- on rat lungs. EHP Environ. Health Perspect.
16: 178-179.
Stephens, R. J. ; Sloan, M. F.; Groth, D. G.; Negi, D. S.; Lunan, K. D. (1978)
Cytologic responses of postnatal rat lungs to 0, or N0? exposure. Am. J.
Pathol. 93: 183-200.
Stewart, R. M. ; Weir, E. K. ; Montgomery, M.R.; Niewoehner (1981) Hydrogen
peroxide contracts airway smooth muscle: a possible endogenous mechanism.
Respir. Physio!. 45: 333-342.
Temple, P. J.; Taylor, 0. C. (1983) World-wide ambient measurements of peroxy-
acetyl nitrate (PAN) and implications for plant injury. Atmos. Environ.
17: 1583-1587.
Thomas, G. ; Fenters, J. D. ; Ehrlich, R. (1979) Effect of exposure to PAN and
ozone on susceptibility to chronic bacterial infection. Research Triangle
Park, NC: U.S. Environmental Protection Agency, Health Effects Research
Laboratory; EPA report no. EPA-600/1-79-001. Available from: NTIS,
Springfield, VA; PB292267.
Thomas, G. B. ; Fenters, J. D.; Ehrlich, R.; Gardner, D. E. (1981a) Effects of
exposure to peroxyacetyl nitrate on susceptibility to acute and chronic
bacterial infection. J. Toxicol. Environ. Health 8: 559-574.
Thomas, G. B. ; Fenters, J. D. ; Ehrlich, R.; Gardner, D. E. (1981b) Effects of
exposure to ozone on susceptibility to experimental tuberculosis. Toxicol.
Lett. 9: 11-17.
Thompson, C. R. ; Hensel, E. G. ; Kats, G. (1973) Outdoor-indoor levels of six1
air pollutants. J. Air Pollut. Control Assoc. 19: 347-351.
019GLY/A 13-103 6/26/84
-------
Tice, R. R.; Bender, M. A.; Ivett, J. L. ; Drew, R. T. (1978) Cytogenetic
effects of inhaled ozone. Mutat. Res. 58: 293-304.
Tuazon, E. C.; Winer, A. M.; Pitts, J. N., Jr. (1981) Trace pollutant
concentrations in a multiday smog episode in the California South Coast
Air Basin by long path length Fourier-transform infrared spectrometry.
Environ. Sci. Technol. 15: 1232-1237.
Tyson, C. A.; Lunan, K. D.; Stephens, R. J. (1982) Age-related differences in
GSH-shuttle enzymes in N0?- or CL-exposed rat lungs. Arch. Environ.
Health 37: 167-176.
U.S. Bureau of the Census. (1982) Statistical abstract of the United States:
1982-1983; National data book and guide to sources, 103d edition.
Washington, D.C.: U.S. Department of Commerce. Available from U.S. Govern-
ment Printing Office.
U.S. Department of Health, Education, and Welfare (1970) Air quality criteria
for photochemical oxidants. Washington, DC: National Air Pollution
Control Administration; publication No. AP-63.
U.S. Department of Health and Human Services. (1981) Current estimates from
the National Health Interview Survey: United States, 1979. Hyattsville,
MD: Public Health Service, Office of Health Research, Statistics and
Technology, National Center for Health Statistics; DHHS publication no.
(PHS) 81-1554. (Vital and health statistics: series 10, no. 136).
U.S. Environmental Protection Agency. (1978) Air quality criteria for ozone
and photochemical oxidants. Research Triangle Park, NC: U.S. Environmen-
tal Protection Agency, Environmental Criteria and Assessment Office;
EPA-6QO/8-78-004. Available from: NTIS, Springfield, VA; PB80-124753.
U.S. Environmental Protection Agency. SAROAD data file for 1979. Office of
Air Quality Planning and Standards, Research Triangle Park, NC 27711.
U.S. Environmental Protection Agency. SAROAD data file for 1980. Office of
Air Quality Planning and Standards, Research Triangle Park, NC 27711.
U.S. Environmental Protection Agency. SAROAD data file for 1981. Office of
Air Quality Planning and Standards, Research Triangle Park, NC 27711.
Vaughan, T. R. , Jr.; Jennelle, L. F. ; Lewis, T. R. (1969) Long-term exposure
to low levels of air pollutants: Effects on pulmonary function in the
beagle. Arch. Environ. Health 19: 45-50.
Viezee, W. ; Johnson, W. B. ; Singh, H. B. (1979) Airborne measurements of
stratospheric ozone intrusions into the troposphere over the United
States. Final Report, SRI Project 6690 for Coordinating Research
Council, Atlanta, Georgia.
019GLY/A 13-104 6/26/84
-------
von Nieding, G. ; Wagner, H. M. ; Lollgen, H. ; Krekeler, H. (1977) Zur akuten
Wirkung von Ozon auf die Lungenfunktion des Menschen. [Acute effects of
ozone on lung function In men.] In: Ozon und Begleitsubstanzen im
photochemischen Smog [Ozone and other substances in photochemical smog]:
VDI colloquium; 1976; Dusseldorf, West Germany. Diisseldorf, West Germany:
Verein Deutscher Ingenieure (VDI) GmbH; pp. 195-210. (VDI-Berichte:
no. 270).
Wegner, C. D. (1982) Characterization of dynamic respiratory mechanics by mea-
surement of pulmonary and respiratory system impedance in adult bonnet
monkeys (Macaca radiata): including the effects of long-term exposure to
low-level ozone. Davis, CA: University of California; Ph.D. dissertation.
Westberg, H.; Allwine, K.; Robinson, R. (1978) Measurement of light hydrocarbon
and oxidant transport: Houston study, 1976. Research Triangle Park, NC:
U.S. Environmental Protection Agency, Environmental Sciences Research
Laboratory; EPA report no. EPA-600/3-78-662.
Whittemore, A. S. ; Korn, E. L. (1980) Asthma and air pollution in the Los
Angeles area. Am. J. Public Health 70: 687-696.
Williams, P. S. ; Calabrese, E. J. ; Moore, G. S. (1983a) An evaluation of the
Dorset sheep as a predictive animal model for the response of G-6-PD-
deficient human erythrocytes to a proposed systemic toxic ozone inter-
mediate. J. Environ. Sci. Health A18: 1-17.
Williams, P. S. ; Calabrese, E. J. ; Moore, G. S. (1983b) The effect of methyl
linoleate hydroperoxide (MLHP), a possible toxic intermediate of ozone,
on human normal and glucose-6-phosphate dehydrogenase (G-6-PD) deficient
erythrocytes. J. Environ. Sci. Health A18: 37-49.
Williams, P. S. ; Calabrese, E. J. ; Moore, G. S. (1983c) The effect of methyl
oleate hydroperoxide, a possible toxic ozone intermediate, on human
normal and glucose-6-phosphate dehydrogenase-deficient erythrocytes.
Ecotoxicol. Environ. Saf. (In press).
Witz, G. ; Amoruso, M. A.; Goldstein, B. D. (1983) Effect of ozone on alveolar
macrophage function: membrane dynamic properties. In: Lee, S. D. ;
Mustafa, M. G. ; Mehlman, M. A., eds. International symposium on the
biomedical effects of ozone and related photochemical oxidants; March
1982; Pinehurst, NC. Princeton, NJ: Princeton Scientific Publishers,
Inc. ; pp. 263-272. (Advances in modern environmental toxicology: v. 5).
World Health Organization. (1977) Manual of the international statistical
classification of diseases, injuries, and causes of death. Based on the
recommendations of the Ninth Revision Conference, 1975. Geneva, Switzer-
land: World Health Organization.
Wright, J. L. ; Lawson, L. M.; Pare, P. D.; Wiggs, B. J.; Kennedy, S. ; Hogg, J. C.
(1983) Morphology of peripheral airways in current smokers and ex-smokers.
Am. Rev. Respir. Dis. 127: 474-477.
Yokoyama, E. (1969) A comparison of the effects of S02, N02 and 03 on the
pulmonary ventilation. Guinea pig exposure experiments. Sangyo Igaku
11: 563-568.
019GLY/A 13-105 6/26/84
-------
Yokoyama, E. ; Frank, R. (1972) Respiratory uptake of ozone in dogs. Arch.
Environ. Health 25: 132-138.
Yokoyama, E. ; Ichikawa, I. (1974) Study on the biological effects of atmos-
pheric pollutants (FY 1972-1975). In: Research report for funds of the
Environmental Agency in 1974 (FY 1972-1975). Tokyo, Japan: Institute of
Public Health, Department of Industrial Health; pp. 16-1 - 16-6.
Young, W. A.; Shaw, D. B.; Bates, D. V. (1964) Effect of low concentrations of
ozone on pulmonary function in man. J. Appl. Physio!. 19: 765-768.
Zagraniski, R. T,; Leaderer, B. P.; Stolwij, J. A. J. (1979) Ambient sulfates,
photochemical oxidants, and acute health effects: an epidemiological
study. Environ. Res. 19: 306-320.
Zelac, R. E. ; Cromroy, H. L.; Bolch, Jr., W. E.; Dunavant, B. G.; Bevis, H. A.
(1971a) Inhaled ozone as a mutagen. I. Chromosome aberrations induced in
Chinese hamster lymphocytes. Environ. Res. 4: 262-282.
Zelac, R. E.; Cromroy, H. L.; Bolch, W. E., Jr.; Dunavant, B. G.; Bevis, H. A.
(1971b) Inhaled ozone as a mutagen. II. Effect on the frequency of chromo-
some aberrations observed in irradiated Chinese hamsters. Environ. Res.
4: 325-342.
Zitnik, L. A.; Schwartz, L. W. ; McQuillen, N. K. ; Zee, Y. C.; Osebold, J. W.
(1978) Pulmonary changes induced by low-level ozone: morphological obser-
vations. J. Environ. Pathol. Toxicol. 1: 365-376.
019GLY/A 13-106 6/26/84
-------
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 urn) 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.CO?): Partial pressure of carbon dioxide
in the air contained in the lung alveoli.
Alveolar oxygen partial pressure (P^Oo): Partial pressure of oxygen in the
air contained in the alveoli ofHne 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.
019CC/C A-l May 1984
-------
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 (V,, a»at): Volume of the conducting airways down to the
level where, duringr air Breathing , gas exchange with 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 (PaCO?): Partial pressure of
dissolved carbon dioxide in arterial blood.
Arterial partial pressure of oxygen (PaCL): 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, ci7H2.3N033 from bel
and related plants, used to relieve spasms of smoorn muscles. It is an
antichol inergic 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 medullo-
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.
019CC/C A-2 May 1984
-------
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 hypersecretiori 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, CgH15ClN?02)
that produces constriction of the bronchial smooth muscles.
Carbon dioxide production (VC02): 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.
019CC/C A-3 May 1984
-------
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 ,,): Resistance to flow through indirect pathways.
See COLLATERAL VENTfL°ATION 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 thl 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 HLO or ml/cm HLO. Since the static volume-pressure
characteristics of lungs are nonliriear (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, , D,02, D.CO,, D.CO): Amount of gas (0.,
CO, C0?) commonly expressed 5s ml gas CSTTO) diffusing between alveofar
gas ana pulmonary capillary blood per torr mean gas pressure difference
per min, i.e., ml 02/(min-torr). Synonymous with transfer factor and
diffusion factor.
Dynamic compliance (C, ): The ratio of the tidal volume to the change in
intrapleural pres^uYe between the points of zero flow at the extremes of
tidal volume in liters/cm H^O or ml/cm H20. 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.
019CC/C A-4 May 1984
-------
Elastance (E): The reciprocal of COMPLIANCE; expressed in cm H?0/liter or cm
H20/ml.
Electrocardiogram (ECG, EKG): The graphic record of the electrical currents
that are associated with the heart's contraction and relaxation.
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.
't
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:
FEF7r
-------
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.
Hematocrit (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 heme+ 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/lDO 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 PQ2 is low in the environment, whether because of
decreased barometric pressure or decreased fractional concentration of
0?, the condition is termed environmental hypoxia. Hypoxia when referring
to the blood is termed hypoxemia. Tissues are said to be hypoxic when
their Pn? 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.
Kilogram-meter/min (kgm/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.
019CC/C A-6 May 1984
-------
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 Ine 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 7ro; = instantaneous forced expiratory flow when the
max Qf its T[_c
V , n = instantaneous forced expiratory flow when the
max J'u lung volume is 3.0 liters
Maximum expiratory flow rate (MEFR): Synonymous with
Maximum mid-expiratory flow rate (MMFR or MMEF): Synonymous with ^25-75%'
Maximum ventilation (max Vr): 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 (Vr): Volume of air breathed in one minute. It is a
product of tidal S/olume (VT) and breathing frequency (fR). See VENTILA-
TION. ' e
Minute volume: Synonymous with minute ventilation.
Mucociliary transport: The process by which mucus is transported, by ciliary
action, from the lungs.
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).
019CC/C A-7 May 1984
-------
Nitrogen oxides: Compounds of N and 0 in ambient air; i.e., nitric oxide (NO)
and others with a higher oxidation state of N, of which N0? is the most
important toxicologically. ^
Nitrogen washout (AN,, dNJ: The curve obtained by plotting the fractional
concentration of Np n'n expired alveolar gas vs. time, for a subject
switched from breatfiing ambient air to an inspired mixture of pure CL. A
progressive decrease of N2 concentration ensues which may be analyzed
into two or more exponential components. Normally, after 4 min of pure
CU 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?, Q0?): Rate of oxygen uptake of organisms, tissues,
or cells. Commpn^unitf: ml 02 (STPD)/(kg-min) or ml 0? (STPD)/(kg-hr).
For whole organisms the oxygenTonsumption is commonly expressed per unit
surface area or some power of the body weight. For tissue samples or
isolated cells QQ2 = u1 02/hr per mg dry weight.
Oxygen saturation ($02): The amount of oxygen combined with hemoglobin,
expressed as a percentage of the oxygen capacity of that hemoglobin. In
arterial blood, SaO?.
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 0? 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.
Physiological dead space (VQ): Calculated volume which accounts for the
difference between the pressures of C0? 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.
019CC/C A-8 May 1984
-------
Plethysmograph: 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.g., gas compression in the lungs, expansion of gas upon
passing into the warm, 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 (Silverman-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 enlargement of the air spaces distal to the
terminal nonrespiratory bronchiole, accompanied by destructive changes of
the alveolar walls. 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.
Resistance flow (R): The ratio of the flow-resistive components of pressure
to simultaneous flow, in cm HpO/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.
019CC/C A-9 May 1984
-------
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 breathing frequency (fg).
Respiratory quotient (RQ, R): Quotient of the volume of (XL 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 C0? output to the 0? uptake by the lungs, "respiratory
quotient" being ^restricted to the actual metabolic C(L output and 02
uptake by the tissues. With this definition, respirarory quotient and
respiratory exchange ratio are identical in the steady state, a condition
which implies constancy of the 02 and C0« 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.
Static lung compliance (C, t): Lung compliance measured at zero flow (breath-
holding) over linear portion of the volume-pressure curve above FRC. See
COMPLIANCE.
Static transpulmonary pressure (P,f): Transpulmonary pressure measured at a
specified lung volume; e.g., rstTLC is static recoil pressure measured at
TLC (maximum recoil pressure).
Sulfur dioxide (S0?): Colorless gas with pungent odor, released primarily from
burning of fossil fuels, such as coal, containing sulfur.
019CC/C A-10 May 1984
-------
STPD conditions (STPD): 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 V-r should be used.
Tissue resistance (R+,-): Frictional resistance of the pulmonary and thoracic
tissues.
2
Torr: A unit of pressure equal to 1,333.22 dynes/cm 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.
Total pulmonary resistance (R,): Resistance measured by relating flow-dependent
transpulmonary pressure TO airflow at the mouth. Represents the total
(frictional) resistance of the lung tissue (R+.-) and the airways (Raw).
RL = "aw + Rti'
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.
019CC/C A-11 May 1984
-------
Transpulmonary pressure (P.): Pressure difference between airway opening
(mouth, nares, or canrrula opening) and the visceral pleura! surface, in
cm H20. Transpulmonary in the sense used includes extrapulmonary struc-
tures, 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.,
Vr- = Expired volume per minute (BTPS),
^ and
Vr = 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.
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 - PjC02)
Ventilation/perfusion ratio (V./O): Ratio of the alveolar ventilation to the
blood perfusion volume flow through the pulmonary parenchyma. This ratio
is a fundamental determinant of the Op and COp 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.
US E-wlronmenta! Protection Agency
n Street
606M
019CC/C A-12 May 1984
------- |