v>EPA
United States
Environmental Protection
Agency
Environmental Criteria and
Assessment Office
Research Triangle Park NC 27711
EPA/600/8-84/020B
November 1985
External Review Draft No. 2
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(Do Not
Cite or Quote)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.
-------
EPA/600/8-84/020B
Draft November 1985
Do Not Quote or Cite External Review Draft No. 2
Air Quality Criteria
for Ozone and Other
Photochemical Oxidants
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.
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, N.C. 27711
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PRELIMINARY DRAFT
NOTICE
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
019FFM/J 11/1/Sb
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PRELIMINARY DRAFT
ABSTRACT
Scientific information is presented and evaluated relative to the health
and welfare effects associated with exposure to ozone and other photochemical
oxidants. Although it is not intended as a complete and detailed literature
review, the document covers pertinent literature through early 1985.
Data on health and welfare effects are emphasized, but additional infor-
mation is provided for understanding the nature of the oxidant pollution pro-
blem and for evaluating the reliability of effects data as well as their
relevance to potential exposures to ozone and other oxidants at concentrations
occurring in ambient air. Information is provided on the following exposure-
related topics: nature, source, measurement, and concentrations of precursors
to ozone and other photochemical oxidants; the formation of ozone and other
photochemical oxidants and their transport once formed; the properties, chem-
istry, and measurement of ozone and other photochemical oxidants; and the
concentrations of ozone and other photochemical oxidants that are typically
found in ambient air.
The specific areas addressed by chapters on health and welfare effects
are the toxicological appraisal of effects of ozone and other oxidants; effects
observed in controlled human exposures; effects observed in field and epidemi-
ological studies; effects on vegetation seen in field and controlled exposures;
effects on natural and agroecosystems; and effects on nonbiological materials
observed in field and chamber studies.
111
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PRELIMINARY DRAFT
TABLE OF CONTENTS
LIST OF TABLES vi i
LIST OF FIGURES ix
LIST OF ABBREVIATIONS xi
AUTHORS, CONTRIBUTORS, AND REVIEWERS xvi
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 Introduction 11-6
11.2.2 At-Rest Exposures 11-7
11.2.3 Exposures with Exercise 11-7
11.2.4 Intersubject Variability and Reproducibi1ity of
Responses 11-21
11.2.5 Prediction of Acute Pulmonary Effects 11-24
11.2.6 Bronchial Reactivity 11-26
11.2.7 Mechanisms of Acute Pulmonary Effects 11-29
11.2.8 Pre-existing Disease 11-30
11.2.9 Other Factors Affecting Pulmonary Responses to
Ozone 11-36
11.2.9.1 Cigarette Smoking 11-36
11.2.9. 2 Age and Sex Di fferences 11-39
11.2.9.3 Environmental Conditions 11-41
11.2.9.4 Vitamin E Supplementation 11-43
11.3 PULMONARY EFFECTS FOLLOWING REPEATED EXPOSURE TO OZONE 11-44
11.4 EFFECTS OF OZONE ON VIGILANCE AND EXERCISE PERFORMANCE 11-57
11.5 INTERACTIONS BETWEEN OZONE AND OTHER POLLUTANTS 11-62
11.5.1 Ozone Plus Sulfates or Sulfuric Acid 11-62
11.5.2 Ozone and Carbon Monoxide 11-70
11.5.3 Ozone and Nitrogen Dioxide 11-71
11.5.4 Ozone and Other Mixed Pollutants 11-72
11.6 EXTRAPULMONARY EFFECTS OF OZONE 11-74
11.7 PEROXYACETYL NITRATE 11-80
11.8 SUMMARY 11-84
11.9 REFERENCES 11-93
12. FIELD AND EPIDEMIOLOGICAL STUDIES OF THE EFFECTS OF OZONE
AND OTHER PHOTOCHECMICAL OXIDANTS 12-1
12.1 INTRODUCTION 12-1
12.2 FIELD STUDIES OF EFFECTS OF ACUTE EXPOSURE TO OZONE
AND OTHER PHOTOCHEMICAL OXIDANTS 12-2
12.2.1 Symptoms and Pulmonary Function in Field
Studies of Ambient Air Exposures 12-3
12.2.2 Symptoms and Pulmonary Function in Field or
Simulated High-Altitude Studies 12-10
12.3 EPIDEMIOLOGICAL STUDIES OF EFFECTS OF ACUTE EXPOSURE 12-12
12.3.1 Acute Exposure Morbidity Effects 12-12
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PRELIMINARY DRAFT
TABLE OF CONTENTS (continued)
12.3.1.1 Symplon Aggravation in
Healthy Populations 12-12
12.3.1.2 Altered Performance 12-15
12.3.1.3 Acute Effects on Pulmonary Function 12-15
12.3.1.4 Aggravation of Existing Respiratory
Diseases 12-22
12.3.1.5 Incidence of Acute Respiratory Illness .... 12-31
12.3.1.6 Physician, Emergency Room, and Hospital
Visits 12-31
12.3.1.7 Occupational Studies 12-37
12.3.2 Trends in Mortality 12-37
12.4 EPIDEMIOLOGICAL STUDIES OF EFFECTS OF CHRONIC EXPOSURE 12-41
12.4.1 Pulmonary Function and Chronic Lung Disease 12-41
12.4.2 Chromosomal Effects 12-45
12.4.3 Chronic Disease Mortality 12-46
12.5 SUMMARY AND CONCLUSIONS 12-46
12.6 REFERENCES 12-52
13. EVALUATION OF 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 13-4
13.2.2 Potential Exposures to Other Photochemical
Oxidants 13-10
13.2.2.1 Concentrations 13-10
13.2.2.2 Patterns 13-12
13.2.3 Potential Combined Exposures and Relationship of
Ozone and Other Photochemical Oxidants 13-13
13.3 HEALTH EFFECTS IN THE GENERAL HUMAN POPULATION 13-15
13.3.1 Clinical Symptoms 13-15
13.3.2 Pulmonary Function at Rest and with Exercise and
Other Stresses 13-18
13.3.2.1 At-Rest Exposures .13-18
13.3.2.2 Exposures with Exercise 13-19
13.3.2.3 Environmental Stresses 13-34
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 13-37
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
VI
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TABLE OF CONTENTS (continued)
13.3.4.3 Conclusions Relative to Attenuation with
Repeated Exposures 13-40
13.3.5 Mechanisms of Responsiveness to Ozone 13-41
13.3.6 Relationship Between Acute and Chronic Ozone
Effects 13-44
13.3.7 Resistance to Infection 13-48
13.3.8 Extrapulmonary Effects of Ozone 13-49
13.4 HEALTH EFFECTS IN INDIVIDUALS WITH PRE-EXISTING DISEASE 13-52
13.4.1 Patients with Chronic Obstructive Lung Disease
(COLD) 13-52
13.4.2 Asthmatics 13-53
13.4.3 Subjects with Allergy, Atopy, and Ozone-Induced
Hyperreactivity 13-55
13.5 EXTRAPOLATION OF EFFECTS OBSERVED IN ANIMALS TO HUMAN
POPULATIONS 13-56
13.5.1 Species Comparisons 13-56
13.5.2 Dosimetry Modeling 13-62
13.6 HEALTH EFFECTS OF OTHER PHOTOCHEMICAL OXIDANTS AND POLLUTANT
MIXTURES 13-64
13.6.1 Effects of Peroxyacetyl Nitrate 13-64
13.6.2 Effects of Hydrogen Peroxide 13-65
13.6.3 Interactions with Other Pollutants 13-65
13.7 IDENTIFICATION OF POTENTIALLY AT-RISK POPULATION GROUPS 13-68
13.7.1 Introduction 13-68
13.7.2 Potentially At-Risk Individuals 13-68
13.7.3 Potentially At-Risk Groups 13-71
13.7.4 Demographic Distribution of the General
Population 13-73
13.7.5 Demographic Distribution of Individuals with Chronic
Respiratory Conditions 13-74
13.8 SUMMARY AND CONCLUSIONS 13-78
13.8.1 Health Effects in the General Human Population 13-78
13.8.2 Health Effects in Individuals with Pre-Existing
Di sease 13-82
13.8.3 Extrapolation of Effects Observed in Animals to
Human Populations 13-82
13.8.4 Health Effects of Other Photochemical Oxidants and
Pollutant Mixtures 13-84
13.8.5 Identification of Potentially At-Risk Groups J3-84
13.9 REFERENCES 13-87
APPENDIX A A-l
VI 1
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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 11-8
11-3 Estimated values of oxygen consumption and minute
ventilation associated with representative types of
exercise 11-13
11-4 Ozone exposure in subjects with pulmonary disease 11-32
11-5 Changes in lung function after repeated daily exposure
to ambient ozone 11-45
11-6 Effects of ozone on exercise performance 11-60
11-7 Interactions between ozone and other pollutants 11-63
11-8 Human extrapulmonary effects of ozone exposure 11-75
11-9 Acute human exposure to peroxyacetyl nitrate 11-81
11-10 Summary table: controlled human exposure to ozone 11-85
12-1 Subject characteristics and experimental conditions in
the mobile laboratory studies 12-4
12-2 Symptom aggravation in health populations exposed to
photochemical oxidant pollution 12-13
12-3 Altered performance associated with exposure to photochemical
oxidant pollution 12-16
12-4 Acute effects of photochemical oxidant pollution on pulmonary
function of children and adults 12-17
12-5 Aggravation of existing respiratory diseases by photochemical
oxidant pollution 12-23
12-6 Incidence of acute respiratory illness associated with
photochemical oxidant pollution 12-32
12-7 Hospital admissions in relation to photochemical
oxidant pol1ution 12-33
12-8 Acute effects from occupational exposure to photochemical
oxidants 12-38
12-9 Daily mortality associated with exposure to photochemical
oxi dant pol1uti on 12-40
12-10 Pulmonary function effects associated with chronic
photochemical oxidant exposure 12-42
12-11 Summary table: acute effects of ozone and other photo-
chemical oxidants in field studies with a mobile laboratory .. 12-48
13-1 Number of times the daily maximum 1-hr ozone concentration
was >0.06, >0.12, >0.18, and >0.24 ppm for specified
consecutive days in Pasadena, Dallas, and Washington,
April through September, 1979 through 1981 13-7
13-2 Relationship of ozone and peroxyacetyl nitrate at urban
and suburban sites in the United States in reports
published 1978 or later 13-14
13-3 Effects of intermittent exercise and ozone concentration on
1-sec forced expiratory volume during 2-hr exposures 13-28
13-4 Comparison of the acute effects of ozone on breathing
patterns in animals and man 13-59
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LIST OF TABLES (continued)
Table Page
13-5 Comparison of the acute effects of ozone on airway reactivity
in animals and man 13-60
13-6 Geographical distribution of the resident population of
the Uni ted States , 1980 13-75
13-7 Total population of the United States by age, sex, and
race, 1980 13-76
13-8 Prevalence of chronic respiratory conditions by sex and
age for 1979 13-77
IX
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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 „,. -yea/) during exposure to filtered air or ozone
(0.5 ppm) for 2 hr. Exercise at 45% maximal aerobic
capacity (max VCL) was performed for 30 min by Group A
after 60 min of ozone exposure and by Group B after
30 min of ozone exposure 11-15
11-2 Frequency distributions of response (percent change from
baseline) in specific airway resistance (SR ) and forced
expiratory volume in 1-sec (FEV, „) for indfviduals exposed
to six levels of ozone. One individual with 260% increase
in SR exposed to 0.4 ppm ozone is not graphed 11-22
11-3 Force! expiratory volume in 1-sec (FEV, „) 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 11-49
11-4 Percent change (pre-post) in 1-sec forced expiratory
volume (FEV, n), as the result of a 2~hr exposure to
0.42 ppm ozone. Subjects were exposed to filtered air,
to ozone for five consecutive days, and exposed to
ozone again: (A) 1 week later; (B) 2 weeks later; and
(C) 3 weeks later 11-52
12-1 Changes in mean symptom score with exposure for all
subjects, for normal and allergic subjects, and for
asthmatic subjects 12-7
13-1 Distributions of the three highest 1-hr ozone concentrations
at valid sites (906 station-years) aggregated for 3 years
(1979, 1980, and 1981) and the highest ozone concentrations
at NAPBN sites aggregated for those years (24 station-years) .... 13-6
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 13-23
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 13-24
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 1imits 13-25
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PRELIMINARY DRAFT
LIST OF FIGURES (continued)
Figure Page
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 1 imits 13-26
13-6 Group mean decrements in 1-sec forced expiratory volume
during 2-hr ozone exposures with different levels of
intermittent exercise: light (VV 64 L/min). Concentration-response curves
are taken from Figures 13-2 through 13-5 13-27
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PRELIMINARY DRAFT
LIST OF ABBREVIATIONS
ACh
AM
ANOVA
AGO
ATPS
BTPS
CC
Cdyn
CE
CHEM
CHESS
CL
CLst
CMS
CO
COHb
COLD
COPD
co2
CV
D,
D
E
LCD
ECG, EKG
EEC
EPA
ERV
FEF
max
FEF
Acetylcholine
Alveolar macrophage
Analysis of variance
Airway obstructive disease
ATPS condition (ambient temperature and pressure, saturated
with water vapor)
BTPS conditions (body temperature, barometric pressure,
and saturated with water vapor)
Closing capacity
Dynamic lung compliance
Continuous exercise
Gas phase chemiluminescence
Community Health Environmental Surveillance System
lung compliance
Static lung compliance
Central nervous system
Carbon monoxide
Carboxyhemoglobi 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
Maximal forced expiratory flow achieved
during an FVC
Forced expiratory flow
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PRELIMINARY DRAFT
LIST OF ABBREVIATIONS (continued)
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
fD Respiratory frequency
K
FRC Functional residual capacity
FVC Forced vital capacity
G Conductance
G-6-PD Glucose-6-phosphate dehydrogenase
Gaw Airway conductance
GS-CHEM Gas-solid chemi luminescence
GSH Glutathione
Hb Hemoglobin
Hct Hematocrit
HO- Hydroxy radical
HO. Hydroperoxy
1C Inspiratory capacity
IE Intermittent exercise
IRV Inspiratory reserve volume
IVC Inspiratory vital capacity
LDH Lactate deyhydrogenase
LD,^ Lethal dose (50 percent)
LM Light microscopy
MAST KI-coulometric (Mast meter)
'xi ii
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PRELIMINARY DRAFT
LIST OF ABBREVIATIONS (continued)
max Vp
max V02
MBC
MEFR
MetHb
MMAD
MMFR or MMEF
MVV
NBKI
(NH4)2S04
N0
V
°3
P(A-a)02
PABA
PAC02
PaC02
PAN
PA°2
Pa02
PB2N
PEF
PEFV
PG
L
PMN
Pst
PUFA
R
Maximum ventilation
Maximal aerobic capacity
Maximum breathing capacity
Maximum expiratory flow rate
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
019FFM/J
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PRELIMINARY DRAFT
LIST OF ABBREVIATIONS (continued)
Raw Airway resistance
RBC Red blood cell
R ,-, Collateral resistance
rh Relative humidity
R, Total pulmonary resistance
RQ, R Respiratory quotient
R. Respiratory resistance
R. . Tissue resistance
RV Residual volume
SaO,, Arterial oxygen saturation
SBNT Single-breath nitrogen test
SBP Systolic blood pressure
SCE Sister chromatid exchange
Se Selenium
SEM Scanning electron microscopy
SGaw Specific airway conductance
SH Sulfhydryls
SOD Superoxide dismutase
S0? 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
n
V./Q Ventilation/perfusion ratio
VC Vital capacity
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PRELIMINARY DRAFT
LIST OF ABBREVIATIONS (continued)
VCO,
anat
VI
VL
max
vo
Carbon dioxide production
Physiological dead space
Dead-space ventilation
Anatomical dead space
Minute ventilation; expired volume per minute
Inspired volume per minute
Lung volume
Maximum expiratory flow
Oxygen uptake
Oxygen consumption
MEASUREMENT ABBREVIATIONS
g
hr/day
kg
kg-m/min
L/min
L/s
ppm
mg/kg
3
mg/m
min
ml
mm
ug/m
urn
MM
sec
gram
hours per day
ki logram
ki logram-meter/min
1iters/mi n
1iters/sec
parts per mi 11 ion
milligrams per kilogram
milligrams per cubic meter
minute
mi 11iliter
mi 11imeter
micrograms per cubic meter
micrometers
micromole
second
019FFM/J
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PRELIMINARY DRAFT
AUTHORS, CONTRIBUTORS, AND REVIEWERS
Chapter 11: Controlled Human Studies of the Effects of Ozone
and Other Photochemical Oxidants
Principal Authors
Dr. Donald H. Horstraan
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
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Dr. Lawrence J. Folinsbee
Combustion Engineering
800 Eastowne Rd., Suite 200
Chapel Hill, NC 27514
Dr. Robert Frank
Department of Environmental
Health Sciences
Johns Hopkins School of Hygiene
and Public Health
615 N. Wolfe Street
Baltimore, MD 21205
Dr. Judith A. Graham
Health Effects Research Laboratory
MD-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
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Dr. Harold A. Menkes
Department of Environmental
Health Sciences
Johns Hopkins School of Hygiene
and Public Health
615 N. Wolfe Street
Baltimore, MD 21205
Dr. Walter S. Tyler
Department of Anatomy
School of Veterinary Medicine
University of California
Davis, CA 95616
Chapter 12: Field and Epidemiological Studies of the Effects of Ozone
and Other Photochemical Oxidants
Contributing Authors
Dr. David V. Bates
Department of Medicine
St. Paul's Hospital
University of British Columbia
Vancouver, British Columbia
Canada V6Z1Y6
Dr. Robert S. Chapman
Health Effects Research Laboratory
MD-58
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Benjamin G. Ferrib
School of Public Health
Harvard University
Boston, MA 02115
Dr. Lester D. Grant
Environmental Criteria and
Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. James R. Kawecki
TRC Environmental Consultants, Inc.
2001 Wisconsin Avenue, N.W.
Suite 261
Washington, DC 20007
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Dr. Michael D. Lebowitz
Department of Internal Medicine
College of Medicine
University of Arizona
Tucson, AZ 85724
Mr. James A. Raub
Environmental Criteria and
Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Ms. Beverly E. Tilton
Environmental Criteria and
Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Authors also reviewed individual sections of the chapter. The following addi-
tional persons reviewed chapter 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. 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 Frank
Department of Environmental
Health Sciences
Johns Hopkins School of Hygiene
and Public Health
615 N. Wolfe Street
Baltimore, MO 21205
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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. Victor Hasselblad
Center for Health Policy
Duke University
Box GM Duke Station
Durham, NC 27706
Dr. Mi Ian 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
Dr. Jonathan M. Samet
Department of Medicine
University of New Mexico Hospital
Albuquerque, NM 87131
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Dr. Jan A. J. Stolwijk
Department of Epidemiology and
Public Health
School of Medicine
Yale University
New Haven, CT 06510
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
Dr. Donald H. Horstman
Health Effects Research Laboratory
MD-58
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
xxn
019FFM/J 11/1/85
-------
PRELIMINARY DRAFT
Dr. Michael D. Lebowitz
Department of Internal Medicine
College of Medicine
University of Arizona
Tucson, AZ 85724
Dr. Daniel B. Menzel
Laboratory of Environmental Toxicology
and Pharmacology
Duke University Medical Center
P.O. Box 3813
Durham, NC 27710
Dr. Frederick J. Miller
Health Effects Research Laboratory
MD-82
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Mr. James A. Raub
Environmental Criteria and
Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Ms. Beverly E. Tilton
Environmental Criteria and
Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Dr. Walter S. Tyler
Department of Anatomy
School of Veterinary Medicine
University of California,
Davis, CA 95616
Authors also reviewed individual sections of the chapter. The following addi-
tional persons reviewed parts of chapter 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
xx i i i
019FFM/J 11/1/85
-------
PRELIMINARY DRAFT
SCIENCE ADVISORY BOARD
CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE
The substance of this document was reviewed by the Clean Air Scientific
Advisory Committee of the Science Advisory Board in public sessions.
Chairman
Dr. Morton Lippmann
Institute of Environmental
Medicine
Lanza Laboratory
Long Meadow Road
New York University
Tuxedo, New York 10987
Members and Consultants*
*Dr. Mary Amdur
Department of Nutrition and
Food Science
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
*Dr. Eileen Brennan
Department of Plant Pathology
Cook College
Rutgers, The State University
New Brunswick, New Jersey 03809
*Dr. Edward Crandall
Division of Pulmonary Disease
Department of Medicine
University of California - Los Angeles
Los Angeles, California 90024
*Dr. James Crapo
Duke University Medical Center
Department of Medicine
P. 0. Box 3177
Durham, North Carolina 27710
*Dr. Ronald Hall
Aquatic and Terrestrial
Ecosystems Studies
Ministry of the Environment
Dorset Research Center
Box 39
Dorset, Ontario POA1EO
*Dr. Ian Higgiiis
American Health Foundation
320 East 43rd Street
New York, New York 10017
019FFM/J
*Dr. Jay Jacobson
Boyce Thompson Institute
Tower Road
Cornell University
Ithaca, New York 14853
Dr. Warren Johnson
Director, Atmospheric Science Center
Advanced Development Division
SRI International
333 Ravenswood Avenue
Menlo Park, California 94025
*Dr. Jane Koenig
Research Associate Professor
Department of Environmental Health
Mail Stop SC-34
University of Washington
Seattle, Washington 98195
Dr. Paul Kotin
4505 South Yosemite
#339
Denver, Colorado 80237
*Dr. Timothy Larson
Department of Civil Engineering
Mail Stop FC-05
University of Washington
Seattle, Washington 98195
Mr. Bill Stewart
Executive Director
Texas Air Control Board
6330 Highway 290 East
Austin, Texas 78723
*Dr. Michael Treshow
Department of Biology
University of Utah
Salt Lake City, Utah 84112
xxiv
11/1/85
-------
PRELIMINARY DRAFT
CASAC Members/Consultants (cont'd.)
*Dr. Mark Utell
Associate Professor of Medicine
and Toxicology
Pulmonary and Critical Care Unit
University of Rochester Medical Center
601 Elmwood Avenue
Rochester, New York 14642
Dr. James Ware
Department of Biostatistics
Harvard School of Public Health
677 Huntington Avenue
Boston, Massachusetts 02115
*Dr. James Whittenberger
Director
Southern Occupational Health Center
19722 MacArthur Boulevard
University of California
Irvine, California 92717
*Dr. George Wolff
General Motors Research Laboratories
Environmental Science Department
Warren, Michigan 48090-9055
xxv
019FFM/J 11/1/85
-------
PRELIMINARY DRAFT
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
(0,) 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 0, 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 10/17/85
-------
PRELIMINARY DRAFT
TABLE 11-1. HUMAN EXPERIMENTAL EXPOSURE TO OZONE UP TO 1978
Ozone
concentration
MgTi3 ppm
196
196
784
1176
1960
294
588
392
980
451
490
725
980
0.10
0.1
0.4
0.6
1.0
0.15
0.3D
0.2
0.5
0.23
0.25
0.37
0.50
. Exposure
Measurement ' duration and
method activity
CHEM, 2 hr
NBKI IE (2xR)
9 15-min intervals
I 1 hr
R
UV, 1 hr (mouth-
NBKI piece) R (11)
& CE (29, 43,
66)
1 3 hr/day
6 days/week
x 12 weeks
CHEM, 2 hr
NBKI IE (2xR)
@ 15-min intervals
CHEM, 2-4 hr
NBKI R 4 IE (2xR)
9 15-min intervals
. No. and sex
Observed effect(s) of subjects Reference
P(A-a)02 and R increased; Pa02 decreased. 12 male von Nieding et al., 1977
Results questionable.
Airway resistance: mean increases of 3.3X 4 male Goldsmith and Nadel , 1969
(0.1 ppm), 3.5% (0.4 ppm), 5.8X (0.6 ppm),
and 19. 3X (1.0 ppm) at 0 hr after exposure;
mean increases of 12.5% (0.4 ppm), 5% (0.6
and 1.0 ppn) 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.o, MMFfi, and V, decreased and fg 6 male OeLucia 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 FEV,.0 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 hyperreactors
(R) at 0. 5 ppm.
-------
PRELIMINARY DRAFT
TABLE 11-1 (continued). HUMAN EXPERIMENTAL EXPOSURE TO OZONE UP TO 1978
Ozone
concentration
ug/m3
725
725
725
1470
-. 725
7^ 980
to 1470
725
980
1470
784
784
980
ppra
0.37
0.37
0.37
0.75
0.37
0.50
0.75
0.37
0.50
0.75
0.4
0.4
0.5
Measurement3'
method
CHEM,
NBKI
CHEM,
NBKI
MAST,
NBKI
MAST,
NBKI
MAST,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
. Exposure
duration and
activity
2 hr
It (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) 4 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)
No changes in spirometry or small airway
function in the combined group; sensitive
subjects had decreased FEV,.0 (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 rain, vent.) and changes in spiro-
metric variables.
fn increased and VT decreased with exercise;
VC2 not affected by exposure. Variables
correlated to total dose of ozone.
FVC and MMEF decreased and R increased at
2 hr and 4 hr; FEV,.0, V50, aHd 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
-------
PRELIMINARY DRAFT
TABLE 11-1 (continued). HUMAN EXPERIMENTAL EXPOSURE TO OZONE UP TO 1978
Ozone b
concentration Measurement '
ug/m3 ppm method
980 0.5 CHEM,
NBKI
980 0.5 MAST,
NBKI
1176 0.6 CHEM,
NBKI
1176 0.6 CHEM,
NBKI
' 1176 0.6 MAST
1568 0.8
1470 0.75 MAST,
NBKI
1470 0.75 HAST,
NBKI
Exposure
duration and
activity0
2 hr
R (9) & IE (37)
for 30 m1n
6 hr
IE (44) for two
!5-m1n periods
2 hr (nosecllps)
R
2 hr
IE fcr two
!5-m1n periods
2 hr
R(9)
2 hr
IE (20-25)
@ 15-min Intervals
2 hr
R & IE (2XR)
@ 15-min Intervals
Observed effect(s)d
Changes 1n pulmonary function (FVC, FEVt.o,
FEF2s_76) were greatest Immediately following
exercise. Heat stress potentiated the re-
sponse while relative humidity had Insignifi-
cant effects.
FVC, FEV3.o, and SG decreased and R, In-
creased. 'Nonsmokerl were more susceptible.
Inconsistent changes In lung mechanics and
small airway function.
Bronchoreact1v1ty to hlstamlne Increased
following exposure; persisted for up to
3 weeks; blocked by atroplne.
Significant decrements 1n splrometrlc
variables (19%-35%). Cough and pain on
deep Inspiration most frequently reported;
no symptoms persisted beyond 48 hr.
OLrn: mean decrease of 25% (11/11 subjects).
VCT mean decrease of 10% (10/10 subjects).
FEV0.j5 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 tracheal Irritation
6 to 12 hr after exposure.
HR , VF, VT, V02 , and maximum workload
aH Decreased. At maximum workload only,
fB Increased (45%) and VT decreased (29%).
FEF60 and PcTTLC decreased, R. Increased;
returned to control levels within 24 hr.
IE Increased changes 1n R. , C, , maxP. ,
and spfrometry. Cough anO 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
FoHnsbee 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
-------
PRELIMINARY DRAFT
TABLE 11-1 (continued). HUMAN EXPERIMENTAL EXPOSURE TO OZONE UP TO 1978
Ozone
concentration
jjgTm3 ppm
17M
2940
3920
1960
5880
0.9
1.5-
Z.O
1-
3
Measurement3 '
method
HAST,
NBKI
I
MAST
Exposure
duration and
activity
5 min
CE
2 hr
R
10-30 min
R
Observed effect(s)
SG decreased during and 5 min following
exposure. Recovery complete within 30 min
post-exposure.
VC: decreased 13% immediately after exposure;
returned to normal in 22 hr. FEV3.0: decreased
16.8% after 22 hr. Maximum breathing capacity
decreased very slightly. CNS depression, lack
of coordination, chest pain, tiredness for
2 weeks.
VC: mean decrease of 16.5% (4/8 subjects
showed decrease > 10%). FEVi.0: mean
No. and sex
of subjects
4 male
1 male
11 subjects
Reference
Kagawa and Toyama, 1975
Griswold et al. , 1957
Hallett, 1965
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). OL-Q: 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 OL-Q. Headache, shortness of
breath, lasting more than 1 hr.
9800 5-
19600 10
Not available
Drowsiness and headache reported.
3 male
Jordan and Carlson, 1913
Measurement methods: MAST = Kl-coulometric (Mast meter); I = iodometric; CHEM = gas-phase chemiluminescence; UV = ultraviolet photometry.
Calibration methods: NBKI = neutral buffered potassium iodide.
cActivity level: R = rest; CE = continuous exercise; IE = intermittent exercise; minute ventilation (VF) given in L/min or in multiples of resting
ventilation.
See Glossary for the definition of symbols.
Source: U.S. Environmental Protection Agency (1978).
-------
PRELIMINARY DRAFT
have been provided to give the reader an overview of the studies discussed in
the text and provide some additional information about measurement techniques
.-•nd exposure protocols. Unless otherwise stated, the 0., concentrations pre-
sented in the text and tables are the levels cited in the original manuscript.
No attempt has been made to convert the concentrations to a common standard,
although suggestions for conversion along with a discussion of 0~ measurement
can be found 1n Chapter 5.
11.2 ACUTE PULMONARY EFFECTS OF OZONE
11.2.1 Introduction
The most prevalent and prominent pulmonary responses to 0- exposure are
cough, substernal pain upon deep inspiration, and decreased lung volumes
(forced vital capacity, FVC; forced expiratory volume in Is, FEVJi0; tidal
volume, V,.). Less substantial increases in airway resistance (R ) also
i a W
occur. In most of the studies reported, greatest attention has been accorded
decrements in FEVt>0. as this variable represents a summation of changes in
both volume and resistance. While this is true, it must be pointed out that
for exposure concentrations critical to the standard-setting process (i.e.,
<0.3 ppm 03), the observed decrements in FEV, 0 primarily reflect FVC decre-
ments of similar magnitude, with little or no contribution from changes in
resistance. As examples, for subjects exposed to 0.3 ppm 0, and performing
exercise with associated minute ventilations (VV) of 31, 50, or 67 L/min,
decrements in FEVli0 and FVC were 0.23 and 0.11, 0.31 and 0.29, 0.38 and 0.40
liters, respectively (Folinsbee et al., 1978). For subjects performing heavy
exercise (V£ = 65 L/min) and exposed to 0.12, 0.18, 0.24, or 0.30 ppm 0.,,
decrements in FEVli0 and FVC were 0.21 and 0.17, 0.29 and 0.23, 0.59 and 0.53,
0.74 and 0.66 liters, respectively (McDonnell et al., 1983). In another study
of subjects performing heavy exercise (VV = 57 L/min and exposed to polluted
ambient air (mean 03 concentration - 0.15 ppm), 0.16 or 0.24 ppm 0,, decrements
in FEVj.o and FVC were 0.20 and 0.18, 0.24 and 0.24, 0.74 and 0.73 liters,
respectively (Avol et al., 1984). Thus, it is highly probable that most of
the decrements in FEV[ 0 reported to result from 0^ exposure are indicative of
restrictive airway changes and that little or no change in FEV1<0/FVC occurs
which would ::idlc5te resistive airway changes.
019PO/A 11-6 10/17/85
-------
PRELIMINARY DRAFT
11.2.2 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
•j
subjects are exposed for 2 hr at rest to 1176-1568 ug/m (0.6-0.8 ppm) of 03
(Young et al., 1964), and to 1479 ug/m3 (0.75 ppm) of 03 (Bates et al., 1972;
Silverman et al., 1976). In addition to decrements in the usual indicators of
pulmonary function, Young et al. (1964) also found decreases in diffusion
capacity of the lung (D.CO).
Results from studies of at-rest exposures published since 1978 (Table 11-2)
have generally confirmed these earlier findings. Folinsbee et al. (1978)
observed decrements in FVC, FEV-. n, and other spirometric variables when
3
10 normal subjects rested for 2 hr while exposed to 980 ug/m (0.5 ppm) of 0.,;
O
R_, was not affected. No changes in pulmonary function resulted from expo-
aw ,
sures to 588 or 196 ug/m (0.3 or 0.1 ppm) of 03. Horvath et al. (1979)
reported that decreases in FVC and FEV.. ,. resulted from 2-hr at-rest exposures
of 15 subjects (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 03>
No changes 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
3
and 980 ug/m (0.3 and 0.5 ppm) of 0.,. In contrast to other studies, this is
the only report of changes in airway resistance resulting from at rest expo-
sures to 03.
Kb'nig 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
OT. Specific airway conductance was measured and samples of arterialized ear
lobe capillary blood were taken for determinations of oxygen tension (PO^)
before and after the exposures. No changes in P09 or SG were observed.
c. 3W
Subjective symptoms (substernal burning) were reported by two individuals at
196 ug/m3 (0.1 ppm), by three at 627 ug/m3 (0.32 ppm), and by eight at 1960
ug/m (1.0 ppm) of 03.
11.2.3 Exposures With Exercise
The majority of controlled human studies since 1978 have been concerned
with the effects of combined rest and exercise exposures to various concentra-
tions of 0, for variable periods of time (Table 11-2). Exercise during these
019PO/A 11-7 10/17/85
-------
PRELIMINARY DRAFT
TABLE 11-2. STUDIES ON ACUTE PULMONARY EFFECTS OF OZONE SINCE 1978
Ozone
concentration
ug/mj
157
314
470
627
196
196
294
392
490
196
588
980
196
627
1960
235
353
470
588
784
235
353
470
588
784
ppm
0.08
0.16
0.24
0.32
0.1
0.10
0.15
0.20
0.25
0.1
0.3
0.5
0.1
0.32
1.0
0.12
0.18
0.24
0.30
0.40
0.12
0.18
0.24
0.30
0.40
Measurement '
method
UV,
UV
CHEM,
NBKI
UV,
UV
CHEM,
NBKI
HAST,
NBKI
CHEM,
UV
CHEM,
UV
^ Exposure
duration and
activity
1 hr
CE (57)
2 hr
IE (2xR)
@ 15-min intervals
2 hr
IE (68)
(4) !4-m1n periods
2 hr
R (10), IE (31,
50, 67)
0 15-mln intervals
2 hr
R
2.5 hr
IE (65)
? 15-mln intervals
2.5 hr
IE (65)
@15-min intervals
A
Observed effect(s)
Small decreases in FVC and FEVj.o at 0-16 ppm
with larger decreases at >0.24 ppm; lower-re-
spiratory symptoms increased at ^0.16 ppn.
Incomplete recovery of function and symptoms
1 hr postexposure.
No effect on Pa02 or R taking Into account
intra-lndlvidual varialYon.
Concentration-response curves produced; exponen-
tial decreases In FVC, FEV, 0, FEF-, ,,», SG ,
1C, and TLC with 1ncreas1ng'03 contenlrStion* at
any given 03 concentration, linear decreases
1n FVC and FEVj 0 with time of exposure. Sig-
nificant Individual variation in response.
Cough, nose and throat Irritation, and chest
discomfort or tightness also showed signifi-
cant concentration-response relationships.
Changes in pulmonary function found at 0.5 ppm
during R and 0.3 and 0.5 ppm with IE. The
magnitude of splroraetrlc changes was gener-
ally related to ozone concentration and
minute ventilation, but concentration showed
stronger association. Effective dose-
functional response curves developed.
No changes 1n SR or P02 following exposure;
SR Increased wnh ACh challenge at £0.32 ppm;
SRdw Increased in 2/3 COLD patients at 0.1 ppm.
aw
Small decreases In FVC, FEV,.0, and
FEF25.75V at 0-12 and 0.18 ppm with larger
decrease? at £0.24 ppm; f and SR In-
creased and V, decreased at £0.29 ppm;
regression curves produced; coughing
reported at all concentrations, pain and
shortness of breath at £0.24 ppm.
Individual responses to 0, (FVC, FEV,-0) were
highly reproducible for periods as long as 10
months and at 03 concentrations >_ 0.18 ppm;
large Intersubject variability in response
due to intrinsic responsiveness to 03.
No. and sex
of subjects
42 male
8 female
(competitive
bicyclists)
11 male
20 male
40 male
(divided Into 4
exposure groups)
13 male
1 female
(3 COLD)
(1 asthma)
135 male
(divided into six
exposure groups)
32 male
Reference
Avol et al. , 1984
von Nleding et al. , 1979
Kulle et al. , 1985
Follnsbee et al. , 1978
KSnig et al . , 1980
McDonnell et al. , 1983
McDonnell et al. , 1985a
-------
PRELIMINARY DRAFT
TABLE 11-2 (continued). STUDIES OF ACUTE PULMONARY EFFECTS OF OZONE SINCE 1978
Ozone
concentration
M9/mJ
235
297
594
294
588
392
392
588
784
392
686
392
823
980
392
784
ppm
0.12
0.15
0.30
0.15
0.3
0.2
0.2
0.3
0.4
0.20
0.35
0.2
0.42
0.50
0.2
0.4
Measurement3'
method
CHEM,
UV
UV,
UV
CHEM,
NBKI
UV,
NBKI
UV,
UV
UV,
UV
UV,
UV
UV,
NBKI
b Exposure
duration and
act1v1tyc
2.5 hr
IE (39)
@ 15-mln Intervals
1 hr (mouthpiece)
CE (55)
+ heat
2 hr
IE
@ 15-mln Intervals
2 hr
IE (2xR)
@ 15-rain Intervals
30-80 m1n
(mouthpiece)
CE (34.9, 61.8)
1 hr (mouthpiece)
IE (77.5) @ vari-
able competitive
Intervals
CE (77.5)
2 hr
IE (30 for
male, 18 for
female subjects)
@ 15-min intervals
2 hr
IE (2xR)
@ 15-min Intervals
Observed effect(s)d
Small decrease 1n FEV1-0; decrement persists
for 24 hr. No change In frequency or severity
of cough.
Increased fp, decreased VT and V. at 0.3 ppm;
FVC, FEV,i0, FEF-, ,,„, and TLC decreased at
0.3 ppm. 'Most soBjects reported pain on inspira-
tion and coughing at 0.3 ppm. FVC decreased with
Increased temperature; Interaction of 03 with
Increased temperature for fD and V,
K A.
Small decreases in SG and FVC after exposure
to 0.15 and 0.30 ppm 63. Increased AN2 at 0.15
ppm 03. Questionable statistics.
No meaningful changes in PA02 , Pa02, and
P(A-a)02. Inconsistent changes in splronetric,
plethysmographlc, and ventllatory distribution
variables.
Progressive impairment of lung function with
increasing effective dose; questionable sig-
nificance during CE (61.8).
FVC, FEV^o, and FEF2s.7s decreased, subjective
symptoms Increased with 03 concentration; fR
Increased and V-, decreased during CE; no efTect
on V02, HR, VE, or Vfl. No exposure mode effect.
Pre-exposure to 0.2 ppm did not alter response
to higher concentrations; FEVi.0 decreased
in sensitive subjects (n = 9) at 0.2 ppm;
no significant sex differences.
SR Increased with histamine challenge
in K subjects at 0.4 ppm. "Adaptation" shown
with repeated exposures.
No. and sex
of subjects Reference
23 male McDonnell et al., 1985b,c
(children aged
8-11 yr)
10 female Gibbons and Adams, 1984
15 male Kagawa, 1983a, 1984
13 male Linn et al. , 1979
5 female
8 male Adams et al. , 1981
10 male Adams and Schelegle,
(distance runners) 1983
8 male Gllner et al . , 1983
13 female
12 male Dimeo et al. , 1981
7 female
(divided Into three
exposure groups)
-------
980 0.50
1470 0.75
PRELIMINARY DRAFT
TABLE 11-2 (continued). STUDIES OF ACUTE PULMONARY EFFECTS OF OZONE SINCE 1978
Ozone
concentration
ug/mj
412
490
980
1470
588
588
588
980
725
1470
ppm
0.21
0.25
0.50
0.75
0.3
0.3
0.3
0.5
0.37
0.75
Measurement3'
method
UV,
UV
CHEM,
NBKI
UV,
NBKI
MAST,
BAKI
CHEM,
NBKI
CHEM,
NBKI
Exposure
duration and
activity
1 hr
CE (81)
2 hr
R (8)
1 hr (mouthpiece)
CE @50X VO,
+V1t E 2max
1 hr (mouthpiece)
CE (34.7 for
female and 51
for male subjects)
2 hr
R
2 hr
R
Observed effect(s)d
Decreases In FVC (6.9%), FEVj.0 (14.8%),
FEFzs.-js^ (18%), 1C (11%), and MVV (17%).
Symptoms reported: laryngeal and tracheal
irritation, soreness, and chest tightness
on Inspiration.
Splrometry: FVC, FEV,.0, and MHFR 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
1n lung function but does not facilitate return
to normal following exposure. No effect on max
V02 following exposure.
RV Increased while VC and FEV1-C decreased with
03. Expired pentane (Hp1d peroxidatlon) in-
creased with exercise but not 03 exposure; atten-
uated by vitamin E supplementation.
FVC, FEV,.0 and FEF25_75v decreased; f»
increased and V, decreased with exercise;
nonsmokers and females may be more sensi-
tive; Increase In subjective complaints
noted.
SG decreased at 0.3 and 0.5 ppm.
TenBency toward increased bronchial
reactivity to ACh challenge. Smoking
effects were similar to those of ozone.
FEV, o decreased at 0.37 ppm; FVC and V ._„
decreased at 0.75 ppm. maxDU*
No. and sex
of subjects
6 male
1 female
(distance cyclists)
8 male
7 female
5 male
5 female
12 male
12 female
(equally divided
by smoking history)
6 male
(equal ly divided
by smoking history)
26 male
6 female
(habitual
smokers)
Reference
Follnsbee et al. , 1984
Horvath et al. , 1979
Oil lard et al. , 1978
DeLucia et al. , 1983
Kagawa and Tsuru, 1979a
Shephard et al. , 1983
2 hr
IE (2.5xR)
@ 15-min intervals
decreased. No
smoking and 03
but smokers may have decreased responsiveness
to 03.
-------
PRELIMINARY DRAFT
TABLE 11-2 (continued). STUDIES OF ACUTE PULMONARY EFFECTS OF OZONE SINCE 1978
Ozone
concentration
|jg/mj ppm
784 0.4
980 0.5
1176 0.6
Measurement3 '
method
CHEM,
MBKI
CHEM,
NBKI
UV,
NBKI
Exposure
duration and
act1v1tyc
3 hr
IE (4-5xR)
for 15 m1n
2 hr
IE (2xR)
@ 15-mln Intervals
+ Vlt E
2 hr (noseclip)
IE (2xR)
@ 15-mln Intervals
Observed effect(s)
FVC and FEV, 0 decreased and bronchial reactivity
to methachoHne Increased following exposure.
Responses attenuated with repeated exposure.
FEV1-0 decreased 1n both placebo and vitamin E -
supplemented subgroups; FVC decreased only 1n
the placebo group. No significant effect of
vitamin E.
No change 1n symptoms; FVC, FEV, Ol FEF,SJ;,
FEF5Q%' aN2' and TLC decreased 1n botn Pltcebo
and vitamin E-supplemented subgroups. No
significant effect of vitamin E.
SR Increased In nonatoplc subjects (n = 7)
wl?n Mstamlne and methachollne and 1n atoplc
subjects (n = 9) with hlstamlne following
exposure, returning to control values by the
following day; response prevented by pre-
treatment with atroplne aerosol.
No. and sex
of subjects
13 male
11 female
(divided Into 2
phases)
9 male
25 female
22 male
11 male
5 female (divided
by history of atopy)
Reference
Kulle et al. , 1982b
Kulle, 1983
Hackney et al. , 1981
Holtzman et al . , 1979
Measurement method:
Calibration method:
MAST = KI-coulometric (Mast meter); CHEM = gas phase chemiluminescence; UV = ultraviolet photometry.
NBKI = neutral buffered potassium Iodide; BAKI = boric add potassium Iodide; UV = ultraviolet photometry.
Activity level: R = rest; CE = continuous exercise; IE = Intermittent exercise; minute ventilation (V,) given In L/m1n or as a multiple of resting
ventilation.
See Glossary for the definition of symbols.
-------
PRELIMINARY DRAFT
exposures has been at different intensities and at different times during the
exposures. The level of minute ventilation (VV), which varies with exercise
intensity, is a primary determinant of the magnitude of pulmonary effects
resulting from exposure to a given level of 0,. Therefore, results from
studies using different regimens of exercise, even with exposure to the same
0, concentration, may be difficult to compare. Most studies used alternating
15-min periods of rest and exercise. Pulmonary function and/or subjective
symptoms were usually measured pre- and post-exposure. In a few studies, such
measurements were also made during the rest periods after each exercise period.
Exposures in these studies were usually performed only on one day, and were
therefore likely to induce smaller functional decrements than would have been
observed if subjects had been exposed on two sequential days, as noted in
Section 11.3 entitled "Pulmonary Effects Following Repeated Exposure to Ozone."
Other factors that may influence the results obtained by different inves-
tigators and account for some of the inconsistencies observed among the find-
ings from various studies are discussed in this chapter. Such factors include
experimental design (more specifically: number of subjects, exposure time,
recurrent exposures, length of and sequencing of exercise periods, and time of
measurements), and specific measurement techniques used to determine 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 0,, such as smoking history, sex, and environmental conditions,
are discussed in this section. Studies on the interaction between CL and other
pollutants are presented in Section 11.5.
As previously stated, increased Vp accompanying exercise is one of the
most important contributors to pulmonary decrements during 0, exposure. While
the more recent reports include actual measurements of Vr obtained during
exposure, earlier publications often included only a description of the exercise
regimen. Table 11-3 may aid the reader in estimating the Vr associated with a
given exercise regimen.
The values for 0^ 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
019PO/A 11-12 10/17/85
-------
PRELIMINARY DRAFT
TABLE 11-3. ESTIMATED VALUES OF OXYGEN CONSUMPTION AND MINUTE VENTILATION ASSOCIATED WITH REPRESENTATIVE TYPES OF EXERCISE3
Level of work
Light
Light
Light
Moderate
Moderate
Moderate
Heavy
Heavy
Very heavy
Very heavy
Severe
Work Performed .
watts kg-m/m1n
25
50
75
100
125
150
175
200
225
250
300
150
300
450
600
750
900
1050
1200
1350
1500
1800
02 consumption,
L/ra1n
0.65
0.96
1.25
1.54
1.83
2.12
2.47
2.83
3.19
3.55
4.27
Minute
vent! latlon,
L/m1n
13
19
25
30
35
40
55
63
72
85
100+
Representative activities0
Level walking at 2 raph, washing clothes
Level walking at 3 raph; bowling; scrubbing floors
Dancing; pushing wheelbarrow with 15- kg load;
simple construction; stacking firewood
Easy cycling; pushing wheelbarrow with 75-kg load;
using sledgehammer
Climbing stairs; playing tennis; digging with spade
Cycling at 13 mph; walking on snow; digging trenches
Cross-country skiing; rock climbing; stair climbing
with load; playing squash and handball; chopping
with axe
Level running at 10 mph; competitive cycling
Competitive long distance running; cross-country
skiing
See text for discussion.
kg-m/m1n = work performed each minute to move a mass of 1 kg through a vertical distance of 1 m against the force of gravity.
cAdapted from Astrand and Rodahl (1977).
-------
PRELIMINARY DRAFT
the Vr and CL consumption. If exercise is conducted on a treadmill, adequate
relative standards for CL consumption and V,- 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 CL criteria document (U.S. Environmental Protection Agency, 1978),
were the first to consider the role of increased ventilation due to exercising
in ?n 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) pg/m3 (0.37 or 0.75 ppm) of 03- These
subjects performed light exercise (\L 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
after 2-hr exposure to 1470 pg/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 03; 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 incon-
clusive, the mean RV and CC increased and TLC was unchanged after exposure to
0.75 ppm of 03-
Kerr et al. (1975) reported small, but significant, decreases in FVC,
FEVo n> R, , and SG when 20 subjects were exposed to 980 ug/m (0.5 ppm) of
O. U L 3W
0., for 6 hr with two 15-min periods of medium exercise (100 W). The symptoms
of dry cough and chest discomfort v/ere also experienced after exposure. No
changes in TLC, FRC, C ., dN_, or D,CO were observed.
Folinsbee et al. (1977b) demonstrated that the heightened pulmonary
effect of 03 associated with intermittent exercise during exposure occurred
principally, it" not entirely, during the exercise period. In this study,
involving subjects who had exercised for a single 30-min period during a 2-hr
3
980-|jg/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,
dW
while TLC was reduced.
019PO/A 11-14 10/17/85
-------
GROUP A
•GROUP B
60 "SO
EXERCISE
30 60
EXERCISE
EXPOSURE, minutes
90 120
Figure 11-1. Change in forced vital capacity (FVC), forc-
ed expiratory volume in 1-sec (FEV i.n), 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
11-15
10/17/85
-------
PRELIMINARY DRAFT
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 03 concentrations; 14
reported symptoms associated with irritation or breathing difficulty on high-
pollution days. Five subjects who had not resided in such areas reported
similar symptoms upon visiting a high-oxidant-pollution region. Nine subjects
had a history of allergy, 11 were former smokers, and one had had asthma as a
child. Ten subjects in each of four groups were exposed four times, in random
order, to filtered air or 196, 588, or 980 ug/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
3
exposure to filtered air or 196 pg/m (0.10 ppm) of 0, at any workload. At
3
rest (10 L/min), pulmonary function changes were confined to 980 pg/m (0.50
ppm) 0, exposures. Some changes were apparent at the lowest work load (30 L/
3 3
min) and 588 (.ig/m (0.30 ppm) of 03, and effects were more marked at 980 (jg/m
(0.50 ppm) of Ov At the two highest work loads (49 and 67 L/min), pulmonary
3
function changes occurred at both 588 and 980 ug/m (0.30 and 0.50 ppm), with
the changes at 980 ug/m (0.50 ppm) of 0-, usually significantly greater than
3
those at 588 pg/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 heaviest work loads and at the highest G, concentrations. Reductions in
TLC and inspiratory capacity (1C), but not RV or functional residual capacity
(FRC), were also noted.
Von Nieding et. al. (1977) exposed normal subjects to 196 Mg/rrf (0.1 ppm)
OT for 2 hr with light intermittent exercise and found no changes in either-
forced expiratory functions or symptoms. However, they found significant
increases (~ 7 mm Hg) in both alveolar-arterial PO,, difference and airway
resistance (••• 05 cm H,0/L/s) and a significant decrease in PO,, (~7 mm Hg).
f. at
These data were later reanalyzed (von Nieding et. al., 1979) using more stringent
statistical criteria and the changes in both airway resistance and PaO^ were
019PO/A 11-16 10/J7/85
-------
PRELIMINARY DRAFT
found to be nonsignificant. In both analyses, the nonparametric Wilcoxen
procedure which ranks paired differences was used. In the 1977 analysis, PaCL
and airway resistance changes < 5 mm Hg and 0.5 cm hLO/L/s, respectively, were
considered as zero but used in the analysis. In the 1979 analysis, PaO~ and
airway resistance changes <5 mm Hg and 0.5 cm HJ3/L/S, respectively, and
within the range of normal variation for each individual subject were not
included in the analysis. Thus, data from about half the subjects analyzed in
1977 were included in the 1979 analysis.
In a study similar to that of von Nieding et al. (1977; 1979), Linn et
al. (1979) exposed normal subjects to 392 ug/m3 (0.2 ppm) of 03_ The 18
subjects exercised at twice resting ventilation for 15 min of every half hour.
Blood and alveolar gas samples were taken shortly after 1 and 2 hr of their
2.5 hr of exposure. Blood samples were taken both from an arterialized ear
lobe and a brachial artery. No significant differences between air and 0,
exposures were observed for changes in P«0?, P 0- or P,._ , 0?.
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 Qy 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-
served for exposures to 588 and 784 ug/m (0.30 and 0.40 ppm) of 0, with the
magnitude of decrement greater at the higher minute ventilation. The magnitude
of decrement also increased with increasing exposure time. No pulmonary
effects were observed for exposures to clean air or 392 ug/m (0.2 ppm) of 0,.
J
The authors suggested that the detectable level for 0, functional effects in
healthy subjects during sustained exercise at a moderately heavy work load (VF
3
of ~62 L/min) occurred between 0^ concentrations of 392 and 588 ug/m (0.2 and
0.3 ppm). The responses to continuous exercise were similar to those observed
in studies usiny intermittent but equivalent exercise.
Kagawa (1983a; 1984) presented data on 15 subjects exercising intermit-
tently (15 min exercise, 15 min rest) during a 2-hr exposure to 294 or 588 ug/m
(0.15 or 0.30 ppm) of Q~. These subjects reported the typical symptoms at the
higher 0., concentrations. Paired t-tests were used to compare responses to
filtered air and 0.. SG decreased 6.4 percent (P <0.05) following the
, J aw ^
294-ug/m (0.15-ppm) exposure and 16.7 percent (P <0.01) following the 588-pg/m-
019PO/A 11-17 10/17/85
-------
PRELIMINARY DRAFT
(0.30-ppm) exposure. In the latter environment, only FVC showed a significant
(P <0.05) decrement; FEV, was unaffected. These subjects had resided in a
low-oxidant-pol lutant environment.
McDonnell et al. (1983) provided further information related to high
levels of ventilation during exercise in 135 healthy subjects exposed to 0.,.
Subjects were excluded from the study if they had smoked within 3 yr or had a
history of asthma, allergy, rhinitis, cardiac disease, chronic respiratory
disease, recent acute respiratory illness, or extensive exposure to pollutants.
They divided their subjects into six groups, each group exposed to a different
concentration of 03; viz. 0.0 (n=20), 0.12 (n=22), 0.18 (n=20). 0.24 (n=21),
0.30 (n=21), and 0.40 (n=29) ppm, equivalent to 0.0, 235, 353, 470, 588, and
784 ug/m of 0-.. The subjects were exposed for 2.5 hr, with exposure consist-
?
ing of alternating 15-min periods of rest and exercise (VV/BSA of = 35 L/m or
Vp = 64 to 68 L/min) during the first 120 min. Forced expiratory spirometry
and pulmonary symptoms were measured between 5 and 10 min after the final
exercise (i.e., at 125 min of exposure), while plethysmography was performed
between 25 and 30 min after the final exercise (i.e. , at 145 min of exposure).
The pulmonary symptom, cough, showed the greatest sensitivity to 07 (it occurred
3
at the lowest concentration, 235 ug/m or 0.12 ppm of 0,). Small changes in
forced expiratory spirometric measures (FVC, FEV,, maximal mid-expiratory flow
3
[FEF25_75470 ug/m (0.24 ppm). The s igmo id-shaped dose-response curves
indicated a relatively large decrease in FVC, FEV,, and FEF pt.Tc^ between 353
and 470 ug/V~ (0.18 and 0.24 ppm) 0,. However, in contrast to the results of
other investigations, a plateau in response was suggested at the higher levels
(>470 ug/m^; 0. ?4 ppm) of 0.,. Regarding SR , a significant increase was
observed beginning at 470 ug/m (0.24 ppm) of 0., and the magnitude of this
change was greater with increasing 0. levels. These findings are in agreement
with the result; of ether investigators. The two different patterns in
response plus the observation that individual changes in SR and FVC were
oW
poorly correlated prompted these investigators to suggest that more than a
single mechanism might have to be implicated to define the effects of 0., on
019PO/A 11-18 10/17/85
-------
PRELIMINARY DRAFT
pulmonary functions. Findings from this study are particularly relevant in
that a large subject population was studied and pulmonary effects were suggested
2
at an 03 concentration (235 |jg/m ; 0.12 ppm) lower than that for which they
had previously been observed.
More recent studies on well-trained subjects have become available. Six
well-trained men and one well-trained woman (all of the subjects except one
male being a competitive distance cyclist) exercised continuously on a bicycle
ergometer for 1 hr while breathing filtered air or 412 |jg/m (0.21 ppm) of 0,
(Folinsbee et al., 1984). They worked at 75 percent maximal aerobic capacity
(max V0?) with mean minute ventilations of 89 L/min. Pulmonary function
measurements were made pre- and post-exposure. Decreases occurred in FVC
(6.9 percent), FEVj Q (14.8 percent), FEF25_?5% (18 percent), 1C (11 percent),
and maximum voluntary ventilation (MVV) (17 percent). The magnitude of these
changes were of the same order as those observed in subjects performing moderate
intermittent exercise for 2 hr in a 686-Mg/m (0.35-ppm) 03 environment.
Symptoms included laryngeal and/or tracheal irritation and soreness as well as
chest tightness upon taking a deep breath.
Adams and Schelegle (1983) exposed 10 well-trained distance runners to
0.0, 392, and 686 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 VV 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
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 fD and decreased
3
VT) when exercise was performed in 392 (jg/m (0.20 ppm) of 0.,. Two-way analysis
of variance (ANOVA) procedures performed on the pulmonary function data indi-
cated significant decrements (P <0.0002) for FVC, FEVj, 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.
Avol et al. (1984) randomly exposed trained cyclists (n = 50) to 0, 157,
314, 470, and 627 |jg/m3 (0.0, 0.08, 0.16, 0.24, and 0.32) ppm 03. Each exposure
019PO/A 11-19 10/17/85
-------
PRELIMINARY DRAFT
consisted of 10 min warm-up, 60 min of exercise at 50% max VO- (Vr = 57 L/min),
5 min cool down (all performed on a bicycle ergometer), and 5 min post-exercise
pulmonary function testing. Most subjects resided in the Los Angeles area and
therefore were subject to prior exposure to ambient 0.,. Two subjects had
histories of asthma; all others were free of chronic respiratory disease.
Three subjects were current smokers, while six others had previously smoked.
Forced expiratory spirometry and respiratory symptoms were evaluated before
exposure, immediately after exercise, and 1 hr after exposure. When compared
to exposure at 0.0 ppm, significant decreases in FVC and FEV1-0 and an increase
in lower respiratory symptom score combined (cough, sputum, dyspnea, wheeze,
substernal irritation, chest tightness) were observed following exposure at
3
and above 314 |jg/m (0.16 ppm) 0.,; no significant changes occurred with exposure
3
to 157 (jg/m (0.08 ppm) 0.,. The magnitudes of change in FVC, FEV,, and symptom
score were concentration-dependent and remarkably consistent with those previ-
ously reported by McDonnell et al. (1983). While they did not return to
levels observed prior to exposure, substantial recovery of both function and
symptoms was observed 1 hr following exposure. Significant changes in FVC,
FEV,, and lower respiratory symptom score also resulted from exposure to
3
polluted ambient air with a mean 03 concentration of 294 (jg/m (0.15 ppm) (see
Chapter 12). Although the pulmonary changes in response to polluted ambient
air appeared to be of lesser magnitude than those in reponses to the nearest
generated 0., level (314 (jg/m ; 0.16 ppm), the difference between the two
exposures was not statistically different.
Kulle et al. (1985) randomly exposed male nonsmokers (n = 20), with no
history of chronic respiratory or cardiovascular disease, to 0, 196, 294, 392,
and 490 |jg/m (0.0, 0.10, 0.15, 0.20, and 0.25 ppm) 03 for 2 hr. Each exposure
consisted of four cycles of 14 min treadmill exercise (VV - 68 L/min) alternated
with 16 min of rest. Forced expiratory spirometry was performed before exposure
and 9 mi n after each exercise. Measurements of R and V. (FRC) were made
aw LS
prior to and after each exposure; respiratory symptoms were evaluated after
each exposure. Significant concentration-dependent decreases in FVC, FEV]i0,
FEF,c -,,-, SG , 1C, and TLC and increases in respiratory symptoms (cough,
£j-/D aw
nose/throat irritation, chest discomfort) were observed; RV and FRC did not
change with exposure to any concentration. Significant responses were best
modeled as an exponential function of 0-, concentration. Additionally, FVC and
FEV]_0 decreased as a linear function of time of exposure. While these results
are discussed by the authors as though significant changes resulted from
019PO/A 11-20 10/17/85
-------
PRELIMINARY DRAFT
exposure to 294 ug/m (0.15 ppm) CL, the magnitude of change at this concentra-
tion was quite small. Moreover, while the statistical procedures (ANOVA) used
by these investigators did indicate a significant CL effect when data from
exposures to all 0., concentrations were analyzed, no statistical comparisons
of responses at individual CL concentrations were performed. Thus, the legiti-
macy of ascribing 0, effects at any individual 0., concentration is questionable
and discussion of data should be confined to the overall concentration-response
relationship.
11.2.4 Intersubject Variability and Reproducibility of Responses
In the majority of the above studies, assessment of the significance of
results was typically based on the mean ± variance of changes in lung function
resulting from exposure to 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 0, and
clean air exposures were not due to chance, the variance of responses was
quite large in most studies. While characterization of reports of individual
responses to 0, is useful since it permits an assessment of the proportion of
the population that may actually be affected during 03 exposure, statistical
treatment of these data is still rudimentary and their validity is open to
question.
Results from a small number of studies (Horvath et al., 1981; Gliner et
al., 1983; McDonnell et al., 1983; Kulle et al., 1985) that have reported
individual responses indicate that a considerable amount of intersubject
variability does exist in the magnitude of response to CL. Figure 11-2 illu-
strates the variability of responses in FEV, n and SR obtained from subjects
J.. U 3W
exposed to different CL 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/m (0.42 ppm) of CL while performing moderate intermittent exercise. When
these same subjects were exposed to clean air under the same conditions, the
response of FEV, Q ranged from an 8-percent increase to an 11-percent decrease
(mean = 0 percent).
Gliner et al. (1983) exposed subjects (13 females, 8 males) performing
intermittent light exercise for 2 hr to clean air and 392 ug/m (0.20 ppm) of-
Oo. Changes in FEV, Q resulting from clean-air exposure ranged between
019PO/A 11-21 10/17/85
-------
(A
111
2
(0
u.
O
c
UJ
O
2
3
Z
O OUIO O Ol O O Ol O
\\llltl\ll
0.40 ppm
0.30 ppm
rTkl-n,r
1 1 1 1 1 1 1 1 i 1
0.24 ppm
10
10
J M 1 1 1 1 1
-
|
0.18
Ti n i
i i
ppm
I I
I 1 1 1 1 M I
0.12
m
JLn
1 1
ppm
1 1
J I I 1 1 1 1 1
0.00
f
-i i i i i
1 1
ppm,
1 1
TfTTrfiri
I 1 1 1 ! I I 1 1 1
0.40 ppm
1 1 1 1 M 1 1 M
0.30 ppm
i 1 1 i 1 1 1 1
0.24 ppm
1 1 1 1 I 1 1 1 1 1
0.18 ppm
JTfln
,,,,
I I I I I I I I I
0.12 ppm
I I 1
1m
0.00 ppm
, ,,
10i 0 >10j .201,30, 40
•20j ,0, .20 .40, 60 80
AFEVj.olDECREASE). percent 'ASRaw
-------
PRELIMINARY DRAFT
+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
3
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, Q ranging from -3 to
-43 percent (mean = -16 percent) at 784 ug/m (0.40 ppm), -4 to -38 percent
(mean = -17 percent) at 588 ug/m (0.30 ppm), -2 to -41 percent (mean =
-15 percent) at 470 ug/m (0.24 ppm), -2 to -22 percent (mean = -7 percent) at
3 "?
353 ug/m (0.18 ppm), +7 to -17 percent (mean = 4 percent) at 235 pg/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
3W
(Figure 11-2).
Kulle et al. (1985) exposed each of his 20 subjects to four 03 concentra-
tions for 2 hr with heavy intermittent exercise. For these subjects, changes
in FEVj_0 ranged from +10 to -10 percent (mean = 0 percent) at 196 ug/m (0.10
ppm), +5 to -10 percent (mean = 2 percent) at 294 ug/m (0.15 ppm), +5 to -20
o
percent (mean = -5 percent) at 392 ug/m (0.20 ppm), and +5 to -35 percent
(mean = -8 percent) at 490 ug/m (0.25 ppm). Concentration-response curves
were also constructed for individual subjects and individual 03 responsiveness
assessed. Three subjects exhibited a slight increase in FEV] following exposures
to all four of the 0, concentrations. Most of the remaining subjects demonstrated
progressive decreases in FEV]-0 with increasing 0, concentrations. Five
subjects exhibited FEV]i0 decreases of <5 percent, seven subjects were between
5 and 10 percent, three subjects were between 10 and 15 percent, and two
subjects exhibited FEVli0 decrease of >15 percent.
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.
exposed subjects performing intermittent light exercise for 2 hr to 392 pg/m
(0.20 ppm) of 0, on three consecutive days, followed the next day by an expo-
T
sure to either 823 or 980 ug/m (0.42 or 0.50 ppm) of 0,. Each subject had
3
also been exposed prior to or was exposed after the study to 823 or 980 ug/m
(0.42 or 0.50 ppm) 0.,. For individual responses of FEV, ,,, 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 03 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
019PO/A 11-23 10/17/85
-------
PRELIMINARY DRAFT
the two exposures was quite high (r = 0.92). Although these comparisons were
confounded by possible effects of prior 0, exposure, they do suggest that indi-
vidual changes in FEV, g resulting from 0, exposure are reasonably reproducible.
Moreover, a given individual's response to a single 0, exposure is probably a
reliable estimate of that individual's intrinsic responsiveness to 0.,.
McDonnell et al. (1985a) exposed each of 32 subjects for 2 hr to one of
five different 03 concentrations (235, 353, 470, 588, and 784 ug/m3; 0.12,
0.18, 0.24, 0.30, and 0.40 ppm) with intermittent heavy exercise. Each subject
was exposed at least twice to the same 03 concentration at 3 to 75-week
intervals. The correlation coefficients between the two exposures closest in
time (mean ± S.D. = 9 ± 4 weeks) for individual changes in FVC, FEV1>0, and
were 0.89, 0.91, and 0.83, respectively. Correlation coefficients
were moderate for changes in SR (r = 0.63) and the pulmonary symptoms of
aw
cough (r = 0.75), shortness of breath (r = 0.65), and pain upon deep respiration
(r = 0.48). With a longer time between exposures (mean ± S.D. = 33 ± 20
weeks), changes in FVC (r = 0.72), FEVJ>0 (r = 0.80), and FEF25_?5% (r = 0.76)
were nearly as reproducible. This high degree of reproducibility indicates
that the magnitude of response to a single exposure is a precise estimate of
that subject's intrinsic responsiveness to 0.,. Moreover, intersubject variabi-
lity in magnitude of 0, -induced effects is probably the result of large differ-
ences in intrinsic responsiveness to 0,.
11.2.5 Prediction of Acute Pulmonary Effects
Nomograms for predicting changes in lung function resulting from the
performance of light intermittent exercise while exposed to different 0,
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 VV. Equations were derived
from lung function measurements at 1 and 2 hr of exposure to 725, 980, and
1470 ug/m (0.37, 0.50, and 0.75 ppm) of 03 under conditions of both rest and
intermittent exercise sufficient to increase vV by a factor of 2.5. Although
the fit of their data to linear and second-order curves was good, the authors
also commented that for a given effective dose, exposure to a high concentra-
tion of 0., for a short period of time induced greater functional decrements
than a longer exposure to a lower concentration. This phenomenon implies that
019PO/A 11-24 10/17/85
-------
PRELIMINARY DRAFT
Oo 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 (L 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. However, these prediction models must be interpreted
with extreme caution since the data base is limited and the great intersubject
variability in responsiveness to 0, makes truly refined modeling of effective
dose highly improbable. Extension of the effective-dose concept was accom-
plished in the studies of Folinsbee et al. (1978) on subjects at rest and
performing intermittent exercise during 2-hr exposures to 0, 196, 588, and
980 ug/m3 (0.0, 0.10, 0.30, and 0.50 ppm) of 03- The exercise loads required
Vr 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 Vr, and second on all subject groups together
after computing the effective dose. Predictions of pulmonary function changes
in FEV, based on effective doses up to 1.5 ml 0., agreed with data collected by
other investigators. Prediction equations using the effective dose for all
measured pulmonary functions were constructed. All equations were significant
at the 0.01 level. These investigators also used a multiple regression approach
to refine further the prediction of changes in pulmonary function resulting
from 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
03 concentration and Vr. For example, these two predictors accounted for
approximately 80 percent (multiple r = 0.89) of the variance in FEV, „.
Moreover, 0, concentration accounted for more of variance than did VV, and for
a given effective dose, exposure to a high concentration with a low Vr induced
greater functional decrements than exposure to a lower concentration with
elevated VV Equations (with appropriately weighted 03 concentration and Vr)
for predicting the magnitude of pulmonary decrements were also provided.
Adams et ol. (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
019PO/A 11-25 10/17/85
-------
PRELIMINARY DRAFT
for pulmonary function variables could be accounted for by 0, concentration,
followed by VV, and then by exposure time. Adams et al. emphasized the predomi-
nant importance of 0, concentration and suggested that the detectable level
for CL functional effects in healthy subjects during sustained exercise at a
moderately heavy work load (VV ~ 62 L) occurred between 0., concentrations of
3
392 and 588 ug/m (0.2 and 0,3 ppm). The responses to continuous exercise
were similar to those observed in studies using intermittent but equivalent
exercise. They also noted, as had others, that the effective-dose concept was
not satisfactory for predicting individual responses.
Colucci (1983) assembled data available from the literature and analyzed
them with the purpose of constructing dose/effects profiles for predicting
pulmonary responses to 0, based on results combined from many different labora-
tories. Basically, he examined changes in R and FEV, n as functions of
aW J., \)
exposure rate (Cu concentration x VV) and total exposure dose (exposure rate x
duration of exposure), which is equivalent to effective dose. The correlation
for changes in R was slightly better than that for changes in FEV, Q. The
author states that he elected to use linear equations to fit the data rather
than polynomials because he found little difference in the degree of correla-
tion between the two methods. The analysis also found an attenuation in the
rate of increase of SR as Vc increased to higher levels; there was no atten-
aw h
uation of the decrease in FEV, n as a function of increasing VV. This observa-
tion suggested to Colucci that different mechanisms may be involved in the
effects on R and FEV-. n. Whether expressed as functions of exposure rate or
ow _L. U
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 (L concentration and VL. The overall finding,
that increases in R and decreases in FEV, n are reasonably correlated with
aW _L. U
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.
11.2.6 Bronchial Reactivity
In addition to overt changes in pulmonary function, several studies have
reported increased nonspecific airway sensitivity resulting from 0. exposure.
019PO/A 11-26 10/17/85
-------
PRELIMINARY DRAFT
Airway responsiveness to the drugs acetylcholine (ACh), methacholine, or
histanrine 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
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/m (0.0, 0.3, and 0.5 ppm) 0,. Their three nonsmoking
subjects were exposed for 2 hr followed by measurements of bronchial reac-
tivity to ACh. They found that these subjects demonstrated an increased
reactivity to ACh. However, because of the small number of subjects and the
large variability of responses, the results may not represent a significant
effect.
The bronchial reactivity of atopic and nonatopic subjects was evaluated
by Holtzman et al. (1979). They studied 16 healthy nonsmoking subjects and
found that nine could be classified as "atopic" based on medical history and
allergen skin testing. All subjects had normal pulmonary functions determined
in preliminary screening tests and were asymptomatic. Both atopic and non-
atopic subjects performed intermittent exercise while wearing noseclips and
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 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 03 exposure when compared to exposure in filtered air. The
increase in SR resulted predominantly from an increase in airway resistance,
9W
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
a W
after histamine inhalation. Atopic subjects appeared to respond to a greater
019PO/A 11-27 10/17/85
-------
PRELIMINARY DRAFT
degree than nonatopic subjects, although the pattern of change and the induc-
tion and time course of increased bronchial reactivity after exposure to CL
were unrelated 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 Oj.
Bronchial reactivity to ACh was determined after exposure. Significant in-
creases in bronchial reactivity were observed with the ACh challenge following
3 3
exposure to 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.,
3W
1981). Seven subjects, intermittently exercising (15 min exercise, 15 min
rest) at a load sufficient to double their resting VE, were exposed to 392 |jg/m
(0.2 ppm) of 0., over a 2-hr period. Two air exposures preceded the On exposure,
which was followed by another air exposure. Another group (five individuals)
were only repeatedly tested pre- and post-air exposure for their response to
histamine. In these two groups, the bronchial responsiveness to histamine was
not different in the air exposures. The bronchomotor response to inhaled
histamine aerosol was not altered following the 392-ug/m (0.2-ppm) 03 exposure.
However, a third group (seven individuals) was also exposed to air for 2 days
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
ug/m (0.4 ppm) of 0,. Baseline SR (i.e., before histamine) after the
j aw
0.4-ppm exposure remained unchanged.
As part of a study of repeated exposures to 03 (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
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 VV of four to five times resting values.
Bronchial reactivity to methacholine was assessed after each exposure and was
significantly enhanced (P <0.01) in both subject groups following exposure to
0., as compared to filtered-air exposure.
Two hypotheses have been proposed that are consistent with the observations
of increased airway reactivity to histamine and methacholine following 03
exposure (Holtzman et al., 1979). The first suggests that 0^ increases airway
epithelial permeability, resulting in greater access of histamine and metha-
choline to bronchial smooth muscle and vagal sensory receptors. The second
hypothesis suggests that 0, or a byproduct of 0,, causes an increase in the
019PO/A 11-28 10/17/85
-------
PRELIMINARY DRAFT
number or the binding affinity of acetylcholine receptors on bronchial smooth
muscle.
11.2.7 Mechanisms of Acute Pulmonary Effects
The primary acute respiratory responses to 03 exposure are decrements in
variables derived from measures of forced expiratory spirometry (volumes and
flows) and respiratory symptoms (notably, cough and substernal pain upon deep
inspiration). Altered ventilatory control during exercise (increased fR and
decreased VT with VV remaining unchanged) and small increases in airway resis-
tance have also been observed.
Decrements in FVC observed at relatively high (1470-(jg/m ; 0.75-ppm) 0,
concentrations have been associated with increases in RV (Hazucha et al.,
1973; Silverman et al., 1976). Since increased RV occurs only at higher 0.,
concentrations, it has been postulated by Hazucha et al. (1973) that this
increase results from gas trapping and premature airway closure caused by a
direct effect of 0, on small airway smooth muscle or by interstitial pulmonary
edema.
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
reduced inspiratory capacity resulting from 0, 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). These hypotheses remain to be
proven.
Unless measured at absolute lung volumes, decrements in forced expiratory
flows (e.g., FEV, Q, FEF25-75%^ are difficu1t to interpret. Most of the decline
019PO/A 11-29 10/17/85
-------
PRELIMINARY DRAFT
in flow is probably related to a reduction in maximal expiratory pressure
associated with the decline in TLC, while a smaller portion may result 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 stimula-
tion, by the interaction of an endogenous or exogenous substance with the
vagal efferent pathway, or by the direct action of 0, (or an 0,-induced,
locally released substance) on smooth muscle or mucosa (Folinsbee et al.,
1978; Holtzman et al., 1979; McDonnell et al., 1983). Beckett et al. (1985)
effectively blocked 0,-induced increases in airway resistance by having subjects
breathe aerosols of atropine, a muscarinic cholinergic antagonist, prior to
exposure. These findings support the conclusion that 0.,-induced increases in
airway resistance involve parasympathetic neural release of acetylcholine at
the site of muscarinic receptors on the smooth muscle of large airways and
suggest mediation of this response by vagal efferent reflex pathways.
It is probable that stimulation of airway receptors is an afferent mechan-
ism common to changes in airway resistance as well as changes in volumes and
flows. However, McDonnell et al. (1983) postulated the existence of more than
one mechanism for the normal processing of this sensory input, implying that a
different efferent mechanism is responsible for 0.,-induced changes in lung
volume. They based this postulation on their observed lack of correlation
between individual changes in lung volumes and airway resistance and on differ-
ences in the concentration-response curves for these variables. Beckett et
al. (1985) provide strong support for the involvement of more than one mechanism
in 0,-induced pulmonary responses. While pretreatment with atropine blocked
increased airway resistance in their CL-exposed subjects, it had no effect on
the 0,-induced decreases in lung volumes (FVC, TLC). Thus, while these findings
indicate increased airway resistance is via a reflex stimulation of airway
smooth muscle, the failure of atropine to the decrease in lung volumes suggests
a separate mechanism for this response which is not dependent on functioning
muscarinic receptors.
11.2.8 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 individuals with
emphysema in the United States. Although there is some overlap of about
019PO/A 11-30 10/17/85
-------
PRELIMINARY DRAFT
1,000,000 in these three categories, it can be reasonably estimated that over
15,000,000 individuals reported chron.ic respiratory conditions. 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 03
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
with limited disability) to 2-hr exposures to clean air, sham 0.,, and 392 (jg/m
(0.20 ppm) 03 with secondary stressors of heat (31°C, 35 percent rh) and
intermittent light exercise (Vr - 2 x resting Vr). Subjects continued the use
of appropriate medication throughout the study. Evaluation of responses was
not made in relation to the severity of the disorder present in these patients.
After baseline (zero 0,) studies were completed, subjects were exposed to
filtered air, a sham (i.e., some 0., was initially present in the exposure
chamber), and a 392- to 490-ug/m3 (0.20- to 0.25-ppm) 03 condition (a 3-day
control study was conducted over 3 days [0 ppm 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 ventllatory
volumes, but because of the relative physical condition of the subjects there
was a wide variation in absolute VV so that inhaled 0, 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 dally variations 1n this function. A slight
increase in symptoms was also noted during 0~ exposures, but this increase was
not statistically different from sham or control conditions. A spectrum of
biochemical parameters was measured in blood obtained only post-exposure. The
significant biochemical changes reported were small, and probably only represent
the normally found individual and group variability seen in these parameters
despite the investigators' suggestion that asthmatics may react biochemically
at lower 0., concentrations than nondiseased individuals.
Clinically documented asthmatics (16 years duration of asthma) were
exposed either to filtered air or 490 ug/m (0.25 ppm) of 0, 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
019PO/A 11-31 10/17/85
-------
PRELIMINARY DRAFT
oo
ro
TABLE 11-4. OZONE EXPOSURE IN SUBJECTS WITH PULMONARY DISEASE
Ozone
concentration
ug/mj
196
627
1960
235
235
353
490
392
392
588
392
588
490
784
ppm
0.1
0.32
1.0
0.12
0.12
0.18
0.25
0.2
0.2
0.3
0.2
0.3
0.25
0.4
Measurement3'
method
MAST,
NBKI
UV,
NBKI
UV
UV,
NBKI
CHEM,
NBKI
CHEM,
NBKI
UV,
UV
CHEM,
NBKI
UV/CHEM,
UV
Exposure
duration and
act1v1tyc
2 hr
R
1 hr
IE (variable)
@ 15-min Intervals
1 hr (mouthpiece)
R
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
40 min
CE (40, graduated)
2 hr
R
3 hr/day
6 days
IE(4-5xR)
for 15 min
Observed effect(s)d
No effect on SR and Pa02; increased bronchial
reactivity to A?H at 0.32 and 1.0 ppm in healthy
subjects. SR Increased following ACh
challenge In 2/3 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 pulmonary function or
symptoms.
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 1n blood biochemistry. Increase
in symptom frequency reported.
No significant changes in pulmonary function or
symptoms. Sa02 decreased during exposure to
0.2 ppm.
No significant changes In pulmonary function,
exercise ventilation, cardiovascular response,
or respiratory symptoms.
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
3 COLD
1 asthma
14 healthy
25 COLD
10 asthma
(adolescents)
28 COLD
22 asthma
13 COLD
6 CHD
17 asthma
20 smokers with
chronic bronchitis
Reference
Kb'nig et al. , 1980
Linn et al. , 1982a
Hackney et al. , 1983
Koenlg et al . , 1985
Linn et al. , 1983
Linn et al. , 1978
Solic et al. , 1982
Kehrl et al. , 1983,
1985
Superko et al. , 1984
Silverman, 1979
Kulle et al. , 1984
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 (\L) given in L/min.
See Glossary for the definition of symbols.
-------
PRELIMINARY DRAFT
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 0, exposure with a decrease in lung
function and an exacerbation of symptoms. One group of six subjects had
demonstrable decreases in function, but information concerning the stage
and/or development of their asthma was inadequately addressed. Such informa-
tion would have been extremely valuable in providing opportunities to study
this more susceptible portion of the asthmatic population further.
Koenig et al. (1985) exposed 10 adolescent asthmatics at rest to clean
air and to 235 ug/m (0.12 ppm) 0.,. Exposure was via a rubber mouthpiece for
1 hr. The subjects, aged 13 to 18 years old, had a history of atopic (Type I,
IgE mediated) extrinsic asthma, characterized by documented reversible airways
obstruction, elevated serum IgE levels, positive reaction to inhaled dust,
mites, mold and/or pollen antigens, and exercise-induced bronchospasm. Because
of the relative severity of their asthma, subjects maintained their usual
medication therapy during testing. No significant changes in pulmonary function
or symptoms resulted from 03 exposure as compared to exposure to clean air.
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 V.-, 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
underwent a control filtered air and a 235-ug/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 (Sa02) (Hewlett-Packard ear oximeter) were made.
019PO/A 11-33 10/17/85
-------
PRELIMINARY DRAFT
No significant differences in forced expiratory performance or symptoms attri-
butable to Oj were found. From pre-exposure values at rest (normal saturations)
to mid-exposure values during exercise, mean SaO? increased by 0.65 ± 2.28
percent with purified air, but decreased by 0.65 ± 2.86 percent with (L. This
difference was significant. However, this small decrement attributable to
0, was near the limit of resolution of the oximeter and was detected by computer
signal averaging; thus, its physiological and clinical significance is uncer-
tain. Moreover, since many of the COLD subjects were smokers, interpreting
changes in SaOp without knowing carboxyhemoglobin saturation (%COHb) is diffi-
cult. 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 0,) and one to 392 ug/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 VY to 20 to 30 L/min
and an oxygen uptake of ^ 1 L/min. SaO. was measured during the last exercise
period. Pulmonary function measurements were made before and after exposure,
with FVC maneuvers also obtained at 1 hr of exposure. There was no statisti-
cally significant difference between the effects of air exposure versus 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)
had exposed to 392 ug/m (0.2 ppm) of 0-,. In this experiment the subjects
3 J
were exposed to 588 ug/m (0.3 ppm) of 0^ with a protocol similar to that used
by Solic et al. Data presented consisted of measurements made during the
o 3
392-ug/m (0.2-ppm) exposure, as well as new data obtained during the 588-ug/m
(0.3-ppm) exposures. The second exposure occurred 6 to 9 months later. No
statistically significant O^induced changes in respiratory mechanics or
019PO/A 11-34 10/17/85
-------
PRELIMINARY DRAFT
symptoms were found in the COLD patients at either (L concentration. Statisti-
cally significant changes in pulmonary function or symptoms were also not
observed when the number of COLD patients exposed to 588 ug/m (0.3 ppm) was
increased to 13 (Kehrl et al., 1985). Arterial oxygen saturation (ear oximeter)
measured in eight of these subjects during the last exercise interval was 0.95
percent less with OT exposure as opposed to clean air exposure; this difference
nearly attained statistical significance (P = 0.07).
Linn et al. (1983) presented data on 28 COLD patients exposed for 1 hr to
0, 353, and 490 yg/m (0.0, 0.18, and 0.25 ppm) of 0,. Subjects had chronic
respiratory symptoms; their mean FEV)i0/FVC was 58%, indicating a mild degree
of obstruction for the group. Severity of COLD was classified as minimal for
12 subjects, moderate for 14 subjects, and severe for 2 subjects. Two subjects
had never smoked, while eleven were ex-smokers and 15 were current smokers.
Subjects continued use of chronic medication during the study but avoided
inhaled bronchodilators of testing days. Subjects exercised 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 corresponding \lf- 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
J J
alert levels. Arterial oxygen saturation (ear oximeter) was not changed
during the second exercise period and post-exposure. Medication and severity
of disease may explain the divergent results previously obtained. Differences
may also be related to the level of exercise and the resulting ventilation.
As a consequence, these patients may have inhaled comparatively small doses of
°3'
In all these studies on COLD patients, a. wide diversity of symptoms and
ventilatory deficits was present. The common findings by Linn and Solic as to
small changes in SaO? 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-,
exposures where COLD patients exercised at higher intensities may be of in-
terest.
Konig et al. (1980) performed studies on 18 individuals, three of whom
suffered from COLD and one of whom had extrinsic allergic asthma (bronchial
symptom free). The bronchial reactivity test used ACh as the test substance.
Specific airv/ay resistance was measured in the patients after a 2-hr exposure
019PO/A 11-35 10/17/8!:
-------
PRELIMINARY DRAFT
to 196 ng/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
3w
after the 0., 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 with some
3
evidence of airway obstruction for 3 hr to filtered air and 804 |jg/m (0.41 ppm)
of Og. 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.
One study (Superko et al., 1984) has attended the physiological responses
of patients with ischemic coronary heart disease (n = 6) randomly exposed to
0, 392, and 588 ug/m3 (0.0, 0.2, and 0.3 ppm) Og. The diagnosis of coronary
disease was made by documented previous myocardial infarction, angiography, or
classic angina pectoris with reproducible ECG changes on graded exercise
testing. Each patient had a well defined and reproducible symptomatic angina
pectoris threshold. Three of the patients also exhibited evidence of obstruc-
tive pulmonary disease as indicated by FEV,_0/FVC of less than 70 percent;
smoking history of the subjects was not included. Each exposure was of 40 min
duration and consisted of 10 to 15 min gradually incremented exercise warm-up
followed by 25 to 30 min exercise at an intensity slightly below the subjects'
symptom threshold (mean VV = 42 L/min). Changes in pulmonary function (RV,
FVC, FEV1<0> FEF^r^r) following exposures were not different among the three
conditions. Considering the magnitude of exercise VV (42 L/min), changes in
pulmonary function might have been expected. This lack of change may be
related to the relatively short exposure duration, small number of subjects,
or past, smoking history of subjects. There were also no significant differences
in cardiopulmonary responses (VV, fR, V0?, HR, SBP) during exercise, time to
onset of angina, or ischemic cardiovascular changes among the three conditions.
11.2.9 Other Factors Affecting Pulmonary Responses to Ozone
11.2.9.1 Cigarette Smoking. Smokers have been studied as a population group
having potentially altered sensitivity to oxidant exposures. Hazucha et al.
(1973) and Bates and Hazucha (1973) reported the responses of 12 subjects
019PO/A 11-36 10/17/85
-------
PRELIMINARY DRAFT
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 0., was
initially detectable by all subjects, but they were unaware of it after one-half
hour. Symptoms of typical oxidant exposures were reported by all subjects at
the termination of exposure. Decrements in FVC and FEFoc.Tcq; were greater for
nonsmokers after either 0., exposure, whereas smokers exhibited greater decre-
3
ments in FEV, n and 50% V . Smokers exposed to 1470 ug/m (0.75 ppm) of 0,
j. . u msx o
had a greater decrease in FEF^r 7cy than did nonsmokers. The FEF 05-75% changes
were much larger than the changes in FEV, n, 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 (VV = 44 L). For the remainder of the exposure time the
subjects were resting. Follow-up measurements were made 2 and 24 hr later. A
control day on which subjects breathed filtered air preceded the 0.,-exposure
day. The 24-hr post-exposure study was conducted in filtered air. Variance
analyses were used to interpret the data. In nonsmokers, significant decre-
ments in ventilatory function were observed following 03 exposure, being most
prominent for FVC and FEV.,. Similar significant decrements were observed for
FEV, and maximum mid-expiratory flow. No decrements were observed in mean
spirometry values in smokers as a group; in fact, all tests disclosed some
degree of improvement, with significance at the 5 percent level for MEF. A
significant reduction in SG and increase in R. were observed, for the most
3W L
part in nonsmokers experiencing subjective symptoms. (All nonsmokers experi-
enced one or more symptoms, while only 4 of 10 smokers had symptoms. These
four smokers had been smoking for relatively short periods of time.)
Six subjects (three nonsmokers and three smokers of 20 cigarettes/day for
2 to 3 years) were studied by Kagawa and Tsuru (1979a). These subjects were
exposed, no smoking on one day and smoking on another day, in either a filtered-
air environment or one containing 588 ug/m (0.3 ppm) of 0.,. 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
019PO/A 11-37 10/17/85
-------
PRELIMINARY DRAFT
slight degree of dizziness and nausea after smoking. Measurements of SG
3V/
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 0,. 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 ug/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
3W
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
the low ambient level of 294 ug/m (0.15 ppm) of 0,, were not presented in
enough detail to permit in depth evaluation of the findings. Thus, the statis-
tical significance, if any, of these findings is unclear.
DeLucia et al. (1983) reported that smokers (six men and six women) were
3
relatively resistant to the oral inhalation of 588 ug/m (0.3 ppm) of 0,. Few
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 FEVpr_7t-w) were made pre- and post-exposure (within 15
min). Overall, the decrements in pulmonary functions were significant and the
authors attributed them to 0.,. The relative insensitivity of smokers based on
these three measurements was indicated by the decrements of 5.9 to 1.2.9 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 ug/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 0.,-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/m (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.
019PO/A 11-38 10/17/85
-------
PRELIMINARY DRAFT
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 CL environment.
Ozone exposure alone (no smoking during exposure) resulted in the typical and
anticipated decreases in pulmonary functions (FVC, FEV, n, 25% V , and 50%
J.. U IDaX
V ) as reported by others. However, the onset of these pulmonary changes
nidx
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 0.,'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 0, exposure. There was no significant interaction
between cigarette smoking and responses to 0,.
11.2.9.2 Age and Sex Differences. Although a number of controlled human
exposures to 0, have used both male and female subjects of varying ages, in
most cases the studies have not been designed to determine age or sex differ-
ences. In fact, normal young males usually provide the subject population,
and where subjects of differing age and sex are combined, the groups studied
are often too small in number to test for potential differences reliably.
Adams et al. (1981) attempted to examine the effects of age on response
to 0, in a small number (n=8) of nonsmoking males varying in age from 22 to 46
years. Comparison of the mean change in pulmonary function between the three
oldest subjects (33 to 46 years old) and the five youngest subjects (22 to 27
years old) revealed only small, inconsistent differences.
McDonnell et al. (1985b) exposed boys (n - 23), aged 8 to 11 yr, once to
0.0 and once to 235 ug/m (0.12 ppm) 03 in random order. The exposure protocol
was identical to that previously employed in their study of adult males
(McDonnell et al., 1983). Exposure duration was 150 min, and the subjects
2
alternated 15-min periods of rest and heavy exercise (Vp = 35 L/min/m BSA)
during the first 120 min of exposure. Forced expiratory spirometry and respira-
tory symptoms were measured before and at 125 min of exposure; airway resistance
was measurerl before and at 145 min of exposure. Definitive statistical analyses
(paired t-tests) were restricted to testing changes in FEV1-0 and cough since
these variables demonstrated the most statistically significant changes in
their previous study of adults. Exploratory statistical analyses were performed
for changes in the other measured variables; however, these analyses cannot be
019PO/A 11-39 10/17/85
-------
PRELIMINARY DRAFT
interpreted as tests of hypotheses. When compared with air exposure, a small
but significant decrement in FEV]j0 was observed, and exploratory analyses
suggest that decrements in FVC and forced expiratory flow rates may also have
occurred. No significant increase in cough wa.s- found due to 0, exposure, and
the other exploratory functions and symptoms did not change. Results from
this study of boys were compared to those of adult males exposed under identical
conditions (McDonnell, 1985c). Actually, exercise VV was less in the children
(39 L/min) than in the adults (65 L/min), however, when normalized for BSA,
both children and adults were exercising at similar ventilation rates (VC/BSA
2
of = 35 L/min/m ). Statistical comparisons of the CL effects between children
and adults were not performed due to the repeated measures design in the
children's study and the use of independent samples in the adult study. With
exposure to 235 pg/m (0.12 ppm) 03, FEVt-.q decreased 3.4 percent for the
children as compared to a 4.3 percent decrease for the adults. Exposure to 03
caused an increase in cough reported by adults while children experienced
little or no increase in cough after 0, exposure. These results indicate that
the effects of CL exposure on lung spirometry were very similar for both
adults and children. However, adults and an increase in cough as a result of
exposure, while children reported no symptoms. The reason for this difference
is not known and needs further study.
Folinsbee et al. (1975), noting the lack of enough subjects for adequate
subdivision, attempted to make sex comparisons in a group of 20 male and 8
female subjects exposed to 0,. No significant differences could be shown in
either symptomology or physiological measurements between male and female
subjects.
Horvath et al. (1979) studied eight male and seven female subjects exposed
for 2 hr to 0, 490, 980, and 1470 (jg/m3 (0, 0.25, 0.50, and 0.75 ppm) of 0-j.
Forced expiratory function decreased immediately following exposure to 980 and
1470 (jg/m (0.50 and 0.75 ppm), with greater changes occurring at the highest
03 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 |jg/m3 (0, 0.20, 0.20. 0.20, and 0.42 or 0.50 ppm) of 03, respectively.
019PO/A 11-40 10/17/85
-------
PRELIMINARY DRAFT
During exposure the subjects alternated 15 min of rest with 15 rain 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, „, and FEFo5-75% ideated that prior exposure to
392 ug/m (0.20 ppm) of 0,, had no effect on functional decrements occurring
3
after subsequent exposure to either 823 or 980 ug/m (0.42 or 0.50 ppm) of 03
on the fourth day (see Section 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 gender by pollutant interactions
for six subjects, indicating that male and female subjects responded to 03 in
a similar fashion.
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 VO, 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
•J
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, 0 (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 V,- during
exercise. These effects are similar to those reported by other investigators.
Gibbons and Adams (1984) reported the effects of exercising 10 young
women for 1 hr at 66 percent of max VO, while the women breathed 0, 297, or
3
594 ug/m (0, 0.15, or 0.30 ppm) of 0,. Significant decrements in forced
3
expiratory function were reported at 594 ug/m (0.30 ppm) of 0.,. 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 groups.
11.2.9.3 Environmental Conditions. Very few controlled human studies have
addressed the potential influence environmental conditions such as heat or
relative humidity (rh) may have on responses to 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
019PO/A 11-41 10/17/85
-------
PRELIMINARY DRAFT
humidity (31°C, 35 percent rh) to simulate ambient environmental conditions
during smog episodes in Los Angeles. No comparisons were made to the effects
from 0, exposure at standard environmental conditions in other controlled
studies.
Folinsbee et al . (1977b) studied the effects of a 2-hr exposure to
980 ug/m (0.5 ppm) of 0., on 14 male subjects under four separate environmental
conditions: (1) 25°C, 45 percent rh; (2) 31°C, 85 percent rh; (3) 35°C,
40 percent rh; and (4) 40°C, 50 percent rh. Wet bulb globe temperature (WBGT)
equivalents were 64.4, 85.2, 80.0, and 92.0°F, respectively. The subjects
exercised for 30 min at 40 percent of their max V0? (Section 11.2.2 and 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=92.0°F),
but this effect was only significant for FVC. In a similar study with eight
3 3
subjects exposed to 980 ug/m (0.5 ppm) of 0., plus 940 ug/m (0.5 ppm) of
nitrogen dioxide (NOp) (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 in-
creased ventilation since ventilatory volume and tidal volume increased signi-
ficantly at the highest thermal condition studied (40°C, 50 percent rh).
More recently, Gibbons and Adams (1984) had 10 trained and heat-acclimated
young women exercise for 1 hr at 66 percent of their maximum oxygen uptake
3 33
while breathing either 0.0 ug/m (0.0 ppm), 297 ug/m (0.15 ppm), or 594 ug/m
(0.30 ppm) of 0.,. These studies were conducted at two ambient conditions,
i.e. 24° or 35°C. (Whether these are only dry bulb (db) temperatures or
represent WBGT values is unclear, since humidity was not reported). No signi-
3
ficant changes in any measured function were observed at 0 ug/m (0.00 ppm) or
297 ug/m3 (0.15 ppm) of 03- Significant reductions in FVC, FEV: Q, TLC, and
^25-75% ^ < 0-004) were reported as a consequence of exercising at 594 ug/m
(0.30 ppm). Pre-post decrements in FVC, FEV, „, and FEF05-757 ^n t^ie ®'^® ppm>
24°C environment were 13.7, 16.5, and 19.4 percent respectively, compared to
observed decrements of 19.9, 20.8, and 20.8 percent, respectively, in the
0.30-ppm OT and 35°C condition. Only FVC differed significantly between the
two temperature conditions. Some subjects failed to complete the exercise
period in 35°C and 0.30 ppm 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
019PO/A 11-42 10/17/85
-------
PRELIMINARY DRAFT
increased. No other effects were reported, although it was observed that 03
(0.30 ppm) exposure and ambient high temperature induced an interactive effect
on VA and fR.
11.2.9.4 Vitamin E Supplementation. The possible protective effects of
vitamin E against short-term responses to 03 exposure have not been as exten-
sively investigated in humans as they have in animals (see Chapter 10). Only
two studies have been published on the pulmonary effects of vitamin E supple-
mentation in healthy subjects exposed to 0,. Both of these have failed to
J
show any protective effect against 0,-induced changes in respiratory symptoms
and lung function (Hackney et al., 1981) or against jm vivo lipid peroxidation
of the lung, as measured by decreased pentane production (Dillard et al.,
1978). Additional studies demonstrating the lack of significant differences
between the extrapulmonary responses of vitamin-F supplemented and placebo
groups exposed to 0, are discussed in Section 11.6.
Dillard et al. (1978) studied ten vitamin E-sufficient adults breathing
3
filtered air or 588 ug/m (0.3 ppm) 0., on a mouthpiece while continuously
exercising for 1 hr at 50 percent V0? . Pulmonary function was measured
before and after each exercise period. Expired air samples were collected
from five subjects at rest, after 5 min of exercise while breathing air, and
after 5, 15, 30, 45, and 60 min of exercise while breathing 0.,. Expired
pentane, an index of lipid peroxidation, was measured during the pre- and
postexercise resting periods by gas chromatography. Exposure to 0~ caused a
significant increase in RV and significant decreases in VC and FEV1-0. All
subjects reported throat tickle associated with 0, while some subjects experi-
enced symptoms such as chest tightness, cough, pain on deep inspiration,
congestion, wheezing, or headache. Exercise alone resulted in an increased
production of pentane. However, there was no change in pentane production as
a result of exposure to 0., above that caused by the stress of exercise.
In a separate experiment, Dillard et al. (1978) tested six subjects
exposed to hydrocarbon-scrubbed air during an initial 5-min rest, during
graded exercise (25, 50, and 75 percent VO,, ) for 20, 40, and 60 min, and
during a 20-min postexposure rest period. The same exercise protocol was
repeated after supplementation of the subjects with 400 IU dl-ortocopherol
three times a day for 2 weeks, which increased plasma tocopheral levels 240
percent. This treatment significantly reduced expired pentane levels at rest
and during exercise. No significant differences in pulmonary function were
019PO/A 11-43 10/17/85
-------
PRELIMINARY DRAFT
obtained in response to 1 hr of exercise before and after vitamin E supplemen-
tation.
Hackney et al. (1981) studied the effects of a 2-hr exposure to filtered
3
air or 980 ug/m (0.5 ppm) 0., in healthy subjects (9 males and 25 females)
receiving either 800 ID dl-crtocopherol (n = 16) or a similar appearing placebo
(n = 18) daily for 9 or 10 weeks. Mean serum vitamin E concentration increased
by 70 percent over this period in the supplemented group while the mean concen-
tration in the placebo group did not change significantly. During exposure,
the subjects alternated 15-min periods of rest and exercise at two times
resting ventilation. Pulmonary function and respiratory symptoms were evaluated
at the end of each exposure. No significant effects of vitamin E supplementa-
tion were found; however, a few of the supplemented male subjects showed a
possible beneficial effect. Since the sample size of male subjects was small
(n = 9), a follow-up study was performed. Subjects received either 1600 ID of
dl-ortocopherol (n = 11) or placebo (n = 11) daily for 11 or 12 weeks. The
mean serum vitamin E concentration increased by 140 percent in the supplemented
group and 30 percent in the placebo group. Exposures took place on three
successive days during the last week of supplementation. The subjects were
exposed to filtered air for 2 hr on the first day, followed by 2-hr exposures
to 980 ug/m (0.5 ppm) 03 on the second and third days. The exercise protocol
during exposure was similar to that described above. Pulmonary function and
respiratory symptoms were evaluated at the end of each exposure. Ozone caused
significant decreases in FVC, FEV1<0, FEV-cw, ^50%' AN?' and ^LC ^n ^oth the
vitamin E-supplemented and placebo groups. The mean changes were not signifi-
cantly different between groups. Although symptoms did not significantly
increase with 0., exposure, there were no differences between the vitamin E and
placebo groups. Results from these studies do not support a protective effect
of vitamin E supplementation against short-term pulmonary responses in human
subjects exposed to 0.,.
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
to 0~ have also been completed (Table 11-5). In general, results from these
studies indicate that with repeated daily exposures to 0,, decrements in pul-
monary function are greatest on the second exposure day. Thereafter, on each
019PO/A 11-44 10/17/85
-------
PRELIMINARY DRAFT
TABLE 11-5. CHANGES IN LUNG FUNCTION AFTER REPEATED DAILY EXPOSURE TO AMBIENT OZONE
Ozone
Concentration
ug/mj
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
Measurement3'
method
CHEM, NBKI
UV, UV
UV, UV
CHEM, NBKI
CHEM, NBKI & MAST, NBKI
CHEM, NBKI & MAST, NBKI
CHEM, NBKI & MAST, NBKI
UV, NBKI
CHEM, NBKI & UV, UV
UV, UV
UV, UV
CHEM, 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
, IE(30)
, IE(18 &
, IE(18 &
, IE(30)
, IE(4-5
, IE(4-5
, IE(4-5
. IE(2 x
. IE(4-5
, IE(30)
, IE(3 x
, IE(30)
hr, 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
a
6
Percent change 1n FEV,.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
Third Fourth Fifth
-1.6
-1.1
-3.2
-2.2
-4.7 -3.2 -2.0
-5.3 -0.7 -1.0
-4.1 -3.0 -1.6
0
0 -0.6 -1.1
-18.0 -6.3 -2.3
-11.9 -4.3
-3.5
-2.4 -0.7
References
Follnsbee et
Gl Iner et al.
Gllner et al.
Follnsbee et
Parrel 1 et al
Kulle et al. ,
Kulle et al. ,
Dlmeo et al. ,
Kulle et al. ,
Horvath et al
Linn et al. ,
Follnsbee et
Hackney et al
al . , 1980
. 1983
. 1983
al. , 1980
. . 1979
1982b
1982b
1981
1984
. , 1981
1982b
al . . 1980
. , 1977a
Measurement methods: MAST = KI-coulometr1c (Mast meter); CHEM = gas-phase chemlluminescence, UV = ultraviolet photometry.
Calibration methods: NBKI = neutral buffered potassium Iodide; UV = UV photometry.
""Exposure duration and Intermittent exercise (IE) Intensity were variable; minute ventilation (Vc) given In L/m1n or as a multiple of resting
.0 of more than 20%.
ventilation.
Subjects especially sensitive on prior exposure to 0.42 ppm 03 as evidenced by a decrease in FEVt.
These nine subjects are a subset of the total group of 21 Individuals used In this study.
eBronch1al reactivity to a methacholine challenge was also studied.
Bronchial reactivity to a Mstamlne challenge (no data on FEV^o). SR measured (T). Note that
day hlstamlne response was equivalent to that observed in filtered a1ra^see text).
^Subjects were smokers with chronic bronchitis.
Seven subjects completed entire experiment.
on third
-------
PRELIMINARY DRAFT
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 03 does not affect the magnitude of decrement in pulmonary function
resulting from exposure at higher (L concentration.
All the reported studies of repeated responses to 0., have used the term
"adaptation" to describe the attenuation of decrements in pulmonary function
that occurs. Unfortunately, since the initial report of such attenuation used
adaptation, each succeeding author chose not to alter the continued use of
this selected term. In the strict sense, adaptation implies that changes of a
genetic nature have occurred as a result of natural selection processes, and
as such, use of adaptation in the prior context is a misnomer.
Other terms (acclimation, acclimatization, desensitization, tolerance)
have been recommended to replace adaptation and perhaps are more suitable.
However, the correct use of any of these terms requires knowledge of (1) the
physiological mechanisms involved in the original response, (2) which mecha-
nisms are affected and how they are affected to alter the original response,
and/or (3) whether the alteration of response is beneficial or detrimental to
the organism. The present state of knowledge is such that we do not fully
understand the physiological pathway(s) whereby decrements in pulmonary func-
tion are induced by 0., exposure, and of course, the pathways involved in
attenuating these decrements and how they are affected with repeated 0, exposure
are even less understood. Moreover, while attenuation of On-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 0, exposure, such as cell injury. Therefore, in the following
discussion of specific studies, results will be presented without use of .a
specific term to describe observed phenomena generally. The use of response
to imply pulmonary decrements resulting from 0, exposure and changes in response
or responsiveness of the subject to imply alterations in the magnitude of
these decrements will be retained.
Hackney et al. (1977a) performed the initial experiments that demon-
strated that repeated daily exposures to 03 resulted in augmented pulmonary
function responses on the second exposure day and diminution of responses
019PO/A 11-46 10/17/85
-------
PRELIMINARY DRAFT
after several additional daily exposures. Six subjects who in prior studies
had demonstrated responsiveness to 0, were studied during a season of low smog
to minimize potential effects from prior 0, exposure. All but one subject had
3
a history of allergies. They were exposed for approximately 2.5 hr to 980 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 FEF,r 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).
Farrell 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 07. Pulmonary function (FVC, FEV,, FEV.,, SG , and FRC) was
*j -L 3 dW
determined at the end of the 3-hr exposures. One bout of exercise (V.- measured
on one subject = 44 L/min) was performed after 1.5 hr of exposure. Statistical
evaluations used a repeated measures analysis of variance for significant
differences between the control and 03 exposure weeks, using each day of each
exposure to make the comparisons. The analysis of variance showed that FVC,
FEVn, FEVo, and SG differed significantly between control and 0, exposure
J. .3 3W -j
weeks. No changes in FRC were found. In the 0., exposure, SG decreased
O 3W
significantly only on the first 2 days; this response was similar to air
exposure day values on the last 3 days. Significant decreases in FVC occurred
on the first three days only; however, the decrements were significantly
greater on the second day than on the first. Decrements in FEV-^ Q and FEV^ Q
019PO/A 11-47 10/17/85
-------
PRELIMINARY DRAFT
were substantial on the first day and increased on the second day of exposure.
These decrements diminished to air exposure levels by the third day (FEV~ Q)
and fourth day (FEV, Q) of (L exposures. The severity of symptoms generally
corresponded to the magnitude of pulmonary function changes. Symptoms were
maximal on the first 2 days, decreasing thereafter with only one subject being
symptomatic on the final day of exposure to 0,. Reporting of symptoms was
maximal on the second 0, day. These investigators noted that five consecutive
3
days of exposure (10 subjects) to 588 ug/m (0.3 ppm) of 03 failed to induce
significant changes in FVC or SG , implying that measurable changes are
3W
likely to occur in pulmonary function at 0, concentrations between 588 and
3
784 |jg/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), 392
1 3
Mg/m (0.20 ppm) of 03; group 2 (n=10), 686 \jq/m (0.35 ppm) of 03; group 3
(n=8), 980 |jg/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 ug/m (0.20 ppm) of 0.,. With
3
exposure to 686 |jg/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, n
3 •"••u
decreased 8.7 percent) after the first exposure to 980 ug/m (0.50 ppm) of 0.,;
these decrements were even greater (FEV-. „ decreased 16.5 percent) after the
second CL exposure (Figure 11-3). While not totally abolished, an attenuation
of these decrements (FEV, „ decreased 3.6 percent) was observed following the
third 0., exposure. The subjects claimed the most discomfort for the second 0,
exposure. Many noted marked reductions in symptoms on the third consecutive
day of exposure to On. Two additional subjects were exposed to 980 (jg/m
(0.50 ppm) of 03 for four consecutive days. Although effects of 0, on pulmonary
function were observed on the first two days of exposure, few effects were
seen on the third day, and no effect was observed on the fourth day. The
authors concluded that there were some short-term (2-day) cumulative effects
of exposure to concentrations of 0-, that produced acute functional effects.
019PO/A 11-48 10/17/85
-------
A. GROUP 2
5.2
<£ . 5.0
m
4 8.
6
14.6
4.4
IFILTEREDI
AIR
DAY1
OZONE
DAY 2
I T^TTJ
OZONE
DAY 3
1
1
| I I I I
OZONE
DAY 4
1
'FILTERED
AIR
DAYS _
2.3.4.H. £(1.2 3.4|S;j8iri,2.3.4|fc £ 1 2 3 4 K £ i 2 3 4 K
g. "• gfa- g a g °- g
B. GROUP 3
2
«
5.2
5.0
4.8
46
4.4
4.2
4.0
3.8
IFILTEREDI
AIR
I
J
OZONE
DAY 2
I
I ' ' ' ' I
OZONE
DAY 3
I *^rr
OZONE
DAY 4
iFILTEREDl
AIR
DAY 5
g 1 2 3.4 K g
O CL
.1 2 3
£
2 3
g «-
'O
O
Figure 11 -3. Forced expiratory volume in 1 -sec (FEV-j Q)
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
11-49
10/17/85
-------
PRELIMINARY DRAFT
This response period was followed by a period in which there was a marked
lessening of the effect of CL 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
further the influence of five consecutive days of exposure to 823 (jg/m (0.42
ppm), but to estimate the persistence of the attenuation of pulmonary responses.
During the 125 min of exposure, 24 male subjects alternately rested and exer-
cised (Vr = 30 L/min) for 15-min periods. Measurements of pulmonary functions
were made daily pre- and post-exposure. A filtered-air exposure was conducted
during the week prior to the 03 exposures. Selected subjects were then randomly
assigned to return after 6 to 7, 10 to 14, and 17 to 21 days for a single
exposure to 0,,. Ambient 0, levels in the locations where the subjects lived
3
seldom exceeded 235 (jg/m (0.12 ppm). The major pulmonary function measurements
made and subjected to statistical analysis on these subjects were FVC, FEV,,
and FEF?c_7cv- Changes with time in all three measurements were similar and
major emphasis was directed toward FEV, changes. Significant interaction
effects occurred between the two within-subject factors (day of exposure and
pre- and post-exposure change in FEV,). The interaction resulted primarily
from the post-exposure FEV, data, which revealed a "U"-shaped pattern across
days during 0-, exposure. A significant decline appeared on day 1 (+1.7 to
-63 percent, mean = -21 percent), and a greater significant decline appeared
on day 2 (-26.4 percent). On day 3 the decrement in FEV, had returned to that
observed on day 1, but it was still significantly greater than during room air
exposure. The decrements in FEV, from preexposure to postexposure on days 4
and 5 were no longer significant although the absolute value of postexposure
FEV( continued to be significantly less than the initial filtered air exposure.
Subjective symptoms followed a similar pattern, with subjects on the fifth day
indicating that they had not perceived any 0^. Two subjects showed little
attenuation of response to 0,, and one subject was not affected by the 0,
exposures. Subjects who were more responsive on the first day of exposure
required more consecutive days of daily exposure to attenuate response to O^.
All 24 subjects returned for an additional exposure to 03 from 6 to 21 days
later; of these, only 16 were considered to be sensitive to 0~, and their data
019PO/A 11-50 10/17/85
-------
PRELIMINARY DRAFT
are shown in Figure 11-4. Although the number of subjects in each repeat
exposure was small, it was apparent that attenuation of response did not
persist longer than 11 to 14 days, with some loss occurring within 6 to 7
days. In general, these authors made some interesting observations: (1) the
time required to abolish pulmonary response to 0., was directly related to the
magnitude of the initial response; (2) the time required for attenuation of
pulmonary responses to occur was apparently inversely related to the duration
of attenuation and (3) in one individual, attenuation of pulmonary response to
03 persisted up to 3 weeks. The mechanism responsible for attenuation of re-
sponse was not elucidated, although two mechanisms were postulated, i.e.,
diminished irritant receptor sensitivity and increased airway mucus production.
Linn et al. (1982b) also studied the persistence of the attenuation of
pulmonary responses that occurs with repeated daily exposures to 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 pg/m (0.47 ppm) 0.,. Exposure consisted of alternating
15-min periods of moderate exercise (VV = 3 x resting VV) and rest. An expo-
sure to filtered air, under otherwise equivalent conditions, was conducted on
the day prior to the first 0, exposure. The pattern of change in pulmonary
response to 0, was similar to that previously reported for repeated daily
exposures. For example, while the initial exposure to filtered air produced
essentially no change, on the first 0., exposure day FEV, decreased 11 percent,
with a further decline to 23 percent on the second day, returning to approxi-
mately 11 percent on the third day. By the fourth day, the mean response was
essentially equivalent to that observed with exposure to filtered air. While
most of the subjects demonstrated attenuation of response (complete data sets
on only seven subjects), the response of one subject, who may have had a
persistent low-grade respiratory infection, never diminished. Two others
showed relatively little response to the initial daily exposures, but showed
some severe responses during follow-up exposures. This pattern was not to be
unexpected, based on other studies demonstrating similar atypical responses.
To evaluate persistence of attenuated response, subjects repeated 0^ exposures
under the above conditions 4 days after the repeated daily exposures and
thereafter at 7-day intervals for five successive weeks. Four days after the
repeated daily exposures, decrements in pulmonary function in response to 0,
exposure were not significantly different from the first exposure (FEV]>0
decreased 11.4 percent on the first day and decreased 8.6 percent four days
019PO/A 11-51 10/17/85
-------
FILTERED
AIR
PRE-EXPOSURE
DAILY 2-hr EXPOSURE
TO 0.42 ppm O,
12345
0.42 ppm Oj.
1 WK
POST-EXPOSURE
FILTERED
AIR
PRE-EXPOSURE
DAILY 2 hr EXPOSURE
TO 0.42 ppm Oi
1 2 3 4 5
*. I I I I I""1
0.42 ppm O3,
2 WKS
POST-EXPOSURE
£
a
u
k
a
a
u.
+ 10
0
-10
-20
-30
-40
GROUP 2 -
n = 6
FILTERED
AIR
PREEXPOSURE
+ 10
DAILY 2-hr EXPOSURE
TO 0.42 ppm Oj
1 2 3 4 5
*
l I I I
0.42 ppm Oi,
3 WKS
POST EXPOSURE
Figure 11 -4. Percent change (pre-post) in
1 -sec forced expiratory volume (FEV-j Q),
as the result of a 2-hr exposure to 0.42
ppm ozone. Subjects were exposed to
filtered air, to ozone for five consecutive
days, and exposed to ozone again: (A) 1
wk later; (B) 2 wks later; and (C) 3 wks
later.
Source: Horvath et al. (1981).
019PO/A
11-52
10/17/85
-------
PRELIMINARY DRAFT
after the repeated exposures). The decrement in FEVi>0 on the subsequent
weekly 03 exposures averaged 13.5 percent. Subjective symptoms generally
paralleled lung-function studies, but were significantly fewer on the (L
exposure which occurred four days after the repeated exposures. Since attenua-
tion of pulmonary responses to CL 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 (Farrell et al., 1979), Kulle
et al. (1982b) exposed 24 subjects (13 men and 11 women) for 3 hr on five con-
secutive days beginning on Monday to filtered air during week 1 and to 784
ug/m (0.4 ppm) of CL 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) of 0., on the
second day, while they exposed the remaining 13 subjects for 4 days to filtered
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
(Vr = 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 0...
Gliner et al. (1983) performed a study to determine whether daily repeated
exposures to a low concentration of 0, (392 (jg/m ; 0.20 ppm) would attenuate
pulmonary function decrements resulting from exposure to a higher 0., concentra-
•3
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
(0.0 ppm 0Q) on day 1, to 392 (jg/m3 (0.20 ppm) of 0, on days 2, 3, and 4, and
3
to 823 or 980 pg/rn (0.42 or 0.50 ppm) of 03 on day 5. For comparison, subjects
who were exposed to 0.42 or 0.50 ppm of 0., were exposed to the same CL 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
019PO/A 11-53 10/17/85
-------
PRELIMINARY DRAFT
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
3
ug/m ; 0.42 or 0.50 ppm).
Subjects were divided into two groups based on the magnitude of their
response to the acute exposure to 823 or 980 ug/m (0.42 or 0.50 ppm) 0_.
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
392 ug/m (0.20 ppm); decreases in FVC and FEV, were about 9 percent. No
3
significant effects of 392-ug/m (0.20-ppm) 03 exposure were found in the
nonresponsive group. In both groups, repeated exposures to 0.20 ppm of 0., had
no influence on the subsequent response to the higher ambient 0, exposure (823
3
or 980 ug/m ; 0.42 or 0.50 ppm). Note that repeated exposures to the low 03
concentration for only three consecutive days may have constituted insufficient
total exposure (some combination of number of exposures, duration of exposures,
Vr, 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 0.,. 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 (V^ = 57
L/min). As expected, pulmonary function decrements were greater on the second
of five consecutive days of 0, exposure; thereafter, the response was attenu-
3
ated. Exposure at rest to 784 (jg/m (0.4 ppm) of 03 for two consecutive days
had no effect on pulmonary function. Ozone exposure on the next two succeeding
days with heavy exercise produced pulmonary function decrements similar to
those observed previously in this study for the first two days of exposure to
ozone.
019PO/A 11-54 10/17/85
-------
PRELIMINARY DRAFT
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 |jg/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 (VV ~ 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 03 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
of 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-
a w
tion of 10 breaths of histamine aerosol (1.6-percent solution). In five
subjects, bronchial reactivity was determined on four consecutive days without
exposure to 0., (group I). In seven other subjects (group II), bronchial
reactivity was assessed on two consecutive days; subjects were exposed to
392 ug/m (0.2 ppm) of 0, on the third succeeding day and bronchial reactivity
was determined after exposure. Seven additional subjects (group III) had
019PO/A 11-55 10/17/85
-------
PRELIMINARY DRAFT
bronchial reactivity assessed for two consecutive days and then again on the
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
(Vr = 2x resting V^). 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
•3
-------
PRELIMINARY DRAFT
reactivity response was therefore much longer than that observed for FVC and
FEV, „ 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 CL 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 0, concentrations. In a subgroup
of 10 subjects, 9 individuals reported detection when the ambient concentration
was as low as 39.2 ug/m (0.02 ppm of 0,). Perception at. this low level did
not persist, being seldom noted after some 0.5 to 12 min of exposure. The
odor of 03 became more intense at concentrations of 98 (jg/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)
for 03 was between 0.015 and 0.04 mg/m (0.008 and 0.02 ppm). The few subjects
on whom electroencephalograms (EEGs) were recorded showed a 30 to 40 percent
reduction of cerebral electrical activity during 3 min of exposure to 0.02 mg/m
(0.01 ppm) of OT. 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/m (0.0, 0.25, 0.50, or 0.75 ppm) of 03 on sustained
019PO/A 11-57 10/17/85
-------
PRELIMINARY DRAFT
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
beyond that, of the normal vigilance decline was observed during the 1470-ug/m
(0.75-ppm) On 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 03 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
3
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 EEC
spectral analysis. Given the inability to obtain a discrimination between
clean air and 1470 ug/m (0.75 ppm) of 0-, using these techniques, EEC 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) 0, exposure.
Mihevic et al. (1981) examined the effects of 0, exposure (0.0, 588,
o J
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/min, and finally
rested for an additional 40 min. Pulmonary function measurements (FVC, FEV,,
and MEFpryr) were made during rest periods and after exercise. The primary
objective of the study was to examine the effects of exposure during exercise
on perception of effort and to evaluate perceptual sensitivity to pulmonary
responses. As expected, decrements in FVC, FEV,, and MFJpr -,,- were signifi-
cantly greater (P <0.01) immediately after exercise than in the rest, condition
during either the 588- or 980-ug/m" (0.30- or 0.50-ppm) 03 exposures. The
work output remained the same in all conditions. However, the ratings of
019PO/A 11-58 10/17/85
-------
PRELIMINARY DRAFT
perceived exertion revealed that the subjects felt they were working harder or
making a greater effort when exercising in the 0.50-ppm 0, 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 pg/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
by 10 percent, maximum ventilation (max VL) decreased 16 percent, and maximum
3
heart rate dropped 6 percent after a 2-hr 0, exposure (1470 ug/m ; 0.75 ppm)
with alternate rest and light exercise. A psychological impact related to the
increased pain (difficulty) induced by maximal inspirations may have been the
important factor in reduction in performance. Savin and Adams (1979) exposed
nine exercising subjects for 30 min to 294 and 588 |jg/m (0.15 and 0.30 ppm)
03 (mouthpiece inhalation). No effects on maximum work rate or max V02 were
found, although a significant reduction in max VF was observed during the
3 •
588-jjg/m (0.30-ppm) exposure. Similarly, max Vn, was not impaired in men and
3
women after 2-hr exposure and at-rest exposure to 0.0, 980, and 1470 ug/m
(0.00, 0.50, and 0.75 ppm) of 03 (Horvath et al., 1979).
Six well-trained men and one well-trained woman (all except one male
being a competitive distance cyclist) exercised continuously on a bicycle
ergometer for 1 hr while breathing filtered air or 412 ug/m (0.21 ppm) of 0^
(Folinsbee et al., 1984). They worked at 75 percent max V02 with "lean minute
019PO/A 11-59 10/17/85
-------
PRELIMINARY DRAFT
TABLE 11-6. EFFECTS OF OZONE ON EXERCISE PERFORMANCE
Ozone
concentration
ug/mj
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
Measurement3'
method
UV,
NBKI
UV,
UV
UV,
UV
CHEM,
NBKI
MAST,
NBKI
. 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)d
No effect on maximum work rate, anaerobic
threshold, or pulmonary function; max Vr
decreased with 0.30 ppm 03.
FVC, FEVpo, and FEF25_75 decreased,
subjective symptoms increased with 03
concentration at 68% max V02; fp in-
creased and VT decreased during CE. , No
significant.Oa effects on exercise V02,
HR, Vr, or V,. No exposure mode effect.
Decreases in FVC (6.9%), FEVj.o (14.8%),
^25.75% (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-r, V02 , and maximum workload
alT fiecreased. At maximum workload only,
fR increased (45%) and Vy decreased (29%).
No. and sex
of subjects
9 male
(runners)
10 male
(distance runners)
6 male
1 female
(distance cyclists)
8 male
7 female
13 male
Reference
Savin and Adams, 1979
Adams and Schelegle, 1983
Folinsbee et al. , 1984
Horvath et al. , 1979
Folinsbee et al. , 1977a
Measurement method: 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 (Vr) given in L/min or as a multiple of resting
ventilation.
See Glossary for the definition of symbols.
-------
PRELIMINARY DRAFT
ventilations of 81 L/min. As previously noted (Section 11.2.3), 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 (L 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 V™) to increase mean VV to 80 L/min. In the last 30 min of the
competitive exercise bout, minute ventilations were approximately 105 L/min.
Subjective symptoms increased as a function of 0., concentration for both
continuous and competitive levels. In the competitive exposure, four runners
(0.20 ppm) and nine runners (0.35 ppm) indicated that they could not have
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 11.2.3), the high ventilation volumes resulted in marked pulmonary
function impairment and altered ventilatory patterns. The decrements were the
result of physiologically induced subjective limitations of performance due to
respiratory discomfort. The authors found it necessary to reduce the 68 percent
max Vp? work load by some 20 to 30 percent in two of their subjects for them
to complete the final 15 min (of the 30-min work time) in their competitive
test.
Although studies on athletes (not all top-quality performers) have sug-
gested some decrement in performance associated with 0, exposure, too limited
a data base is available at this time to provide judgmental decisions concern-
ing the magnitude of such impairment. Subjective statements by individuals
engaged in various sport activities indicate that these individuals may volun-
tarily limit strenuous exercise during high-oxidant concentrations. However,
increased ambient temperature and relative humidity are also associated with
episodes of high-oxidant concentrations, and these environmental conditions
may also enhance subjective symptoms and physiological impairment during 0^
exposure (see Section 11.2.9.3). Therefore, it may be difficult to differen-
tiate any performance effects due to ozone from those due to other conditions
in the environment. Several reviews on exercising subjects have appeared in
0190LG/A 11-61 10/17/85
-------
PRELIMINARY DRAFT
the literature (Horvath, 1981; Folinsbee, 1981; McCafferty, 1981; Folinsbee
and Raven, 1984).
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.
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)
exposed eight volunteer male subjects to a mixture of 725 pg/m (0.37 ppm) of
03 and 0.37 ppm of sulfur dioxide (SO-) for 2 hr. Temperature, humidity,
concentrations, and particle sizes of ambient aerosols (if any) were not
measured. Sulfur dioxide alone had no detectable effect on lung function,
while exposure to 0, alone resulted in decrements in pulmonary function. The
combination of gases resulted in more severe respiratory symptoms and pulmonary
changes than did 03 alone. Using the maximal expiratory flow rate at 50 percent
vital capacity as the most sensitive indicator, no change occurred after 2 hr
3
of exposure to 0.37 ppm S0? alone. However, during exposure to 725 pg/m
(0.37 ppm) 0, a 13 percent reduction occurred, while exposure to the mixture
3
of 725 ng/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
S02 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 0.,-sensitive subjects. They showed that the 03 + SOp mixture
had an overall greater effect on pulmonary function measures than did 03
alone. Differences ranging from 1.2 percent for FVC to 16.8 percent for ^5
were detected during 0, + S0? exposure relative to 0., exposure alone in normal
subjects. The mean FEVj >0 decreased 4.7 percent after 0., + SO,, exposure
relative to 0, alone in the sensitive subjects. When normals and sensitives
3
were combined, the mean FEV1>0 and FVC were both significantly lower after the
0190LG/A 11-62 10/17/85
-------
PRELIMINARY DRAFT
TABLE 11-7.
INTERACTIONS BETWEEN OZONE AND OTHER POLLUTANTS
Ozone
concentration
ug/mj
ppn
Pollutant3
Measurement >c
method
Exposure
duration and
activity0
No. and sex
Observed effect(s)6 of subjects
Reference
A. 03 + S02:
294
393
588
2620
725
970
725
£ 970
en
U)
725
970
100
784
1048
784
1048
0.15
0.15
0.3
1.0
0.37
0.37
0.37
0.37
0.37
0.37
0.4
0.4
0.4
0.4
03
S02
03
S02
03
S02
03
S02
03
S02
H2SO<
03
S02
03
S02
CHEM, NBKI
EC
UV, UV
FP
MAST, NBKI
EC
CHEM, NBKI
FP
UV, NBKI
FP
1C
CHEM, NBKI
FP
CHEM, NBKI
FP
2 hr
IE(25)
@ 15-mln
Intervals
2 hr
IE (38);
alternating
30-mln
exercise and
I0-m1n rest
periods
2 hr
IE(2xR)
@ !5-m1n
Intervals
2 hr
IE(2xR)
9 15-mln
Intervals
2 hr
IE(2xR)
@ 15-mln
Intervals
2 hr
IE(30)
9 15-mln
Intervals
2 hr
IE(30)
@ 15-mln
Intervals
SG decreased; possible synerglsm Is ques- 6 male
tlonable. Statistical approach 1s weak.
FVC, FEV,, and FEF2S_75~ decreased after 22 male
exposure to 03 alone; wflen combined with
S02 , similar but smaller decreases were
observed. No additive or synerglstlc
effects were found.
Decrement 1n splrometrlc variables (FVC, MEFR 8 male
50%); synerglsm reported. Interpretation com-
plicated by the probable presence of H2S04.
Decreased forced expiratory function 4 normal (L.A)
(FEVi-o, FVC) relative to 03 exposure alone 5 sensitive (L.A.)
In combined group of normal and sensitive 4 normal (Montreal)
L.A. subjects; more severe symptoms and
greater decrement of FEVj.0 1n Montreal
(5.2%) than L.A. sensitive (3.7%) subjects.
Small decreases In pulmonary function (FVC, 19 male
FEV,. 2. 3, MMFR, V BO, V 25) and slight
Increase 1n symptom? due primarily to 03
alone; H2S04 was 93% neutralized.
Decreased forced expiratory function (FVC, 9 male
FEV^o, FEF25_75~, FEF50~) following expo-
sure to either 07 or 03 * S02; no differences
observed between 03 alone and 03 + S02.
Observed decrement In pulmonary function 8 male
(FEV,.0, FVC, FEF25_75%, FEF50,,, ERV, TLC)
and Increase In symptoms reflected changes
due to 03; no synergism was found.
Kagawa and Tsuru, 1979c
Follnsbee et al . , 1985
Hazucha, 1973
Bates and Hazucha, 1973
Hazucha and Bates, 1975
Bell et al. , 1977
Klelnman et al. , 1981
Bedl et al. , 1979
Bed1 et al. , 1982
B. 03 + H2S04:
294
200
0.15
03
H2SO«
CHEM, NBKI
1C
2 hr
IE @15-m1n
Intervals
SGaw decreased; no Interaction reported. 7 male
Questionable statistics.
Kagawa, 1983a
-------
PRELIMINARY DRAFT
TABLE 11-7 (continued). INTERACTIONS BETWEEN OZONE AND OTHER POLLUTANTS
Ozone
concentration
ug/mj ppm
58fl 0.3
100
784 0.4
100
133
116
80
Pollutant3
03
H2S04
03
H2S04
(NH4)2S04
NH4HS04
NH4N03
Measurement 'c
method
MAST, NBKI
& CHEM, NBKI
TS
CHEM, NBKI
Exposure
duration and
activity
2 hr
IE(35)
for 15 min
4 hr
IE(35)
for 15 min
2-4 hr
IE
for two 15-min
periods
Observed effect(s)6
No significant 03-related changes in pulmo-
nary function or bronchial reactivity to
methacholine. Bronchial reactivity decreased
following a 4-hr exposure to H2S04.
Decrement in pulmonary function due to
03 alone; more apparent after 4 hr than
2 hr; no interaction; recovery within 24 hr.
No. and sex
of subjects Reference
7 male Kulle et al. , 1982a
5 female
124 male Stacy et al. , 1983
(divided into
10 exposure
groups)
C. 03 + CO:
588 0.3
115000 100.0
03
CO
MAST, BAKI
IR
1 hr (mouth-
piece) CE (51
for male and
34.7 for female
subjects).
Decrement in pulmonary function due to
03 alone: FVC, FEV,.0 and FEF2S.75%
decreased; fp increased and V, decreased
with exercise.
12 male DeLucia et al . , 1983
12 female
(equally divided
by smoking history)
0. 03 + N02:
196 0.1
9400 5.0
294 0. 15
280 0. 15
490- 0.25-
980 0.5
560 0.3
35000 30.0
980 0.5
940 0. 5
03
N02
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 NO; 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, FEVi-o, FEF2s_75v, and
FEF5o~; ventilatory and metabolic Variables
were not changed; response was similar to
that observed in 03 exposure alone. Tight-
ness in the chest and difficulty taking deep
a breath was reported along with cough, sub-
sternal soreness, and shortness of breath.
12 male von Nieding et al. , 1977
von Nieding et al. , 1979
6 male Kagawa and Tsuru, 1979b
16 normal and Hackney et al., 1975a,b,c
reactive subjects
8 male Folinsbee et al., 1981
-------
PRELIMINARY DRAFT
TABLE 11-7 (continued). INTERACTIONS BETWEEN OZONE AND OTHER POLLUTANTS
Ozone
concentration
ug/mj
980-
1372
940
1320
ppm
0.5-
0.7
0.5-
0.7
Pollutant3
03
N02
Measurement >c
method
MAST, NBKI and
CHEM, NBKI
MAST (N02)
and CHEM, C
Exposure
duration and
activity
1 hr
(mouthpiece)
R
No. and sex
Observed effect(s) 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
900
196
9400
13100
294
280
393
0.025-
0.1
0.06-
5.'0
0.12-
5.0
0.08
0.16
0.34
0.1
5.0
5.0
0.15
0.15
0.15
03
N02
S02
03
NO,
S02
03
N02
S02
03
N02
S02
CHEM, NBKI
MAST (N02)
TS
CHEM, NBKI
and GS, CHEM
CHEM, C
CHEM, NBKI
CS, CHEM
CHEM, C
CHEM, NBKI
CHEM, C
EC
2 hr
IE (2xR)
@ 15-min
intervals
8 hr
R
2 hr
IE
2 hr
IE
@ 15-min
intervals
Decreases in Pa02 and increases in Raw due 11 male
to NO 2 alone at maximum concentrations; no
effect at minimum concentrations. No inter-
action reported.
No effect on lung function, blood gases, or 15 male
blood chemistry; questionable statistics.
Random effects reported; questionable 24 male
statistics; unknown exercise level. (divided into
3 age groups)
Decreases in SG due to 03 alone. No 7 male
interaction reported. Questionable
statistics.
von Nieding et al. , 1979
Islam and Ulmer, 1979b
Islam and Ulmer, 1979a
Kagawa, 1983a, 1983D
aPollutants studied for interactive effects: 0 = ozone; SO = sulfur dioxide; H2S04 = sulfuric acid; (NH4)2S04 = ammonium sulfate; NH4HS04 = ammonium bisulfate;
NH4N03 = ammonium nitrate; CO = carbon monoxide; N02 = nitrogen dioxide.
Measurement method: MAST = Kl-Coulometric (Mast meter); MAST (NO.^) = microcoulometric N02 analyzer; CHEM = gas-phase chemiluminescence; UV = ultraviolet
photometry; GS-CHEM •= gas solid chemiluminescence; 1C = ion chromatography; EC = electrical conductivity S02 analyzer; FP = flame photometry S02 analyzer;
TS = total sulfur analyzer; IR = infrared CO analyzer.
Calibration method: NBKI = neutral buffered potassium iodide; BAKI = boric acid potassium iodide; C = colorimetric (Saltzman).
Activity level: R = rest; CE = continuous exercise; IE = intermittent exercise; minute ventilation (Vr) given in L/min or as a multiple of resting
'
See Glossary for the definition of symbols.
Part of a larger study of 231 subjects.
-------
PRELIMINARY DRAFT
0, + S0? exposure. Four of the Hazucha and Bates (1975) study subjects were
also studied by Bell et al. (1977). Two of these subjects had unusually large
decrements in FVC (40 percent) and FEV, (44 percent) in the first study (Bates
and Hazucha, 1973), while the other two had small but statistically significant
decrements. None of the subjects responded in a similar manner in the Bell
et al. (1977) study.
To determine why some of the Montreal subjects were less reactive to the
S02-03 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 S0? and 0, could have reacted rapidly with each other and
with ambient impurities like olefins, to form a large number of sulfuric acid
(hLSCL) nuclei which grew by homogeneous condensation, coagulation, and absorp-
tion of ammonia (NH,) during their 2-min average residence time in the chamber.
A retrospective sampling of the aerosol composition used for the original
SOp-Oo 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 (jg/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 |jg/m H^SO. did not alter the response
obtained with the S0?-0, mixture alone. (See later discussion in this section.)
Bedi et al. (1979) exposed nine young healthy nonsmoking men (18 to 27
years old) to 784 ug/m (0.4 ppm) 03 and 0.4 ppm S02 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 S0? showed no significant changes in pulmonary
function. When exposed to either 0., or 03 plus SO-, the subjects showed
statistically significant decreases in maximum expiratory flow (FEV, „,
FEFpr jro/, and FEFr^o.) and FVC. There were no significant differences between
the effects of 03 alone and the combination of 03 + $02; 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.
0190LG/A 11-66 10/17/85
-------
PRELIMINARY DRAFT
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 S0?; filtered air; and
finally 0.15 ppm of 0, +0.15 ppm of S0?. Pulmonary function measurements
were obtained prior to exposure, after 1 hr in the chamber, and after leaving
the chamber. Although a number of pulmonary function tests were performed,
change in SG was used as the most sensitive test of change in function.
They reported a significant decrease in five of the six young male subjects
exposed to 0., alone. In three of the subjects, they reported a significantly
greater decrease in SG after exposure to the combination of pollutants than
cLW
with 0, exposure alone. Two other subjects had similar decreases with either
0, or On + S0~ exposure. Subjective symptoms of cough and bronchial irrita-
tion were reported to occur in subjects exposed to either 0., or the 0, + SO.
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-
aw
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 SO,, 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 S0?. While
intermittently exercising (Vr -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 ug/m3 (0.4 ppm) of 03, and 0.4 ppm of S02 plus 784 ug/m (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 SO^, but decreases in FEV.^ Q
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 SOp (7.4 per-
cent). Thoracic gas volume (TGV) increased and FEF,-Q FEF50?" ERV> and TLC a11 decreased in tne
0,/SO? and 0, exposures. However, no significant differences were found
0190LG/A 11-67 10/17/85
-------
PRELIMINARY DRAFT
between the CL exposure and the 03 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-
gistic effect consequent to exposure to 0.15 ppm of S0? and 294 ^ig/m (0.15
ppm) of 0, using t-tests. The experimental designs of the Bedi et al. and the
Kagawa and Tsuru studies were essentially similar. Reanalysis of the Bedi et
al. data using t-tests and expressing data as relative changes indicated that
the SG was not altered in the 25°C-45 percent rh environment but decreased
aw
10.6 percent (P < 0.05) in the S02 exposure and 19 percent (P < 0.01) in 03
plus SOp exposure in hot, wet conditions. These investigators concluded that
in one sense they confirmed the findings (based on t-tests) of Kagawa and
Tsuru, but under different conditions. This might suggest a small potential
effect on SG . They then stated, "Nonetheless, we believe that the use of a
aw
more stringent statistical approach provides for better analysis of collected
data and that we are correct in stating that synergism had not occurred."
Folinsbee et al. (1985) exposed 22 healthy nonsmoking men (23.6 ±8.1
years of age) for 2 hr to a combination of 588 ng/m (0.3 ppm) 0, and 1.0 ppm
S0? as well as to each gas individually. The subjects alternated 30-min
periods of treadmill exercise at a ventilation of 38 L/min with 10-min rest
periods during the exposure. Forced expiratory maneuvers were performed
before exposure and 5 min after each of three exercise periods; MVV, FRC, R ,
o w
and TGV were measured before and after exposure. After 0., exposure alone,
there were significant decreases in FVC, FEV-., and {^25-15%' There were no
significant changes in pulmonary function after S0? exposure alone. Combined
exposure to S0? + 0, produced similar but smaller changes compared to those
found after 0., exposure alone. These small differences were not in a direction
that would support the hypothesis of either a synergistic or additive effect
on pulmonary function. In general, there were no important health-related
differences between the effects of 0, alone and 0., + S0~.
Few studies have been reported in which subjects were exposed to 0., and
H?SO.. Kagawa (1983a) summarized some results obtained on seven subjects
intermittently resting and exercising during a 2-hr exposure to 294 pg/m
3
(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 .
o W
However, not enough details are provided to allow adequate analysis.
0190LG/A 11-68 10/17/85
-------
PRELIMINARY DRAFT
Kleinman et al. (1981) conducted studies in which 19 volunteers with
normal pulmonary function and no history of asthma were exposed on two separate
days to clean air and to an atmospheric mixture containing 0, (725 ug/m , 0.37
•i *
ppm), SOp (0.37 ppm), and H2SO. aerosol (100 pg/m , MMAD = 0.5 urn; a = 3.0).
Chemical speciation data indicated that 93 percent of the H?50. 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., ., on the
exposure day was depressed by 3.7 percent of the control value. However, the
magnitudes of the FEV, Q 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 HpSO. aerosols did not substantially alter the
irritability resulting from 0,-SCL.
Stacy et al. (1983) studied 234 healthy men (18 to 40 years old) exposed
for 4 hr to air, (k, NO-, or S02; to H^SO., ammonium sulfate [(NH.^SO^,
ammonium bisulfate (NH.HSO.), 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 ug/m (0.4 ppm) of Ck
(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 |.ig/m3 of NH4N03 (n = 12); and the mixtures
03 + H2S04 (n = 13), 03 + (NH4)2S04 (n = 15), 03 + NH4HS04 (n = 11), and 03 *
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. Minute ventilations were not
reported. Pulmonary function was measured during a rest period before expo-
sure. 5 to 6 min following the termination of the exercise, and 24 hr later.
Data were analyzed by multivariate analyses of variance. Airway resistance,
lung volume, and flow rates showed a statistically significant effect of the
0190LG/A 11-69 10/17/85
-------
PRELIMINARY DRAFT
gaseous pollutant (0.,) with greater changes reported at 4 hr than at 2 hr of
exposure. None of the participates significantly altered pulmonary functions
compared with the filtered-air exposure, and there was no indication of inter-
action between 0, and the particulates. Exposure to 03 alone and with particles
was also associated with symptoms of irritation, such as shortness of breath,
coughing, and minor throat irritation. At 24 hr post-exposure, all pulmonary
values had returned to pre-exposure levels.
Kulle et al. (1982a) studied the responses of 12 healthy nonsmokers
(seven men, five women) exposed to 0, and H9SO,. aerosols. Ozone concentra-
3 3
tions were 588 ug/m (0.3 ppm) and hLSO. aerosol levels were 100 ug/m (MMAD =
0.13 urn; o = 2.4). These studies were conducted over a 3-week period; a 2-hr
exposure to 03 during the first week, a 4-hr exposure to hLSO. during the
second week, and a 2-hr exposure to 0~ followed by a 4-hr exposure to H-SO.
during the third week. The protocol followed in each of these weekly exposure
regimes was day 1 - filtered air, day 2 - pollutant, and day 3 - filtered air.
A methacholine aerosol challenge was made at the completion of each exposure
day. Subjects were exercised for 15 min I hr prior to the completion of the
exposure. The work load was 100 W at 60 rpm, with an assumed Vp of approxi-
mately 30 to 35 L. No discernible risk was apparent as a consequence of
exposing the nonsmoking healthy young adults to 03 followed by respirable
H?SO. 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 methacho-
3W J. j
line) 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 03- Subjects exercised at 50 percent max
Vn9 for 1 hr in the following ambient conditions: filtered air, 100 ppm of
T ->
CO, 588 ug/m (0.30 ppm) of 0.,, 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
0190LG/A 11-70 10/17/85
-------
PRELIMINARY DRAFT
be responsible for some of the differences reported. Cardiorespiratory perform-
ance, heart rate, oxygen uptake, and minute ventilation were not substantially
higher during exercise bouts where 0, was present. All subjects exercised at
50 percent max Vn?, equivalent to a mean Vr 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
nonsmokers1 levels of 7.3 ± 0.8 percent.
Based on the limited data available, exposure to CO and 0, does not
appear to result in any interactions. The effects noted appear to be related
primarily to Cu.
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 |jg/m3 (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
cLW
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-
vals, i.e., filtered air, 294 |jg/m (0.15 ppm) of 0-, filtered air, 0.15 ppm
of N02, filtered air, 0.15 ppm (03 + NO^), and filtered air. Statistical
analyses were by t-tests. Subjective symptoms were reported in some subjects
only when 0, was present. Significant decreases in SG occurred.in five of
j aW
six subjects exposed to 0_, three of six subjects exposed to N0?, 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 03 + 0.15 ppm N02) SGaw, V5Q%, and VC decreased. However.
no significant differences were observed between 0, alone and the combination
of 0, + N0?. Subjective symptoms were equivalent in both 0, exposures.
Five subjects sitting in a body plethysmograph inhaled orally either
filtered air, 0.7 ppm of N02> 1372 ug/m3 (0.7 ppm) of 03, or 0.5 ppm of 03 +
0.5 ppm of N0? for 1 hr (Toyama et al., 1981). Specific airway conductance
0190LG/A 11-71 10/17/85
-------
PRELIMINARY DRAFT
and isovolume flows (V 2t$ anc' V 50%) were measured before and at the
end of exposure, and 1 hr later. No significant changes were observed for any
of the ambient conditions and consequently no interactions could be detected.
Folinsbee et al. (1981) exposed eight healthy men for 2 hr to either
filtered air or 980 |jg/m (0.5 ppm) of 0, plus 0.5 ppm of N0? 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
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, Q, FF-F^c-ycv, and FEFrQ^ during the 0.,-NOp
exposure. Ventilatory and metabolic variables, expired ventilation, oxygen
uptake, tidal volume, and respiratory frequency were unaffected by 0., and NOp
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.,, NOp, and SOp singly
and in various combinations. The subjects were exposed for 2 hr with 1 hr
devoted to exercise (intermittent), which doubled their ventilation. The work
periods were of 15 min duration alternating with 15-min periods at rest. In
the actual exposure experiments, no significant alterations were observed for
P0?, PCO?, and pH in arterialized capillary blood or in TGV. Arterial oxygen
tension (Pa02) was decreased (7 to 8 torr) by exposure to 5.0 ppm of N02 but
was not further decreased following exposures to 5.0 ppm of N09 and 5.0 ppm of
•>
SOp or 5.0 ppm of NOp, 5.0 ppm of SO- and 196 pg/m (0.1 ppm) of 03 or 5.0 ppm
of NO- and 196 ug/m (0.1 ppm) of 0.,. Airway resistance increased significant-
ly (0.5 to 1.5 cm HpO/L/s) in the combination experiments to the same extent
as in the exposures to N0? alone. In the 1-hr post-exposure period of the
N09, SO,, and 0., experiment, R. continued to increase. Subjects were also
L. £. J t n
exposed to a mixture of 0.06 ppm N02, 0.12 ppm of S02, and 49 ug/m (0.025 ppm)
of 0,. No changes in any of the measured parameters were observed. These
0190LG/A 11-72 10/17/85
-------
PRELIMINARY DRAFT
same subjects were challenged with 1-, 2-, and 3-percent aerosolized solutions
of ACh following control (fi1tered-air) exposure and exposure to 5.0-ppm NO-,
5.0-ppm SO-, and 0.1-ppm 0- mixture, as well as after the 0.06-ppm NO-, 0.12-
ppm SO-, and 49-ug/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
QW
TGV) was significantly greater following the combined pollutant exposures than
in the control study.
In another study of simultaneous exposure to SO-, NO-, and 0.,, three
groups of eight subjects, each of different ages (<30, >49, and between 30 to
40 years) were exposed for 2 hr each day in a chamber on three successive days
(Islam and Ulmer, 1979a). On the first day, subjects breathed filtered air
and exercised intermittently (levels not given); on the second day they were
•j
exposed at rest to 5.0 ppm of S02, 5.0 ppm of NO-, and 196 ug/m (0.1 ppm) of
0,; and on the third day the environment was again 5.0 ppm of SO-, 5.0 ppm of
3
NO-, and 196 ug/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
33 3
exposures to 0.9 mg/m (0.34 ppm) SO-, 0.3 mg/m (0.16 ppm) NO-, and O.lb mg/m
(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-,
PaCO-, 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.
0190LG/A 11-73 10/17/85
-------
PRELIMINARY DRAFT
11.6 EXTRAPULMONARY EFFECTS OF OZONE
The high oxidation potential of 03 has led early investigators to suspect
that the major damage from inhalation of this compound resulted from oxidation
of labile components in biological systems to produce structural or biochemical
lesions (Chapter 10). Initial studies by Buckley et al. (1975) suggested that
statistically significant changes (P < 0.05) occurred in erythrocytes and sera
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 03 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
784 ug/m (0.4 ppm) of 03 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, dlcentrics, 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
human subjects exposed to 784 ug/m (0.4 ppm) of 0., for 4 hr on one day and
3
for 4 hr/day on four consecutive days, or to 1176 pg/m (0.6 ppm) for 2 hr on
one day only. One hundred metaphases per blood sample per subject for chromo-
some aberrations, and 50 metaphases per blood sample per subject were analyzed
for SCEs. Each study was conducted on 10 to 30 healthy, nonsmoking human
subjects. No statistically significant differences were observed in the
0190LG/A 11-74 10/17/85
-------
PRELIMINARY DRAFT
TABLE 11-8. HUMAN EXTRAPULMONARY EFFECTS OF OZONE EXPOSURE.
Ozone
concentration
ug/mj ppm
294 0.15
588 0.30
392 0.2
392 0.2
490 0.25
725 0.37
784 0.4
784 0.4
784 0.4
784 0.4
Measurement3'
method
UV,
NBKI
NO
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
. Exposure
duration and
activity
1 hr (mouthpiece)
R (11) & CE
(29, 43, 66)
0.5-1 hr
2 hr
IE (2xR)
@ !5-n1n Intervals
2 hr
IE (2xR)
@ 15-raln Intervals
4 hr
IE for two
!5-m1n periods
4 hr
R
4 hr
IE for two
!5-m1n periods
2.25 hr
IE (2xR)
@ 15-raln Intervals
Observed effect(s)d
No effect on NPSH, G-6-PD, 6-PG-O, GRase,
Hb.
Spherocytosls.
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.
H1ld suppression PHA- Induced lymphocyte
transformation. Questionable decrease 1n
PMN phagocytosis and Intracellular killing.
No statistically significant depression 1n 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 cytogenetlc effect.
RBC fragility Increased. RBC enzymes: AChE
decreased; LDH Increased In new arrivals.
Serum glutathlone reductase Increased In
new arrivals.
No. and sex
of subjects Reference
6 male OeLucIa and Adams, 1977
e Brlnkman et al. , 1964
20 male Linn et al. , 1978
2 female
(asthna)
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 Savlno et al., 1978
26 male McKenzle et al., 1977
6 female (L.A.) Hackney et al., 1976
7 female (new arrival)
2 male (new arrival)
-------
PRELIMINARY DRAFT
TABLE 11-8 (continued). HUMAN EXTRAPULMONARY EFFECTS OF OZONE EXPOSURE
Ozone
concentration
ug/m-5 ppm
784
784
1176
980
980
980
980
980
0.4
0.4
0.6
0.5
0.5
0.5
0.5
0.5
Measurement3'
method
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
uv,
NBKI
Exposure
duration and
activity
4 days
4 hr/day
IE for two
15-min periods
4 days
4 hr/day
2 hr
IE for two
15-min periods
2 hr
IE (2xR)
@ 15-rain intervals
± Vit E
2 hr
IE (2xR)
@ 15-min intervals
intervals
2.75 hr
IE (2xR)
§ 15-min intervals
4 days
2.5 hr/day
IE (2xR)
@ 15-min intervals
2 hr
IE (2xR)
@ 15-min intervals
Observed effect(s)d
RBC G-6-PO increased. Serum vitamin E
increased. Complement Ca 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
f ema 1 e
Reference
Chaney et al. , 1979
McKenzie, 1982
Hamburger et al. , 1979
Posin et al. , 1979
Buckley et al. , 1975
Hackney et al. , 1978
Guerrero et al . , 1979
-------
PRELIMINARY DRAFT
TABLE 11-8 (continued). HUMAN EXTRAPULMONARY EFFECTS OF OZONE EXPOSURE
Ozone
concentration
ug/m
980
1176
1960
•> ppm
0.5
0.5
1.0
Measurement3'
method
MAST,
NBKI
CHEM,
NBKI
ND
Exposure
duration and
activity0
6-10 hr
IE for two
15-min periods
2 hr
IE for two
15-min periods.
10 min
Observed effect(s)d
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 Hb02 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; ND = not described.
Calibration method: NBKI = neutral buffered potassium iodide.
Activity level: R = rest; CE = continuous exercise; IE = intermittent exercise; minute ventilation (VV) given in L/rain 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; LDH = lactate dehydrogenase; AChE = acetylcholinesterase; PHA = phytohemagglutinin; GSSRase = glutathione
reductase; GSH = reduced glutathione; 2,3-DPG = 2,3-diphosphoglycerate; Hb02 = oxyhemoglobin; PMN = polymorphonuclear leukocytes.
eDetails not given.
-------
PRELIMINARY DRAFT
frequencies of numerical aberrations, structural aberrations, or SCEs between
0., pre-exposure and post-exposure values. The nonsignificant differences were
observed at all concentrations and durations tested, and in the multiple
exposures as well as in the single 03 exposures.
Chromosome and chromatid aberrations were investigated by Merz et al.
(1975) in lymphocytes collected from subjects exposed to 980 ug/m (0.5 ppm)
of 0, for 6 to 10 hr. Increases in the Frequency of chromatid aberrations
(achromatic lesions and chromatid deletions) were observed in lymphocytes
after 03 exposure, with a peak in the number of aberrations 2 weeks after
exposure. No increase was observed in the number of chromosome aberrations.
While these results suggest human genotoxicity after 0, exposure, the results
did not differ significantly from pre-0, 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 ug/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
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 0, for 1 hr i_n vitro was shown to have a
j -
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
3
for 4 hr to to 784 ug/m (0.40 ppm) of 03 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 03 exposure, or at 2 weeks after 03
exposure. The nadir of neutrophil function was observed at 72 hours after 0,
0190LG/A 11-78 10/17/85
-------
PRELIMINARY DRAFT
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
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
0, 764-ug/m (0.39-ppm) exposure (20 subjects), lymphocyte transformation
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 (jg/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
2
subjects exposed to 1176 ug/m (0.6 ppm) of 0-,. 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
3
784 ug/m (0.4 ppm) 0, for 4 hr, B-lymphocyte rosette formation was signifi-
cantly depressed. Rosette formation is an j_n vitro method that measures the
binding of antigenic red blood cells with surface membrane sites on lymphocytes.
Different antigenic red cells are used to distinguish T from B lymphocytes. A
normal B-lymphocyte response was restored by 72 hr after 0- exposure.
Biochemical parameters (erythrocyte fragility, hematocrit, hemoglobin,
erythrocyte glutathione, acetylchol inesterase, 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
conditions were filtered air on day 1 and 980 ug/m (0.50 ppm) 0., on day 2;
2 hr of exposure alternating with 15 min of exercise (double the resting
0190LG/A 11-79 10/17/85
-------
PRELIMINARY DRAFT
minute ventilation) and 15 min of rest. Vitamin E intakes for nine or more
weeks were 800 or 1600 ID. The number of subjects and the percent of men and
women differed in each of the three studies conducted. No significant differ-
ences between the responses of the supplemented and placebo groups to the 03
exposure were found for any of the parameters measured. Hamburger et al.
(1979) obtained blood from the 29 subjects in one of the above three experi-
ments (800 ID vitamin E and placebo). Blood was obtained before and after the
2-hr exposures to filtered air or 980 ug/m (0.5 ppm) of 03_ No statistically
significant change in erythrocyte agglutinability by concanavalin A was found.
In summary, the overall impression of available human data raises doubts
that cellular damage or altered function to circulating cells occurs as a
consequence of exposure to 0, concentration under 980 ug/m (0.5 ppm).
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 VO- 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 VO, was determined in 20 young men
t Mia X
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
0190LG/A 11-80 10/17/85
-------
PRELIMINARY DRAFT
TABLE 11-9. ACUTE HUMAN EXPOSURE TO PEROXYACETYL NITRATE
oo
Concentration
Mg/mJ
1187
1187
1336
1336
1336
1484
1484
ppm
0.24
0.24
0.27
0.27
0.27
0.30
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
2 hr
IE(27) with
alternating 15-min
rest and 20-min
exercise
. 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 IS male
35% VO, in 10 young and nine middle-aged
subjects. No interaction between exposure
and temperature (25° & 35°C).
No significant change in VO- in young non- 20 male
smokers (n = 10) or smokers °fl= 10) during
treadmill walk at 35°.
No significant change in VO- in middle- 16 male
aged nonsmokers (n = 9) or sraOKers (n = 7)
during treadmill walk at 25°C and 35°C.
No significant change in VO- 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.
No significant changes in pulmonary 10 male
function or exercise ventilation with PAN.
Simultaneous effect of PAN and 0.45 ppm
03; decrements in TLC, FVC, FEV,-0. and
FEF2S_75~ were significantly greater (10%)
with PAN703 when compared with 03 alone.
Reference
Raven et al. , 1976
Gliner et al., 1975
Drinkwater et al . ,
1974
Raven et al. , 1974 a
Raven et al. , 1974b
Smith, 1965
Orechsler-Parks
et al. , 1984
Activity level: IE = intermittent exercise; minute ventilation (Vc) given in L/min.
L t
See Glossary for the definition of symbols.
-------
PRELIMINARY DRAFT
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
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 percent) reduction in standing FVC in young men after 3.5 hr of
light exercise (35 percent V09 ) during a 4-hr exposure to 0.24 ppm PAN.
L. fflflX
Dreschler-Parks et al. (1984) studied metabolic and pulmonary function
effects in ten nonsmoking young men randomly exposed for 2 hr to each of four
conditions: (1) filtered air. (2) 0.30 ppm PAN, (3) 882 ug/m3 (0.45 ppm) 03>
and (4) 0.30 ppm PAN + 0.45 ppm 03 PAN/03). The subjects alternated 15-min
periods of rest and 20-min periods of moderate exercise (VF = 27 L/min) on a
bicycle ergometer during the exposure. Forced expiratory volume and flow were
determined before and after exposure and 5 min after each exercise period.
Functional residual capacity was determined pre- and postexposure. Heart rate
was measured throughout the exposure, and Vr, VOp, fn, and Vy were measured
during the last 2 min of each exercise period. There were no significant
changes in exercise VO- or heart rate during any of the pollutant exposures.
The changes in breathing patterns occurring during exercise were significant
decreases in V-, with exposure to 03 and PAN/0., and significant increases in fn
with PAN/0., exposure. No effects on lung function or respiratory symptoms
were reported after exposure to filtered air or PAN. Exposure to 03 and
PAN/03 produced significant decrements in FVC, FEV^ FEV,,, FEV3, FEF25-75%'
1C, ERV, and TLC. The decrements in TLC, FVC, FEV-L, and FEF25-75% were signi-
ficantly greater (10 percent) with PAN/0., exposure and occurred in a shorter
period of time when compared with exposure to 0., alone. A wide range of
individual responsiveness to 0, and PAN/0, was noted among subjects; four
subjects had greater than 30 percent decrements in FEV-. while one subject
showed no change at all. Symptoms reported after 0, and PAN/0., exposures were
similar, although a greater number of symptoms were reported after the PAN/0.,
exposure. The results by Dreschler-Parks et al. (1984) suggest a simultaneous
effect of the oxidants PAN and 0.,. However, because the large individual
*J
responsiveness to 0, makes direct comparisons to extant data difficult to
perform, it is not clear if the greater decrements observed after PAN/03
0190LG/A 11-82 10/17/85
-------
PRELIMINARY DRAFT
exposure are related to total oxidant load. Additional research is needed to
further clarify the relationship between PAN and 0, at concentrations found in
ambient air.
The interaction of PAN and CO was also evaluated in the series of studies
on healthy young and middle-aged men exercising on a treadmill (Raven et al.,
1974a, 1974b; Drinkwater et al., 1974; Gliner et al., 1975). Both smokers and
nonsmokers were exposed to 0.27 ppm PAN and 50 ppm CO. No interactions between
CO and PAN were found. 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 Vn?) 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. Carboxyhemoglobin 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 Vg2
was found in middle-aged smokers breathing 50 ppm of CO. Another study con-
ducted under similar pollutant conditions at an ambient temperature of 35°C,
20 percent rh was carried out on 20 young male subjects (10 smokers and 10
nonsmokers) (Drinkwater et al. , 1974). Maximal aerobic power was not affected
by any pollutant condition. Exposure to CO was effective in reducing work
time of the smokers. The same subjects were also involved in a study conducted
at 25°C, 20 percent rh under similar pollutant conditions except that they
inhaled the pollutants orally for 40 min (Raven et al., 1974b). Exposure to
the two pollutants singly or in combination produced only minor, nonsignificant
alterations in cardiorespiratory and temperature regulatory parameters. The
influence of PAN and CO, singly or in combination, was evaluated in 10 young
(22 to 26 years) and nine middle-aged (45 to 55 years) men performing submaxi-
mal work (35 percent max VQ2) for 210 min (Gliner et al., 1975). Five subjects
in each age group were smokers. Studies were conducted at two different
ambient temperatures, i.e., 25°C and 35°C, rh 30 percent. The pollutant
concentrations were 0.25 ppm of PAN and 50 ppm of CO. Two physiological
alterations were reported. Stroke volume decreased during long-term work,
being enhanced in the higher ambient temperatures. Heart rate was significantly
(P <0.05) higher when exercise was being performed during the CO exposures.
0190LG/A 11-83 10/17/85
-------
PRELIMINARY DRAFT
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,
exposure (Table 11-10). In most of the studies reported, greatest attention
has been accorded decrements in FEV, „, as this variable represents a summation
of changes in both volume and resistance. While this is true, it must be
pointed out that for exposure concentrations critical to the standard-setting
process (i.e., <0.3 ppm CL), the observed decrements in FEV, Q primarily
reflect FVC decrements of similar magnitude, with little or no contribution
from changes in resistance.
Results from studies of at-rest exposures to 0, have demonstrated decre-
3
ments in forced expiratory volumes and flows occurring at and above 980 ug/m
(0.5 ppm) of 03 (Folinsbee et al., 1978; Horvath et al., 1979). Airway resist-
ance is not clearly affected at these 0, concentrations. At or below 588
3
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 On-induced
pulmonary symptoms has been suggested (Kb'nig et al., 1980).
With moderate intermittent exercise at. a VE of 30 to 50 L/min, decrements
in forced expiratory volumes and flows have been observed at and above 588
ug/m3 (0.30 ppm) of 03 (Folinsbee et al., 1978). With heavy intermittent
exercise (Vr = 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
occur at 314 to 470 ug/m (0.16 to 0.24 ppm) of 03 following 1 hr of continuous
heavy exercise at a VF of 57 L/min (Avol et al., 1984) or very heavy exercise
at a VE of 80 to 90 L/min (Adams and Schelegle, 1983; Folinsbee et al., 1984)
and following 2 hr of intermittent heavy exercise at a VE of 65 L/min (McDonnell
et al., 1983). Airway resistance is only modestly affected with moderate
exercise (Kerr et al., 1975; Farrell et al., 1979) or 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 maintain-
ing the same Vr, occur with prolonged heavy exercise when exposed at 392 to
0190LG/A 11-84 10/17/85
-------
PRELIMINARY DRAFT
TABLE 11-10. SUMMARY TABLE: CONTROLLED HUMAN EXPOSURE TO OZONE
Ozone3 .
concentration Measurement ' Exposure
ug/W
ppm method duration
Act1v1tyd
level (VE) Observed effects(s)
No. and sex
of subjects Reference
HEALTHY ADULT SUBJECTS AT REST
627
1960
980
930
1470
0.32 MAST, NBKI 2 hr
1.0
0.5 CHEM, NBKI 2 hr
0.50 CHEM, NBKI 2 hr
0.75
R Specific airway resistance Increased with
acetylchollne 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.
13 male Konlg et al. , 1980
1 female
40 male Follnsbee et al.,
(divided Into four 1978
exposure groups)
8 male Horvath et al. ,
7 female 1979
EXERCISING HEALTHY ADULTS
235
353
470
— 588
V 784
00
c_n
314
470
627
353
470
588
784
0.12 CHEM, UV 2.5 hr
0.18
0.24
0.30
0.40
0.16 UV, UV 1 hr
0.24
0.32
0.18 CHEM, UV 2.5 hr
0.24
0.30
0.40
IE (65) Decrement 1n 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 g 0. 24 ppra.
CE (57) Small decrements 1n forced expiratory
volume at 0.16 ppm with larger decrements
at >0.24 ppra; lower-respiratory symptoms
Increased at >0.16 ppm.
IE (65) Individual responses to 03 were highly
@15-nin Intervals reproducible for periods as long as 10
months; large Intersubject variability
In response due to Intrinsic responsiveness
to 03.
135 male McDonnell et al.,
(divided Into six 1983
exposure groups)
42 male Avol et al. , 1984
8 female
(competitive
bicyclists)
32 male McDonnell et al.,
1985a
-------
CO
784
0.4
PRELIMINARY DRAFT
TABLE 11-10 (continued).
SUMMARY TABLE: CONTROLLED HUMAN EXPOSURE TO OZONE
Ozone3 b c
concentration Measurement '
jjg/m-"
392
686
392
823
980
392
490
412
588
980
725
980
1470
ppm method
0.20 UV. UV
0.35
0.2 UV, UV
0.42
0.50
0.20 UV, UV
0.25
0.21 UV, UV
0.3 CHEM, NBKI
0.5
0.37 MAST, NBKI
0.50
0.75
Exposure Activity
duration level (Vp)
1 hr IE (77.5) @ vari-
(mouth- able competitive
piece) intervals
CE (77.5)
2 hr IE (30 for male,
18 for female
subjects)
@ 15-min intervals
2 hr IE (68)
(4) 14-min periods
1 hr CE (81)
2 hr R (10), IE (31,
50, 67)
9 15-min intervals
2 hr R (11) & IE (29)
@ 15-min intervals
Observed effects(s)
Decrement in forced expiratory volume and
flow with IE and CE; subjective symptoms
increased with 03 concentration and nay
limit performance; respiratory frequency
increased and tidal volume decreased with
CE.
Repeated daily exposure to 0.2 ppm did not
affect response at higher exposure concen-
trations (0.42 or 0.50 ppm); large inter-
subject variability but individual
pulmonary function responses were highly
reproducible.
Large intersubject variability in response;
significant concentration-response relation-
ships for pulmonary function and respiratory
symptoms .
Decrement in forced expiratory volume and
flow; subjective symptoms may limit per-
formance.
Decrement in forced expiratory volume and
flow; the magnitude of the change was
related to 03 concentration and V,.
Total lung capacity and inspiratoPy
capacity decreased with IE (50, 67); no
change in airway resistance or residual
volume even at highest IE (67). No
significant changes in pulmonary function
were observed at 0. 1 ppm.
Good correlation between dose (concen-
tration x Vp) and decrement in forced
expiratory Volume and flow.
No. and sex
of subjects Reference
10 male Adams and Schelegle,
(distance runners) 1983
8 male Gliner et al. , 1983
13 female
20 male Kulle et al. , 1985
6 male Folinsbee et al. ,
1 female 1S84
(distance cyclists)
40 male Folinsbee et al.,
(divided into four 1978
exposure groups)
20 male Silver-man et al. ,
8 female (divided into 1976
six exposure groups)
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 &
M«ST, NBKI
3 hr
IE (4-5xR)
Decrement in forced expiratory volume and
SG was greatest on the 2nd of 5 exposure
daf?; attenuated response by the 4th day
of exposure.
10 male
4 female
Farrell et al., 1979
-------
PRELIMINARY DRAFT
TABLE 11-10 (continued). SUMMARY TABLE: CONTROLLED HUMAN EXPOSURE TO OZONE
Ozone3 b d
concentration Measurement ' Exposure Activity
jjg/m^ ppm method duration level (Vr)
784 0.4 CHEM, UV 3 hr IE (4-5xR)
for 15 rain
823 0.42 UV, UV 2 hr IE (30)
921 0.47 UV, NBKI 2 hr IE (3xR)
p—i
• 980 0.5 MAST, NBKI 6 hr IE (44) for two
S3 15-rain periods
1176 0.6 UV, NBKI 2 hr IE (2xR)
(noseclip) @ 15-min intervals
1470 0.75 MAST, NBKI 2 hr IE (2xR)
@ 15-min intervals
Observed effects(s)
Decrement in forced expiratory volume was
greatest on the 2nd of 5 exposure days;
attenuation of response occurred by the
5th day and persisted for 4 to 7 days.
Enhanced bYonchoreactivity with
methacholine on the first 3 days;
attenuation of response occurred by
the 4th and 5th day and persisted
for > 7 days.
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.
Small decrements in forced expiratory
volume and specific airway conductance.
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.
No. and sex
of subjects
13 male
11 female
(divided into two
exposure groups)
24 male
8 male
3 female
19 male
1 female
11 male
5 female (divided
by history of atopy)
12 male
Reference
Kulle et al. , 1982b
Horvath et al. , 1981
Linn et al. , 1982b
Kerr et al. , 1975
Holtzman et al . ,
1979
Hazucha et al . ,
1973
EXERCISING HEALTHY CHILDREN
235 0.12 CHEM, UV 2.5 hr IE (39)
@15-min intervals
Small decrements in forced expiratory
volume, persisting for 24 hr. No subjec-
tive symptoms.
23 male
(8-11 yrs)
McDonnell et al. ,
1985b,c
-------
PRELIMINARY DRAFT
TABLE 11-10. (continued) SUMMARY TABLE: CONTROLLED HUMAN EXPOSURE TO OZONE
Ozone3
concentration Measurement ' Exposure
ug/ma ppm method duration
Activity*1
level (VE)
Observed effects(s)
No. and sex
of subjects Reference
ADULT ASTHMATICS
392 0.2 CHEM, NBKI 2 hr
490 0.25 CHEM, NBKI 2 hr
IE (2xR)
9 15-min Intervals
R
No significant changes 1n pulmonary func-
tion. Small changes 1n blood biochemistry.
Increase 1n symptom frequency reported.
No significant changes In pulmonary func-
tion.
20 male Linn et al. , 1978
2 female
5 males Silverman, 1979
12 female
ADOLESCENT ASTHMATICS
235 0.12 UV 1 hr
(mouthpiece)
R
No significant changes In pulmonary function
or symptoms.
4 male Koenig et al. , 1985
6 female
(11-18 yrs)
SUBJECTS WITH CHRONIC OBSTRUCTIVE LUNG DISEASE
235 0.12 UV, NBKI 1 hr
353 0.18 UV, NBKI 1 hr
490 0.25
392 0.2 CHEM, NBKI 2 hr
588 0.3
784 0.41 UV, UV 3 hr
IE (variable)
@ !5-m1n Intervals
IE (variable)
9 15-min Intervals
IE (28) for
7.5 roln 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 1n pulmonary function
or symptoms. Decreased arterial oxygen
saturation during exposure to 0.2 ppm.
Small decreases in FVC and FEV3.0.
18 male Linn et al. , 1982a
7 female
15 male Linn et al. , 1983
13 female
13 male Solic et al. , 1982
Kehrl et al. , 1983,
1985
17 male Kulle et al. , 1984
3 female
Ranked by lowest observed effect level.
Measurement method: MAST = Kl-Coulometric (Mast meter); CHEM = gas phase chemiluminescence; UV = ultraviolet photometry.
Calibration method: NBKI = neutral buffered potassium iodide; UV = ultraviolet photometry.
Minute ventilation reported in L/min or as a multiple of resting ventilation. R = rest; IE = Intermittent exercise; CE = continuous exercise.
-------
PRELIMINARY DRAFT
470 |jg/m3 (0.20 to 0.24 ppm) of 03 (McDonnell et al., 1983; Adams and Schelegle,
1983). While an increase in RV has been reported to result from exposure to
1470 (jg/rn3 (0.75 ppm) of 0, (Hazucha et al., 1973), changes in RV have not
3
been observed following exposures to 980 ug/m (0.50 ppm) of 0, or less, even
with heavy exercise (Folinsbee et al., 1978). Decreases in TLC and 1C have
been observed to result from exposures to 980 |jg/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 On concentration than for V^. A greater degree of predic-
tive accuracy is obtained if the contribution of these variables is appropri-
ately weighted (Folinsbee et al., 1978). However, several additional factors
make the interpretation of prediction equations more difficult. There is
considerable intersubject variability in the magnitude of individual pulmonary
function responses to 0, (Horvath et al., 1981; Gliner et al, 1983; McDonnell
et al., 1983; Kulle et al., 1985). Individual responses to a given 0, concen-
tration have been shown to be quite reproducible (Gliner et al., 1983; McDonnell
et al., 1985a), indicating that some individuals are consistently more respon-
sive to 0, than are others. No information is available to account for these
differences. Considering the great variability in individual pulmonary re-
sponses to 0, exposure, prediction equations that only use some form of effec-
tive dose are not adequate for predicting individual responses to 0,.
In addition to overt changes in pulmonary function, enhanced nonspecific
bronchial reactivity has been observed following exposures to 0., concentrations
•3 J
>588 |jg/m (0.3 ppm) (Holtzman et al., 1979; Konig et al., 1980; Dimeo et al.,
1981). Exposure to 392 pg/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
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 0., exposure is probably initiated by a similar mechanism. Different
efferent pathways have been proposed (Beckett et al., 1985) to account for the
0190LG/A 11-89 10/17/85
-------
PRELIMINARY DRAFT
lack of correlation between individual changes in SR and FVC (McDonnell
3W
et al., 1983). The increased responsiveness of airways to histamine and
methacholine following (L exposure most likely results from an 0.,-induced
increase in airways permeability or from an alteration of smooth muscle charac-
teristics.
Decrements in pulmonary function were not observed for adult asthmatics
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. Likewise, no significant changes in pulmonary function or symptoms were
found in adolescent asthmatics exposed for 1 hr at rest to 235 ug/m (0.12
ppm) of 0., (Koenig et al., 1985). Although these results indicate that asthma-
tics 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 OT
concentrations of 588 ug/m3 (0.30 ppm) and less (Linn et al., 1982a, 1983;
Solic et al., 1982; Kehrl et al., 1983, 1985) and only small decreases in
forced expiratory volume are observed for 3-hr exposures of chronic bronchitics
to 804 ug/m3 (0.41 ppm) (Kulle et al., 1984). Small decreases in Sa02 have
also been observed in some of these studies but not in others; therefore,
interpretation of these decreases and their clinical significance is uncertain.
Many variables have not been adequately addressed in the available clini-
cal data. Information derived from 03 exposure of smokers and nonsmokers is
sparse and somewhat inconsistent, perhaps partly because of undocumented
variability in smoking histories. Although some degree of attenuation appears
to occur in smokers, all current results should be interpreted with caution.
Further and more precise studies are required to answer the complex problems
associated with personal and ambient pollutant exposures. Possible age differ-
ences in response to 0-, have not been explored systematically. Young adults
usually provide the subject population, and where subjects of differing age
are combined, the groups studied are often too small in number to make adequate
statistical comparisons. Children (boys, aged 8 to 11 yr) have been the
subjects in only one study (McDonnell et al., 1985b) and nonstatistical compari-
son with adult males exposed under identical conditions has indicated that the
effects of 0^ on lung spirometry were very similar (McDonnell et al., 1985c).
0190LG/A 11-90 10/17/85
-------
PRELIMINARY DRAFT
While a few studies have investigated sex differences, they have not conclu-
sively demonstrated that men and women respond differently to 0,, and consid-
eration of differences in pulmonary capacities have not been adequately taken
into account. Environmental conditions such as heat and relative humidity may
enhance subjective symptoms and physiological impairment following CL exposure,
but the results so far indicate that the effects are no more than additive.
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 CL, decrements in pulmonary function
are greatest on the second exposure day (Farrell et al., 1979; Horvath et al.,
1981; Kulle et al., 1982b; Linn et al., 1982b); thereafter, pulmonary respon-
siveness to 0- is attenuated with smaller decrements on each successive day
than on the day before until the fourth or fifth exposure day when small
decrements or no changes are observed. Following a sequence of repeated daily
exposures, this attenuated pulmonary responsiveness persists for 3 (Kulle
et al., 1982b; Linn et al., 1982b) to 7 (Horvath et al., 1981) days. Repeated
daily exposures to a given low effective dose of 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 CL. Decrements in forced expiratory flow occurring with 0,
exposure during prolonged heavy exercise (VV = 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 V0?) 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 pg/m (0.4 to 0.6 ppm). Chromosome or chromatid aberrations would
therefore be unlikely at lower 0, levels. Limited data have indicated that 0,,
can interfere with biochemical mechanisms in blood erythrocytes and sera but
the physiological significance of these studies is questionable.
No significant enhancement of respiratory effects has been consistently
demonstrated for combined exposures of 0, with SOp, NO,,, and sulfuric acid or
0190LG/A 11-91 10/17/85
-------
PRELIMINARY DRAFT
participate aerosols or with multiple combinations of these pollutants. Most
of the available studies with other photochemical oxidants have been limited
to studies on the effects of peroxyacetyl nitrate (PAN) on healthy young and
middle-aged males during intermittent moderate exercise. No significant
effects were observed at PAN concentrations of 0.25 to 0.30 ppm, which are
higher than the daily maximum concentrations of PAN reported for relatively
high oxidant areas (0.037 ppm). One study (Dreschler-Parks et al., 1984)
suggested a possible simultaneous effect of PAN and 0.,; however, there are not
enough data to evaluate the significance of this effect. Further studies are
also required to evaluate the relationships between 0, and the more complex
mix of pollutants found in the natural environment.
0190LG/A 11-92 10/17/85
-------
PRELIMINARY DRAFT
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0190LG/A 11-99 10/17/85
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0190LG/A 11-100 10/17/85
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0190LG/A 11-101 10/17/85
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0190LG/A 11-103 10/17/85
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PRELIMINARY DRAFT
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 exposures to
ozone or photochemical oxidants in ambient air; (2) assesses the degree to
which relationships between exposures to these agents and observed effects
are quantitative; and (3) identifies population groups at greatest risk for
such health effects. Studies of both acute and chronic exposure effects are
summarized and discussed. Tables are provided to give the reader an overview
of the studies reviewed in this chapter.
In many of the epidemiological studies available in the literature,
exposure data or health endpoint measurements were used that were inadequate
or unreliable for quantifying exposure-effect relationships. Also, results
from these studies have often been confounded by factors such as variations in
activity levels and time spent out of doors, cigarette smoking, poor hygiene,
coexisting pollutants, weather, and socioeconomic status. Thus, selection of
those studies thought to be most useful in deriving health criteria for ozone
or oxidants is of critical importance. Assessment of the relative scientific
quality of epidemiological studies for standard-setting purposes is a difficult
and often controversial problem; therefore, the following general guidelines
(as modified from U.S. Environmental Protection Agency, 1982) have been suggested
as useful for appraising individual studies:
1. The aerometric data are adequate for characterizing geographic
or temporal differences in pollutant exposures of study popula-
tions in the range(s) of pollutant concentrations evaluated.
2. The study populations are well defined and allow for statisti-
cally adequate comparisons between groups or temporal analyses
within groups.
3. The health endpoints are scientifically plausible for the
pollutant being studied, and the methods for measuring those
endpoints are adequately characterized and implemented.
019DCD/A 12-1 8/19/85
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PRELIMINARY DRAFT
4. The statistical analyses are appropriate and properly per-
formed, and the data analyzed have been subjected to adequate
quality control.
5. Potentially confounding or covarying factors are adequately
controlled for or taken into account.
6. The reported findings are internally consistent and biologically
plausible.
For present purposes, studies most fully satisfying these suggested
criteria provide the most useful information on exposure-effect or exposure-
response relationships associated with ambient air levels of ozone or photo-
chemical oxidants likely to occur in the United States during the next 5
years. Accordingly, the following additional guidelines were used to select
studies for detailed discussion: (1) the results provide information on
quantitative relationships between health effects and ambient air ozone or
oxidant concentrations with emphasis on concentrations less than or equal to
0.5 ppm (measurement methods and calibrations are reported when available);
and (2) the report has been peer-reviewed and is in the open literature or is
in press. A number of recent studies not meeting the above guidelines but
considered to be sources of additional supportive information are also discussed
below and their limitations noted.
The remaining studies not rigorously meeting all of these guidelines are
tabulated chronologically by year of publication. Since the lack of adequate
aerometric data is a frequently noted limitation of epidemiological studies, an
attempt has been made to provide as detailed a description as possible of
the photochemical oxidant concentrations and averaging times reported in the
original manuscripts. In addition, the tables summarize comments on earlier
studies described in detail in the 1978 EPA criteria document for ozone and
other photochemical oxidants (U.S. Environmental Protection Agency, 1978).
12.2 FIELD STUDIES OF EFFECTS OF ACUTE EXPOSURE TO OZONE AND OTHER PHOTO-
CHEMICAL OXIDANTS
For the purposes of this document, field studies are defined as laboratory
experiments where the postulated cause of an effect in the population or environ-
ment is tested by removing it under controlled conditions (Morris, 1975; Mausner
and Bahn, 1974; American Thoracic Society, 1978; World Health Organization, 1983).
019DCD/A 12-2 8/19/85
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PRELIMINARY DRAFT
Field studies of symptoms and pulmonary function contain elements of both
controlled human exposure studies (Chapter 11) and of epidemiologic studies.
These studies employ observations made in the field along with the methods and
better experimental control typical of controlled exposure studies.
Studies classified here as field studies used exposure chambers but exposed
subjects to ambient air containing the pollutants of interest rather than to
artificially generated pollutants, as well as to clean air as a control. These
studies thus form a bridge or continuum between the studies discussed in the
preceding chapter (Chapter 11) and the epidemiological studies assessed later
in this chapter.
12.2.1 Symptoms and Pulmonary Function in Field Studies of Ambient Air Exposures
Researchers at the Ranches Los Amigos Hospital in California (Linn et
al., 1980, 1982, 1983; Avol et al., 1983, 1984, 1985a,b) have used a mobile
laboratory containing an exposure chamber to study the effects of ambient air
exposures on symptoms and pulmonary function in high-oxidant (Duarte) and
low-oxidant (Hawthorne) areas of the Los Angeles Basin. In these field studies,
pre- and post-exercise measurements of pulmonary function, often used in
controlled human exposure studies, were made to compare the effects of short-
term exposures to ozone and oxidants in ambient air versus clean air (sham
control) exposures. The subject characteristics and experimental conditions
in the respective studies are summarized in Table 12-1. The mobile laboratory
has been described previously (Avol et al., 1979), as have the methods for
studies of lung function.
In 1978 Linn et al. (1980, 1983) evaluated 30 asthmatic and 34 normal
subjects exposed to ambient and purified air in a mobile laboratory in Duarte,
CA, during two periods separated by 3 weeks. Only five subjects were smokers,
and the two groups were similar with respect to the age, height, and sex of
subjects. Asthmatic subjects had heterogeneous disease characteristics, as
determined by questionnaire responses. Of the "normal" group, 25 subjects were
considered allergic based on a history of upper respiratory allergy or reported
undiagnosed wheeze that they called "allergic." 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. Measurements of 0,
by the ultraviolet (UV) method were calibrated against California Air Resources
Board (CARB) reference standards and were corrected to those obtained by the KI
method.
019DCD/A 12-3 8/19/85
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PRELIMINARY DRAFT
TABLE 12-1. SUBJECT CHARACTERISTICS AND EXPERIMENTAL CONDITIONS IN THE MOBILE LABORATORY STUDIES
Year and place of study
Subjects/conditions
Subject characteristics:
Total number
Hales
Asthmatics
Smokers
Avg. age, yr ± SO
Avg. ht, cm ± SD
Avg. wt, kg i SD
64
26
30
5
30
170
70
1978, Duarte3
t 10
± 10
t 14
1979, Hawthorneb
64
26
21
14
34 t
170 ±
69 ±
11
12
16
1980, Duartec
60
45
7
8
30 ±
173 ±
69 ±
11
15
10
98
57
50
7
28
172
67
1981, Duarted
t 8
± 9
± 11
1982, Duarte6
50
42
0
3
26 ±
177 ±
70 ±
7
8
10
1983, Duartef
59
46
2
0
14 i 1
162 ± 13
54 ± 13
Experimental conditions:
Exercise level
Exposure duration
Pollutant concentration,
mean ± SD
03, ppm9
S02, ppm
N02l ppm
CO, ppm
Participate:
light Intermittent
2 hr (p.m.)
0.174 ± 0.068
0.012 ± 0.003
0.069 ± 0.014
2.9 ± 1.1
light Intermittent
2 hr (a.m.)
0.022 ± 0.011
0.018 ± 0.099
0.056 ± 0.033
1.6 ± 0.9
heavy continuous
1 hr (p.m.)
0.165 ± 0.059
0.009 ± 0.005
0.050 ± 0.028
3.1 ± 2.0
heavy continuous
1 hr (p.m. )
0.156 ± 0.055
0.005 ± 0.033
0.062 ± 0.023
2.2 ± 0.7
heavy continuous
1 hr (p.m.)
0.153 ± 0.025
0.006 ± 0.004
0.040 ± 0.016
2.2 ± 0.8
moderate continuous
1 hr (p.m.)
0.144 ± 0.043
0.006 ± 0.001
0.055 ± 0.011
1.1 ± 0.3
Total, ug/m3
SOi, ug/m3
N03, ug/m3
182 ± 42
16 ± 7
h
112 ± 45
13 ± 6
19 ± 10
227 ± 76
17 i 12
22 ± 9
166 ± 52
9 ± 4
32 1 10
295 ± 52
13 ± 8
40 ± 10
152 ± 29
5 1 4
19 ± 4
aL1nn et al. (1980, 1983).
bL1nn et al. (1982, 1983).
GL1nn et al. (1983); Avol et al. (1983).
dL1nn et al. (1983); Avol et al. (1983).
eAvol et al. (1984).
fAvol et al. (1985a,b).
9Ultrav1olet photometer calibration method.
Measurements unsatisfactory due to artifact nitrate formation on filters.
Source: Adapted from Linn et al. (1983).
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PRELIMINARY DRAFT
Ozone and participate pollutants predominated in the ambient air mixture,
as shown in Table 12-1 for the 1978 study (Linn et al., 1980, 1983). Ozone
levels (corrected to the KI method) averaged 427 ug/m (0.22 ppm) inside the
mobile laboratory chamber and 509 ug/m (0.26 ppm) outside the laboratory
during ambient air exposures; and 7.8 ug/m (0.004 ppm) during purified air
exposures. The respective maximum 0., concentrations were 498 ± 186 ug/m
-3
(0.25 ± 0.10 ppm) inside; 597 ± 217 ug/m (0.31 ± 0.11 ppm) outside; and
o
19 ± 17 ug/m (0.01 ± 0.009 ppm) in purified air. Levels of TSP averaged
182 ug/m inside the chamber and 244 ug/m outside the laboratory during
3
ambient air exposures, but 49 ug/m inside the chamber during purified-air
exposures. Average N0?, 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 N0?; 0.009 ppm
for SOp; 2.8 ppm for CO; 0.9 ppm for sulfates). Gases were monitored continu-
ously, with inside and outside air sampled alternately for 5-min periods.
Particles were measured during testing inside and outside the laboratory.
Temperature and humidity were controlled inside the laboratory.
During the exposure studies (Tuesday through Friday), four subjects
(maximum) were tested sequentially in the morning at 15-min intervals, each
first breathing purified air at rest followed by "pre-exposure" lung-function
tests. Ambient-air chamber tests were performed in the early afternoon (after
odors were masked by a brief outside exposure). The ambient-air exposure
period lasted 2 hr and included exercise on bicycle ergometers for the first
15 min of each half-hour; this was followed by "post-exposure" lung function
testing during continuing ambient-air exposure. Ergometer workloads ranged
from 150 to 300 kg-m/min and were sufficient to double the respiratory minute
ventilation relative to resting level. Lung function measures before and
after exposure were compared by t-tests and nonparametric methods. The
purified-air control study for each subject took place at least 3 weeks after
the ambient-air exposure session, with identical procedures except for purified
air in place of the ambient. Note that 12 healthy subjects from the project
staff were tested apart from the study cohort in order to validate various
aspects of the study. The validation tests were performed to determine whether
there were any gross differences in response to indoor and outdoor ambient
exposures. While no significant differences were found in this comparison,
small differences would have been difficult to detect because of the small
number of subjects tested.
019DCD/A 12-5 8/19/85
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PRELIMINARY DRAFT
In the main set of experiments (Linn et al. , 1980, 1983), 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 (L was correlated with decreasing peak flow and 1-sec forced expira-
tory volume (FEV,). No explanation was given for the observed association of
increasing CO with increasing RV and with the slope of the alveolar plateau
(SBNT). Increasing S0? 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 (Vmax25%)'
as well as in the FEV, normalized for forced vital capacity (FEV,/FVC%), TLC,
and pulmonary resistance (R.) in the normal/allergic group. Although other
pollutant variables contributed to the observed effects, none did so consis-
tently. Apart from CL, functional changes on control days (intraindividual
variability), smoking habits, and age appeared to explain the functional
changes in normals/ allergies during exposure. In asthmatics, all pollutant
variables except TSP were significant in one or more analyses, but not all
consistently. Asthmatics and normals/allergies also had significantly increased
symptom scores during ambient air exposure sessions (Figure 12-1).
Nine of 12 subjects from this study (Linn et al., 1980, 1983) known to be
highly reactive to 0, (four from the normal/allergic group and five asthmatics,
a similar proportion from each group), who had experienced a fall in FEV, greater
than 200 ml during ambient exposure (compared to purified-air exposure), under-
went a controlled 2~hr exposure experiment at 392 ug/m (0.2 ppm) with intermit-
tent exercise. Among these nine reactive subjects, the mean FEV, change in the
ambient exposure was -273 ± 196 ml (-7.8 ±6.3 percent of pre-exposure). This
change was significantly greater than the mean change of -72 ± 173 ml (3.1 ±
6.6 percent pre-exposure) in the control setting. Although the authors sug-
gested the possibility that ambient photochemical pollution may be more toxic
than chamber exposures to purified air containing only ozone, other explanations
for the differences were given, including the effect of regression toward the
mean. More direct comparative findings published recently by Avol et al.
(1984) (see following text) showed no differences in response between chamber
exposures to oxidant-polluted ambient air and purified air containing a
019DCD/A 12-6 8/19/85
-------
30
§ 20
10
I I I I
AMBIENT AIR
PURIFIED AIR
I I
I I
PE JC LO
ALL
PE 1C LD
NORMAL
AND
ALLERGIC
PE 1C LD
ASTHMATIC
Figure 12-1. Changes in mean symptom score with
exposure for all subjects, for normal and allergic
subjects, and for asthmatic subjects. PE = pre-
exposure; 1C = in chamber (near end of exposure
period); LD = later in day. Circles (O or •) indicate
total symptom scores; triangles (A or A) indicate
lower-respiratory symptom scores. Solid symbols
indicate that ambient exposure score is significantly
higher for indicated time period and/or increased
significantly more relative to pre-exposure value.
Open symbols indicate that the difference between
ambient and purified air scores was not significant.
Source: Adapted from Linn et al. (1980).
12-7
-------
PRELIMINARY DRAFT
controlled concentration of On. Normal/allergic subjects in the validation
studies also showed similar findings in the exposure chambers compared to the
outside ambient air when the levels were similar inside and out.
Linn et al. (1982, 1983) repeated the initial experiment (Linn et al.,
1980) with 64 different subjects, ages 18 to 55, in Hawthorne, CA, which had
low 03 levels (0.04 ± 0.02 ppm, 82 ± 39 pg/m3) but elevated levels of other
pollutants. They found no statistically significant lung-function or symptom
changes, and they concluded that 03 was primarily responsible for the effects
seen in the original study.
In 1980, a third experiment (Linn et al., 1983; Avol et al., 1983) was
conducted at the original oxidant-polluted location (Duarte) with 60 physic-
ally fit subjects, aged 18 to 55, who exercised heavily (four to five times
resting minute ventilation) and continuously for 1 hr. The mean 0., concentra-
3
tion was 314 ug/m (0.16 ppm) in ambient air (measured by the UV method).
Total reported symptoms did not differ significantly between exposure and
control (purified-air) conditions. For the complete group, small functional
decrements in FEV, were found (3.3 percent loss, P < 0.01), more or less
comparable to those in the original (1978) study. A number of the subjects
showed functional losses during exposure that were still present after a 1-hr
recovery period at rest in filtered air. Those in the most reactive quartile
(those who experienced 320 to 1120-ml losses, versus control) were compared
with the least reactive quartile (increases of 60 to 350 ml). They did not
differ by age, height, sex, smoking, medication use, prevalence of atopy, or
asthma. Negative FEV, changes occurred more frequently (34 of 47 cases) at 0.,
3
exposure concentrations above 235 ug/m (0.12 ppm), up to the maximum observed
(549 |jg/m3; 0.28 ppm) in the total study group (P = 0.02). Even at the upper
end of this range, however, a number of subjects showed no decrement in func-
tion. The authors stated that the marked functional losses measured in the
most reactive subjects in this study were not necessarily accompanied by
symptoms, nor were they related to obvious prior physical or clinical status.
In 1981, a fourth study (Linn et al. , 1983; Avol et al., 1983) presented
data on 98 subjects, including 50 asthmatics, who were exposed in Duarte to
mean 0, levels of 306 ug/m (0.156 ppm) and 166 ug/m TSP (lower than in
3
1980). The highest 03 exposure concentration was 431 ug/m (0.22 ppm), which
was lower than the levels measured in 1982. The subjects were exposed to
heavier, continuous exercise (though lower exercise ventilation levels than in
1980). The normal subjects showed a pattern of forced expiratory changes that
0190CD/A 12-8 8/19/85
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PRELIMINARY DRAFT
were similar to those reported in 1980; however, the mean FEV, decrease with
exposure to ambient air was much smaller. The only significant change reported
for this group was for FVC (P <0.003). The asthmatics had decrements in forced
expiratory performance during both exposures, but the mean FEV.. decrease remained
depressed for up to 3 hr after exposure to ambient air. Maximum mean changes in
FVC and FEV, for asthmatics after exposure to ambient air were 12? ml and 89 ml,
respectively, with the former returning more quickly to control levels. The
value for V ,-,-q; was more variable with a maximum mean change of 132 L/s after
exposure to ambient air. There were also significant interactions of ambient
and purified air after exposure in asthmatics for FEV.. and V r^y.
The subject population was expanded in the summer of 1982 to include
well-conditioned athletes undergoing 1 hr of continuous heavy exercise (six to
ten times resting minute ventilation) (Avol et al., 1984) Volunteer competi-
tive bicyclists (n=50) were exposed in the mobile chamber to purified air
containing 0, 157, 314, 470, and 627 ug/m3 (0, 0.08, 0.16. 0.24, and 0.32 ppm)
0., and to ambient air in the Duarte location. Pollution conditions were
milder than in previous summers so that comparable ambient exposure data were
available for only 48 subjects (Table 12-1). Mean concentrations during
o
ambient exposures were 294 ug/m (0.15 ppm) 0, with a range of 235 to 372
3 3
ug/m (0.12 to 0.19 ppm) and 295 ug/m total suspended participate matter
(TSP). Mean particulate nitrate and sulfate concentrations were 40 ug/m and
13 ug/m', respectively. For the controlled exposure studies, no functional
3
decrements in FEV. were found at 0 or 157 ug/m (0 or 0.08 ppm) 0,; however,
3
statistically significant decrements were found at 314, 470, and 627 ug/m
(0.16, 0.24, and 0.32 ppm) 0., (See Chapter 11). Symptom increases generally
paralleled the FEV.. decrements. Statistically significant decrements in FEV,
were also observed during the ambient exposure studies (5 percent) and were
not significantly different from those obtained with 0.16 ppm 0,. Comparisons
on an individual basis showed that ambient exposure responses differed only
randomly from predictions based on the generated 03 concentration-response
information. Symptom increases during ambient exposure were slightly less
than predicted. Thus, no evidence was found to suggest that any pollutant
other than 0^ contributed to the observed effects produced by ambient air.
The mobile laboratory was used again in Duarte, CA, during the
summer of 1983 to determine if younger subjects were affected by exposure to
ambient levels of photochemical oxidants. Avol et al. (1985a,b) studied
forced expiratory function and symptom responses in 59 healthy adolescents,
019UCD/A 12-9 8/19/85
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PRELIMINARY DRAFT
12 to 15 years of age (Table 12-1). Each subject received a screening exami-
nation including medical history, pulmonary function tests, resting EKG, and
exercise stress test. All subjects denited smoking regularly. Fifteen of the
subjects had a history of allergy and two of the subjects gave a history of
childhood asthma but denied recent asthmatic symptoms. The subjects were
randomly exposed to purified air and to ambient air containing 282 ug/m (0.144
3
ppm) 0^ and 153 ug/m total suspended particulates while continuously exercising
on bicycle ergometers at moderate levels (VV = 32 L/min) for 1 hr. Pulmonary
function tests were performed pre- and post-exposure. Symptoms were recorded at
15-min intervals and immediately post-exercise. Following the exposure period,
the subjects rested in purified air for 1 hr, after which symptoms and pulmonary
function were measured again. After ambient exposure, there were statistically
significant decrements in FVC (2.1 percent), FEVQ -,,. (4.0 percent), FEV, Q
(3.7 percent), and PEFR (4.4 percent) relative to control exposure. Although
some reversal of these changes was evident at 1 hr post-exposure, decrements in
pulmonary function were still present compared to the preexposure levels. A
linear regression analysis showed that individual FEV, „ responses were
negatively correlated (r = 0.37, P <0.01) with individual ambient 03 exposure
concentrations. Analysis of the data set revealed no significant differences
in responses between the fifteen "allergic" subjects and the rest of the
group. In addition, although girls tended to show larger decreases in FEV. ~
with ambient exposure than boys (7.5 percent and 3.4 percent, respectively),
the difference was not statistically significant. The authors attributed the
lack of significance as possibly due to the small number (n = 13) of girls in
the study. There were no significant increases in symptoms with ambient
exposure relative to control. The lack of symptoms in adolescents at ambient
0., concentrations that produce statistically significant decrements in pulmonary
3
function is an interesting and potentially important observation from this
study, since adults exposed in the mobile laboratory under similar conditions
report symptoms of lower respiratory irritation accompanying decrements in
forced expiratory function (Linn et al., 1980, 1983; Avol et al., 1983, 1984).
Factors contributing to the differences in response between adolescents and
adults are not yet known.
12.2.2 Symptoms and Pulmonary Function in Field or Simulated High-Altitude
Studies
Early reports of high 0., concentrations in aircraft flying at high alti-
0190CO/A 12-10 8/19/85
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PRELIMINARY DRAFT
tudes prompted a series of field and high-altitude simulation studies. In
1973, Bischof reported that 0., concentrations (measured by a Comhyr ECC meter)
during 14 spring polar flights (1967-1971) varied from 0.1 to 0.7 ppm, with
1-hr peaks above 1.0 ppm occurring, despite ventilation. More recently, Daubs
(1980) reported 0., concentrations in Boeing 747 aircraft ranging from 0.04 to
0.65 ppm, with short-term (2 to 3 min) levels as high as 1.035 ppm. Other
reports (U.S. House of Representatives, 1980; Broad, 1979) have indicated that
0, concentrations in high-altitude aircraft can reach excessively high levels;
for example, on a flight from New York to Tokyo a time-weighted concentration
of 0.438 ppm was recorded, with a maximum of 1.689 ppm and a 2-hr exposure of
0.328 ppm.*
Flight attendants and passengers in high-altitude aircraft have complained
of certain symptoms (chest pain, substernal pain, cough), which are identical to
those typically reported in subjects exposed to 0., and other photochemical oxi-
dants (see 12.3.1.1). The symptoms were most prevalent during late winter and
early spring flights. Similar symptoms have also been observed in more systematic
studies of high-altitude effects, such as (1) the study by Reed et al. (1980), in
which symptoms among 1,330 flight attendants were found to be related to
aircraft type and altitude duration but not to sex, medical history, residence,
or years of work; and (2) the Tashkin et al. (1983) study, in which increased
0,-related symptoms were reported by flight attendants on Boeing 747SP (higher-
altitude) flights in comparison to attendants on lower-flying 747 flights. In
neither of these two studies, however, were concentrations of 0, or other
photochemical oxidants measured in the aircraft.
In a series of altitude-simulation studies, Lategola and associates
(1980a,b) attempted a more quantitative evaluation of effects on cardiopulmonary
function and symptoms associated with CL exposures of male and female flight
attendants, crew, and passengers. Two studies (Lategola et al., 1980a) were
conducted on young surrogates of a mildly exercising flight attendant popula-
tion, while a third study (Lategola et al., 1980b) evaluated older surrogates
*Note that, as ambient pressure decreases at high altitude, 03 concentra-
tions remain the same as expressed in terms of ppm levels, but 03 mass concen-
trations (in ug/m3) decrease in direct proportion to increasing altitudes.
Therefore, knowledge of prevailing atmosphere pressure and temperature is
generally needed for correct conversion of ppm 03 readings to ug/m3 03 concen-
trations under specific measurement conditions.
019DCD/A 12-11 8/19/85
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PRELIMINARY DRAFT
for sedentary airline passengers and cockpit crew. All studies simulated
in-flight environmental conditions at 1829 m (6000 ft) and all subjects served
as their own controls. The studies tended to confirm the occurrence of small
but significant respiratory effects at 475 (jg/m (0.3 ppm) of 0, among nonsmok-
ing normal adults under high-altitude conditions. It should be noted that the
0~ levels used in the Lategola studies are generally lower than 0., concen-
trations reported to occur in certain aircraft at high altitudes, as are the
simulated altitudes employed in the studies.
12.3 EPIDEMIOLOGICAL STUDIES OF EFFECTS OF ACUTE EXPOSURE
Effects of the acute exposure of communities to photochemical oxidants
are generally assessed by comparing the functional or clinical status of
residents during periods of high and low 03 or oxidant concentrations. Occa-
sionally, two or more communities with different concentrations are compared.
The concentrations measured have been 24-hr averages, maximum hourly averages,
or instantaneous peaks.
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 healthy subjects and in patients with asthma and other
chronic lung diseases; and effects on pulmonary function, athletic performance,
auto accident rates, school absenteeism, and hospital admissions.
12.3.1.1. Symptom Aggravation in Healthy Populations. Various symptoms,
including eye irritation, headache, and respiratory irritation, have been
reported during ambient air exposure in a number of studies (Table 12-2). Eye
irritation, however, has not been associated with 0., exposure in controlled
laboratory studies (Chapter 11). This symptom has been associated with other
photochemical oxidants such as peroxyacetyl nitrate (PAN) and with formaldehyde,
acrolein, and other organic photochemical reaction products (National Air
Pollution Control Administration, 1970; Altshuller, 1977; U.S. Environmental
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. It also appears
to be a short-term, reversible effect, however, since damage to conjunctiva
and subjacent tissue has not been reported.
019DCD/A 12-12 8/19/85
-------
PRELIMINARY DRAFT
TABLE 12-2. SYMPTOM AGGRAVATION IN HEALTHY POPULATIONS EXPOSED TO PHOTOCHEMICAL OXIDANT POLLUTION
Concentratlon(s)
ppm
0.08-0.50 max 1-hr/day
(1954)
0.04-0.78 max 1-hr/day
(1955)
0.05-0.49 max 1-hr/day
(1956)
Pollutant
Study description
Oxldant Panel studies of office and factory
workers 1n Los Angeles during 1954-
1956.
Results and comments Reference
Eye Irritation Increased with oxidant concen- Renzettl and Gobran, 1957a
tratlon; no discrete oxidant threshold.
Although oxidants explained a higher propor-
tion of the variation 1n eye Irritation,
other pollutants were associated with this
symptom.
<0.27 (@ 11:00 a.m.
~ dally)
Oxtdant Effectiveness of air filtration for
removing eye Irritants In 40 female
telephone company employees over 123
work days In Los Angeles from May to
November 1956.
Increased eye Irritation associated with
oxidant concentration and temperature In
the nonflltered room; severity Increased
above 0.10 ppm. No correlations with N02
or PM; however, other pollutants were not
measured.
Richardson and Htddleton,
1957a, 1958a
I
M
C.)
<0.04-0.50
max 1-hr/day
Oxidant Symptom rates from dally diaries of
students at two nursing schools 1n
Los Angeles from October 1961 to
June 1964. Maximum hourly oxidant
concentrations from two monitors
located within 0.9 to 2 miles of
both hospitals.
Eye discomfort reported at oxidant levels
between 0.15 and 0.19 ppm, cough at 0.30
to 0.39 ppm, headache and chest discomfort
at 0.25 to 0.29 ppm. Symptom frequencies
related more closely to oxidants than CO,
N02, or temperature, although rigorous statis-
tical treatment Is lacking.
Hammer et al., 1974a
<0.3 max l-hr(?)/day
Oxidant Dally symptom rates from 854 students
1n Tokyo during July 1972 to June
1973. Measurement methods for oxidant,
NO, N02, S02, and PM were not reported.
Highest correlations reported between symp-
toms and oxidants; Increased rates for eye
Irritation, cough, headache, and sore throat
on days with max. hourly oxidant >0.10 ppm;
no significant correlations with S02, N02 or
NO, although some symptoms were correlated with
temperature. Effects of acute respiratory
Illness were not considered; measurement meth-
ods not reported.
MaMno and Mlzoguchl, 1975a
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PRELIMINARY DRAFT
TABLE 12-2 (continued). SYMPTOM AGGRAVATION IN HEALTHY POPULATIONS EXPOSED TO PHOTOCHEMICAL OXIDANT POLLUTION
Concentratlon(s)
ppm
Pollutant
Study description
Results and comments
Reference
0.07-0.19
max 1-hr/day
0x1 dant Questionnaire survey on subjective
symptom rates at two junior high
schools In Osaka, Japan during the
fall of 1972.
Symptoms classified as (a) eye Irritation,
(b) cough and sore throat, and (c) nausea,
dizziness, and numbness of the extremities;
symptom rate and distribution correlated with
physical exercise. Findings point out vari-
able symptom distribution from multiple
pollutants 1n ambient air.
Shlmlzu, 1975a
<0.39 max
(undefined)
Oxidant
Survey of student health during 180
days 1n 1975.
Number of students reporting symptoms
Increased with Increasing oxidant concen-
tration. No symptom rates reported;
questionnaire use presented likely bias;
other pollutants were not considered.
Japanese Environmental
Agency, 1976a
<0.23
max 1-hr/day
Oxidant Questionnaire survey on subjective
symptoms In 515 students at a junior
high school In Tokyo from May to
July 1974; maximum hourly oxidant
concentrations by KI.
Differences between high- and low-oxldant
days 1n symptom rates for eye Irritation
and lacrlmatlon, sore throat, and dyspnea.
Other pollutants, particularly S02, SO ,
or acroleln, may have been contributing
factors.
Increased symptom rates for eye Irritation,
sore throat, headache, and cough on days with
oxidant >0.15 ppm compared to days with oxi-
dant <0.10 ppm. Some symptoms were corre-
lated with S02, PM, and rh; however, not all
possible environmental variables were consi-
dered.
Shlmlzu et al., 1976°
Hlzoguchl et al.. 1977a
0.02-0.21 dally
maxima
(undefined)
Oxidant Association between eye Irritation
and photochemical oxldants In 71
Tokyo high school students for 7 days
during two summer sessions; dally
maximum oxidant concentrations by KI;
tear lysozyme, pH, and eye exam
measured dally.
Tear lysozyme and pH decreased on two highest
oxidant days compared to two lowest oxidant
days; eye Irritation Incidence rates Increased
with oxidant concentrations >0.1 ppm; eye
Irritation produced by HCHO, PAN, and PBZN.
Okawada et al., 1979
Reviewed 1n U.S. Environmental Protection Agency (1978).
-------
PRELIMINARY DRAFT
Qualitatively, the occurrence of an association between photochemical
oxidant exposure and symptoms such as cough, chest discomfort, and headache is
plausible, given similar findings of occupational exposure to oxidants (see
12.3.1.7) and of controlled human exposure studies (Chapter 11). The primary
issues in question, however, in the studies cited in Table 12-2, are: (1) the
composition of the mixture to which the subjects were exposed; (2) the concen-
trations and averaging times for oxidants in ambient air; and (3) the adequacy
of methodologic controls for other pollutants, meteorological variables, and
non-environmental factors in the analysis. For these reasons, the studies are
of limited use for developing quantitative exposure-response relationships for
ambient oxidant exposures.
12.3.1.2 Altered Performance. The possible effects of photochemical oxidant
pollution on athletic and driving performance have been examined in studies
described in Table 12-3. The absence of definitive monitoring data for impor-
tant pollutants as well as confounding by environmental conditions such as
temperature and relative humidity detracts from the quantitative usefulness of
these studies. Qualitatively, however, the epidemiological findings relative to
athletic performance are consistent with the evidence from controlled human
exposure studies indicating that exercise performance may be limited by exposure
to 03 (Chapter 11).
12.3.1.3 Acute Effects on Pulmonary Function. A summary of studies on the
acute pulmonary function effects of photochemical oxidant pollution is given
in Table 12-4. Previously reviewed studies (U.S. Environmental Protection
Agency, 1978) suggested a possible association between decrements in pulmonary
function in children and ambient ozone concentrations in Tucson, Arizona (Lebowitz
et al., 1974) and Tokyo, Japan (Kagawa and Toyama, 1975; Kagawa et al., 1976).
An additional study (McMillan et al., 1969) comparing acute effects in children
residing in high- and low-oxidant areas of Los Angeles failed to show any
significant differences in pulmonary function. None of these studies, however,
meets the criteria necessary for developing quantitative exposure-response
relationships for ambient ozone exposures.
Lippmann et al. (1983) studied 83 nonsmoking, middle-class, healthy
children (acjes 8 to .13) during a 2-week summer day camp program in Indiana,
PA. The children exercised outdoors most of the time. Afternoon measurements
included baseline and post-exercise spirometry (water-filled, no noseclips).
@
Peak flow rates were obtained by Mini-Wright Peak Flow Meter, a technique
validated by Lebowitz et al. (1982b), at the beginning of the day or at lunch,
019DCD/A 12-15 8/19/85
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PRELIMINARY DRAFT
TABLE 12-3. ALTERED PERFORMANCE ASSOCIATED WITH EXPOSURE TO PHOTOCHEMICAL OXIDANT POLLUTION
Concentration(s)
ppm
Pollutant
Study description
Results and comments
Reference
0.03-0.30
max 1-hr/day
0 06-0.38
max 1-hr/day
Oxidant Athletic performance of student
cross-country track runners in
21 competitive meets at a high
school in Los Angeles County
from 1959 to 1968. Daily maximum
hourly concentrations of oxidants,
NO, N02, CO, and PM by LA-APCD.
Data extended to include the seasons
of 1966 to 1968.
Percentage of team members failing to improve their
performance increased with increasing oxidant
concentration in the hour before the race; however,
convincing individual linear relationships were not
demonstrated.
Inverse relationship between running speed and
speed and oxidant after correcting for average
speed, time, season, and temperature. No correla-
tion with NO , CO, or PM; however, S02 was not
examined. x
Wayne et al. , 1967
Herman, 1972
0.02-0.24
max 1-hr/day
Oxidant Association of automobile acci-
dents with days of elevated
hourly oxidant concentrations
in Los Angeles from August
through October for 1963 and
1965.
Association of automobile acci-
dents in Los Angeles with elevated
oxidant concentrations from the
summers of 1963 and 1965 and
with CO concentrations from the
winters of 1964-1965 and 1965-
1966.
Accident rates were higher on days with hourly
oxidant levels >0.15 ppm compared to days <0.10
ppm. Other pollutants were not evaluated.
Sample size reduced by excluding accidents in-
volving alcohol, drugs, mechanical failure, rain,
or fog.
Strong relationship between accident rates and
oxidant levels; temporal pattern suggests
the importance of oxidant precursors; no
consistent relationship with lagged oxidant
concentration or with CO concentrations. Other
pollutants, possibly NO and SO , may have
confounded the association, questionable effect
of traffic density.
Ury, 1968
Ury et al., 1972a
0.004-0.135
avg time-weighted
15-min max
Ozone Pulmonary function of healthy aaults
exercising vigorously at a high
school track near Houston, TX during
May-October, 1981. Continuous moni-
toring of 03 (CHEM), S02, N02, CO,
temperature, and rh at the track
averaged over 15-min intervals
during the time of running; 12-hr
averages for fine inhalable
particulates.
Simple linear regression analysis showed a significant
association between decreased lung function and in-
creasing 03 concentration; however, after adjusting
for rh, the changes were no longer statistically signi-
ficant. Weighted multiple linear regression analysis
adjusted for temperature and rh was not significant for
03. Other pollutants were not considered.
Selwyn et al., 1985
Reviewed in U.S. Environmental Protection Agency (1978).
-------
PRELIMINARY DRAFT
TABLE 12-4. ACUTE EFFECTS OF PHOTOCHEMICAL OXIDANT POLLUTION ON PULMONARY FUNCTION OF CHILDREN AND ADULTS
Concentratlon(s)
ppm
Pollutant
Study description
Results and comments
Reference
0.01-0.67
dally maxima
(undefined)
Oxldant Comparison of ventllatory performance
1n two groups of third-grade children
residing In high (n=50) and low (n=28)
oxidant areas of Los Agneles from
November 1966 to October 1967.
No correlation between acute effects on PEFR
(Wright Peak Flow Meter) and oxidant concen-
centratlons; however, persistently higher
PEFR and greater variance were obtained
from the children residing In the high oxidant
area; possible confounding by respiratory
Infections.
McMillan et al.
1969a
0.01-0.12 range
of hourly averages
for 1 day
Oxidant Combined effects of air pollution and
weather on the ventllatory function
of exercising children, adolescents,
and adults 1n Tucson, Arizona during
the spring and summer of 1972.
Significant post-exercise decreases In lung
function were observed In adolescents but not
adults; however, differences In exercise
regimens suggest a possible exercise effect.
Monitors recording hourly peak oxidant con-
centrations for adolescents and adults were
at least 3 miles away; no oxidant data given
for children's study. TSP may have contri-
buted to the observed effect.
Lebowltz et al.
1974a
0.01-0.15
u-j max 1-hr/day
, 0.03-0.17
1 max 1-hr/day
Ozone Effects of environmental factors on
the pulmonary function of 21 children,
aged 11 yrs, at an elementary school
Oxidant 1n Tokyo, Japan from June to December
1972; hourly average concentrations
of oxidant (NBKI), 03 (CHEM), N02, NO,
HC, and PM measured on top of the three-
story school.
Pulmonary function correlated with temperature
far more than any other environmental variable;
03, NO, S02, and HC were the pollutants most
frequently correlated with changes In pulmonary
function; 03 was correlated with Raw, SGaw, and
FVC In only 25% of the subjects. Partial
analyses after correcting for temperature
reduced the number of significant
correlations.
Kagawa and Toyama,
1975a
<0.30 averaged over
each 2-hr study
period
Ozone Effects of high- and low-temperature
seasons on the pulmonary function of
19 children at an elementary school 1n
Tokyo, Japan from November 1972 to October
1973; hourly average concentrations of
03, NO, N02, S02, and PM were measured
at the school.
Temperature was positively correlated with
Raw, Vso, and V2S, and negatively correlated
with SGaw; however, the effect of temperature
on Raw was season-dependent. 03 was positively
correlated with Raw and negatively correlated
with SGaw In both high- and low-temperature
seasons; however, correlations were more consis-
tent 1n the low-temperature period when 03 was
lowest (<0.10 ppm); partial analyses after
correcting for temperature still revealed signi-
ficant 03 correlations with Raw. Five subjects
showed correlations of function and multiple
environmental factors, Indicating selective
sensitivity In the population.
Kagawa et al.
1976a
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PRELIMINARY DRAFT
TABLE 12-4 (continued). ACUTE EFFECTS OF PHOTOCHEMICAL OXIDANT POLLUTION ON PULMONARY FUNCTION OF CHILDREN AND ADULTS
Concentration(s)
ppm
Pollutant
Study description
Results and comments
Reference
0.046-0.122
max 1-hr/day
Ozone Effects of ambient photochemical oxidant
exposure on pulmonary function of 83
children (aged 8 to 13) at a 2-week
day camp in Indiana, PA during the summer
of 1980; 1-hr peak 03 concentrations were
estimated by regional exposure modeling
techniques; 6-hr ambient TSP and H2S04
were monitored at the campsite.
Significant relationship for peak flow
(Wright Peak Flow Meter) and daily peak 0,
for 23 children; FVC and FEVL were
significantly lower on 1 day when the 0^
peak was 0.11 ppm compared to days when the
0, peak was <0.08 ppm. Analysis of regres-
sion slopes does not demonstrate any conclusive
associations for sex, other pollutants, or
ambient temperature. Questionable exposure
modelling raises uncertainty about the
quantitative interpretation of these results.
Lippmann et al.
1983°
0.09-0.12
max 1-hr/day
rs:
CO
Ozone As part of a community population sample
of 117 families from Tucson, AZ, venti-
latory function was studied in 24 healthy
children and young adults (aged 8 to 25
yrs) for an 11-month period in 1979 and
1980; 1-hr maximum concentrations of
03 (CHEM), N02, CO, and daily levels of
TSP, allergens, and weather variables
were monitored at central stations within
!} mile of each cluster of subjects.
Correlation of peak flow (Wright Peak Flow
Meter) with average maximum hourly 03 was not
significant; after correcting for season and
other pollutants, 03 and TSP were negatively
correlated with peak flow; use of multifactor
analysis to control for person days, weather
variables, CO, N02, and TSP showed significant
independent correlations of 03 with peak flow
and significant interactions between 03 and TSP
and 03 and temperature. Regressions of resi-
dual and predicted Vmax with 03 were also
significant. Small number of subjects and
interaction with other environmental condi-
tions limit the quantitative interpretations
of these studies.
Lebowjtz et al.
19836;
Lebowitz, 1984
0.02-0.14
max 1-hr/day
Ozone Effects of ambient photochemical oxidant
exposure on pulmonary function of healthy
active children (aged 7 to 12) at a summer
day camp in Mendham, NJ from July 12 to
August 12, 1982; state regional pollution
monitoring of 03 (CHEM), TSP (H , S04,
and N03), temperature, and rh at a station
6 km from the camp.
Linear regression and correlation coefficient
analyses between 03 and pulmonary function (FVC,
FEV, PEFR, and MMEF) showed a significant asso-
ciation for PEFR only. Girls appeared to be more
susceptible than boys but there was no statistical
treatment of the differences. Large variability
in regression slopes suggests effects from other
environmental conditions (temp, S04, H ); results
of aerosol sampling were not reported and other
pollutants were not considered. Lack of signi-
ficant effect for FEV, and FVC which have lower
coefficients of variation than PEFR is question-
able. In addition, difficulty in judging the
relationship between 03 and acid sulfates or
other environmental conditions limits the
quantitative use of these studies.
Lippmann and Lioy
lnQ,D.
1985"; Lioy et al.
198Sb.
Reviewed in U.S. Environmental Protection Agency (1978).
See text for discussion.
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PRELIMINARY DRAFT
adjusted for both age and height. No day-of-week effect was seen. Ambient
air levels of TSP, hydrogen ions, and sulfates were monitored by a high-volume
sampler on the rooftop of the day camp building. Ozone concentrations 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 0- estimates
3
within ±16 ug/m (0.008 ppm) on the average. Estimated 1-hr peak 0, levels
o •*
(early afternoon) varied from 90 to 249 ug/m (0.046 to 0.122 ppm), and TSP
levels were <103 ug/m (6-hr samples) and maximum sulfuric acid (FLSO,) con-
3
centrations were £6.3 ug/m .
Lippman et al . (1983) reported significant inverse correlations between
FVC and FEV, and estimated maximum 1-hr 0., levels for 4 or more days on which
03 concentrations covered a twofold range. Differences in correlations (i.e.,
slopes) were not related to other pollutants (TSP, H?SO.) or ambient tempera-
tures. Qualitatively, the Lippmann et al. (1983) study results suggest low-level
0^ effects; however, because exposure modeling (rather than on-site monitoring)
was used to estimate 0, levels, and because the effects were seen almost
entirely on one day of the study, there is uncertainty about the precise
quantitative interpretation of these findings.
A similar group of children was studied during the summer at a day camp
in Mendham, NJ (Lippman and Lioy, 1984; Bock et al., 1985; Lioy et al., 1985).
Pulmonary function data were obtained from the children, aged 7 to 13 years,
during 16 days of a 5-week period from July 12 to August 12, 1982. In order
to provide better air monitoring data, 0_ concentrations were measured (UV) at
the Mendham camp site and at a NJ sampling station 3.5 mi away. Only data
from the sampling station were used in the analysis. The average highest peak
1-hr 0, concentration measured on a study day was 280 ug/m (0.143 ppm);
3
values ranged from 39 to 353 ug/m (0.02 to 0.18 ppm) 0.,. Daily averages for
ambient temperature, relative humidity, and precipitation were provided by the
National Weather Service. Ambient aerosol samples were also analyzed on a
daily basis, but the results were not reported. A linear regression was
calculated for each child between peak 1-hr 03 and each of four measures:
FVC, FEV,, PEFR, and MMEF. In addition, a summary weighted correlation coeffi-
cient was calculated for all subjects. No adjustments were made for covariates.
Linear regressions were negative except for FVC in boys. Decrements in PEFR
were significantly correlated with peak 0, exposure but there were no significant
correlations with FVC, FEV. or MMEF.
019DCD/A 12-19 8/19/85
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PRELIMINARY DRAFT
Several comparisons can be made between the data reported by Lippmann et
al. (1983) and those reported by Lippman and Lioy (1984), Bock et al. (1985),
and Lioy et al. (1985). There were 39 children (22 girls, 17 boys) in the
follow-up study for whom sufficient data existed for linear regression analysis.
The children in Mendham, NJ, were not as physically active as the children
studied in the previous study in Indiana, PA, which may account for some
observed differences in results from the two studies. While CL-dependent
changes in PEFR were reported in both studies, the authors did not observe the
0,-dependent change in FVC and FEV, in the follow-up study that they found in
the previous study. This lack of a significant effect for FVC and FEV,, which
are known to have smaller coefficients of variation than PEFR, is surprising,
especially considering the higher 0., concentrations reported in Mendham, NJ.
J '
Concentrations of inhalable particulate matter were also reported to be higher
in association with a large-scale regional photochemical smog episode which may
have had some effect on baseline lung function (Lioy et al., 1985). In addition,
adjustments for covariates such as temperature and relative humidity, which might
influence lung function, would have strengthened the reported results. The diff-
erences in transient reponses to 0.,, the lack of definitive exposure data for
other pollutants (particularly ambient aerosols), and the lack of adjustment for
covariates limit the usefulness of these studies for determining quantitative
exposure-response relationships for 0,.
Lebowitz et al. (1983) and Lebowitz (1984) measured daily lung function
in 24 Tucson, AZ, residents, aged 8 to 25 years. The subjects were part of a
stratified sample of families from geographic clusters of a large community
population under study. Over an 11-month period in 1979 and 1980, randomly
chosen subsets of these subjects were tested during each season of the year.
®
Measurements of peak flow were made in the late afternoon, using a Minn-Wright
Peak Flow Meter (Wright, 1978; Williams, 1979; van As, 1982; Lebowitz et al.,
1982b). All age- and height-adjusted baseline peak flows were within the
published normal range. To adjust for seasonal effects and for inter-individual
differences in means and variances, the daily peak flow for each person was
transformed into a standard normal variable. Seasonal means and standard
deviations were then used to generate daily z-scores, or standardized deviations
from seasonal averages.
Regional ambient 03 (measured by UV), CO, and NO,, were monitored daily at
three sites in the Tucson basin (Lebowitz et al., 1984). Every 6 days, 24-hr
TSP was measured at 12 sites, including stations at the center of each cluster
019DCD/A 12-20 8/19/85
-------
PRELIMINARY DRAFT
of subjects within a 0.25- to 0.5-mi radius. Since previous ambient monitoring
showed significant homogeneity of 0, in the basin, average regional values were
used for analysis of all geographic clusters, and closest-station values for
individual clusters. Comparisons showed no significant changes in results when
using regional averages or closest daily hourly maximum values. Indoor and
outdoor monitoring was conducted in a random cluster sample of 41 representative
houses. Measurements of air pollutants, pollen, bacilli, fungi, algae, tempera-
ture, and humidity were recorded once in each home for 72 hr during the two-year
study period. Regional daily ambient maximum hourly 0, went up to 239 ug/m
(0.12 ppm) and was highest in the summer months. Indoor 0, concentrations
3
were between 0 and 69 ng/m (0 and 0.035 ppm). Levels of CO were less than
2.4 ppm (2736 g/m3) indoors and 3.8 to 4.9 ppm (4332 to 5586 g/m3) outdoors.
Indoor CO was correlated with gas-stove use only. Daily average ambient N0?
ranged from 0.001 to 0.331 ppm (2 to 662 ug/m3). Outdoor TSP ranged between 20
3 3
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) ranges
3 3
were 5.7 to 68.5 ug/m and 0.1 to 49.7 ug/m , respectively, and were correlated
with indoor cigarette smoking but not gas-stove use.
In a preliminary analysis, 0^ and TSP levels were negatively correlated
with peak flow, after correction for season and other pollutants. In a multi-
variate analysis of variance, controlling for person-days of observation,
meteorologic factors, CO, N0?, and TSP, a significant effect of 0~ on peak
flow remained (p <0.001). A significant interaction of 0., with TSP was also
observed (z-scores more negative than predicted by an additive model at high
0^ and TSP levels). In multiple regression analyses, the z-scores for person-
days with maximum hourly 0, level and mean 0., level of at least 0.08 ppm were
statistically significant (p <0.007 and p <0.0001, respectively). These
scores represented decreases in mean peak flow of 12.2 percent and 14.8 percent,
respectively. These changes were significantly different (p <0.05) from
changes reported in previously published data (Lebowitz et al., 1982b) on
normal day-to-day variation in another, comparable group of children.
Lebowitz et al. (1983) and Lebowitz (1984) observed a consistent short-
term effect of ambient ozone exposure on peak flow. The quantitative usefulness
of the study, however, for standard setting is limited by several factors.
Sample sizes were small in relation to the number of covariates. The fixed-
station aerometric data employed did not allow quantitation of individual
ambient pollution exposures. Likewise, since the time spent indoors and out-
019DCD/A 12-21 8/19/85
-------
PRELIMINARY DRAFT
doors was not measured in the children, the proper relative weights of indoor
and outdoor pollution measurements could not be determined for quantisation of
exposure.
12.3.1.4 Aggravation of Existing Respiratory Diseases. A number of studies
have examined the effects of photochemical oxidants on symptoms and lung
functions of patients with asthma, chronic bronchitis, or emphysema. Most of
the earlier studies were evaluated in the 1978 EPA criteria document for ozone
and other photochemical oxidants (U.S. Environmental Protection Agency, 1978).
The results of these as well as more recent studies are summarized in Table
12-5.
For 10 weeks from July to September 1976, Zagraniski et al. (1979) followed
82 patients with asthma or hay fever (patient group) and 192 healthy telephone
company employees (worker group) in New Haven, CT. Subjects were asked to
complete daily symptom diaries, which were distributed and collected weekly.
The groups differed in their distributions of age, gender, smoking history,
and job type, though these variables, as well as ethnic group, appear to have
been controlled in the statistical analysis.
Air pollution was monitored at two downtown sites 1.2 km apart. Concen-
trations of SCL, TSP, sulfates (from dried glass-fiber filters), and CL (by
chemiluminescence) were measured, as was the pH of filter samples (using KC1
in distilled water). Previously measured NO,, and CO levels had been low.
Daily maximum temperature was treated as a covariate. Maximum hourly 0,
3 3
levels ranged from 8 to 461 (jg/m (0.004 to 0.235 ppm) and averaged 157 ug/m
(0.08 ppm). Eight- and 24-hour mean TSP levels were 83 and 73 ug/m , respec-
tively. The 24-hour mean SO. level was 12.5 (jg/m . Ozone and 50^ peaks often
occurred simultaneously. Reported outdoor exposure, working, and home condi-
tions were judged to be equivalent for most subjects for most pollutants.
The data were analyzed by pairwise correlation and multiple regression,
in which daily symptom prevalence was the dependent variable. Few associations
of symptoms with pollution levels were observed. The maximum hourly 0~, however,
was positively and significantly correlated (p <0.05) with cough and nasal
irritation in heavy smokers, with cough in hay fever patients, and with nasal
irritation in asthmatics. In multiple regression analysis, the 0., level was
associated with cough and eye irritation in heavy smokers, and with cough in
hay fever patients. Cough frequency increased linearly with maximum hourly 0.,
levels, particularly in heavy smokers and in subjects with pre-existing illness.
Filter pH was negatively associated with eye, nose, and throat irritation in
019DCD/A 12-22 8/19/85
-------
PRELIMINARY DRAFT
TABLE 12-5. AGGRAVATION OF EXISTING RESPIRATORY DISEASES BY PHOTOCHEMICAL OXIOANT POLLUTION
Concentratlon(s)
ppm
Pollutant
Study description
Results and comments
Reference
0.2-0.7
max 1-hr/day
0.20-0.53
max 1-hr/day
Oxldant Effects of air filtration on pulmonary
function of 47/66 subjects with emphysema
staying for variable times In a Los Angeles
Ozone hospital during a 3^ yr period In the late
1950's; dally maximum hourly concentrations
of oxtdant, 03, NO, N02, S02, and CO by
LA-APCO.
Improved lung function In eraphysematous
subjects staying 1n the filtered room for
>40 hr; lack of control for smoking and
other pollutants.
Motley et al.
1959*
0.13 median
Oxldant Dally records of the times of onset and
severity of asthma attacks of 137 asthmatics
residing and working 1n Pasadena, California
between September 3 and December 9, 1956;
dally maximum hourly average oxidant levels
(KI) from LA-APCD.
Of the 3435 attacks reported, <5% were asso-
ciated with smog and most of these occurred 1n
the same Individuals; time-lagged correlations
were lower than concurrent correlations; mean
number of patients having attacks on days
>0.25 ppm was significantly higher than days
<0.25 ppm.
Schoettlln and
Landau, 1961
(Not reported)
Oxldant Effects of community air pollution,
occupational exposure to air pollution, and
smoking on armed forces veterans with chronic
respiratory disease In the Los Angeles
Basin between August and December 1958;
total oxldant (KI) measured at the site.
No statistically significant effect of air
pollution on respiratory function or symptoms.
Schoettlln, 1962
<0.42 peak
(undefined)
Oxldant Longitudinal study of the effects of environ-
mental variables on pulmonary function of 31
patients with chronic respiratory disease
(predominantly emphysema) 1n a Los Angeles
hospital over a period of 18 months; total
oxldants (KI), 03, NO, N02, CO, PM, and
environmental conditions monitored at a
station >t mile upwind from the hospital.
No consistent pattern of response to episodes
of high pollution exposure; possibility of
selective sensitivity In some subjects.
Unknown measurement method for oxldants. This
was only a preliminary study.
Rokaw and Massey,
1962a
<0.2 peak
(undefined)
Oxldant Effects of air filtration on pulmonary
function of 15 patients with moderately
severe COLD In a Los Angeles County
Hospital between July 1964 and February
1965; total oxldant (KI), NO, and N02
monitored five times dally.
Raw decreased and P 02 Increased 1n both Remmers and
smokers and nonsmokers after 48 hr In the Balchum, 1965 ;
filtered room. Decreases 1n Raw were more Balchum, 1973;
strongly related to oxldants than N02 or NO; Ury and Hexter,
however, study lacks rigorous statistical 1969
treatment. Questionable effects of smoking
and other pollutants.
0.09-0.37 maxima
(undefined)
Ozone Dally diaries for symptoms and medication
of 45 asthmatics (aged 7-72 yr) residing
1n Los Angeles from July 1974 to June 1975;
daily average concentrations of 03, NO,
N02, S02, and CO by LA-APCD within the
subjects' residential zone.
No significant relationship between pollutants
and asthma symptoms; Increased number of
attacks at >0 28 ppm 1n a very small number
of subjects; other factors such as animal
dander and other pollutants may be important.
Kurata et al.,
1976
-------
PRELIMINARY DRAFT
TABLE 12-5 (continued). AGGRAVATION OF EXISTING RESPIRATORY DISEASES BY PHOTOCHEMICAL OXIDANT POLLUTION
Concentratlon(s)
ppra
Pollutant
Study description
Results and comments
Reference
(Not reported)
Ozone Dally log for symptoms, medication, and
hospital visitation of 80 children with
asthma (aged 8-15 yrs) in the Chicago
area during 1974-1975; air quality data
on S02, CO, PM; partial data for 03,
pollen and climate.
Bad weather and high levels of S02, CO, and
PM exerted a minor Influence on asthma,
accounting for only 5-15X of the total vari-
ance; high levels of 03 Increased both the
frequency and severity of asthmatic attacks;
pollen density 1n fall, and winter temperature
variations had no Influence. No exposure data
given for quantitative treatment.
Khan, 1977
0.004-0.235
max 1-hr
Ozone Dally symptom rates 1n 82 asthmatic and
allergic patients compared to 192 healthy
telephone company employees In New Haven,
CT from July to September 1976; average
maximum hourly levels of 03 and average
dally values for S02, TSP, SO,, pollen,
and weather were monitored wltln 0.8 km
of where the subjects were recruited.
Maximum oxldants associated with Increased
dally prevalence rates for cough, eye, and
nose Irritation 1n heavy smokers and patients
with predisposing Illnesses; pH of partlculate
was also associated with eye, nose, and throat
Irritation while suspended sulfates were not
associated with any symptoms. Questionable
exposure assessment, use of prevalence rather
than Incidence data, lack of correction for
auto regression, and possible bias due to high
dropout rates limit the usefulness of this
study for developing quantitative exposure-
response relationships.
Zagran1sk1 .
et al., 1979°
<0.21
max 1-hr/day
Ozone Longitudinal study of dally health symptoms
and weekly splrometry In 286 subjects with
COLD In Houston, TX between July and October
1977 ("Houston Area Oxldants Study"); dally
maximum hourly concentration of 03 measured
at site nearest the subjects' residential
zone; partial peak levels of PAN, N02, S02,
HC, CO, PM, allergens, and temperature at some
monitoring sites.
Increased Incidence of chest discomfort, eye
Irritation, and malaise with Increasing
concentrations of PAN; Increased Incidence
of nasal and respiratory symptoms and In-
creased frequency of medication use with
Increasing 03 concentration; FEV,, and FVC
decreased with Increasing 03 and total
oxldant (03 + PAN) concentration. Questionable
exposure assessment and statistical analysis,
weak study design, and lack of control for
confounding variables limit the usefulness of
this study for developing quantitative exposure-
response relationships.
Johnson et al.,
1979°;
Javltz et al.,
19836
-------
PRELIMINARY DRAFT
TABLE 12-5 (continued). AGGRAVATION OF EXISTING RESPIRATORY DISEASES BY PHOTOCHEMICAL OXIDANT POLLUTION
Concentrat1on(s)
ppm
Pollutant
Study description
Results and comments
Reference
0.03-0.15 medians
at 6 sites
Oxldant Statistical analysis (repeated-measures
design) of CHESS data on dally attack
rates for juvenile and adult asthmatics
residing In six Los Angeles area communi-
ties for 34-week periods (May-December)
during 1972-1975; dally maximum hourly
averages for oxldants (KI) by LA-APCDs,
24-hr averages for TSP, RSP, SO , NO ,
S02, and N02 by EPA, and meteorSlogieal
conditions were monitored within 1 to
8 miles of homes 1n each community.
Dally asthma attack rates Increased on days
with high oxldant and participate levels and
on cool days; presence of attack on the pre-
ceding day, day of week, and day of study
were highly significant predictors of an
attack; questionable exposure assessment In-
cluding lack of control for medication use,
pollen counts, respiratory infections, and
other pollutants and possible reporting biases
limit the usefulness of this study for
developing quantitative exposure-response
relationships.
Whittemore and
Korn, 1980
0.038-0.12
max 1-hr/day
i
M
Ozone As part of a community population sample of
117 families from Tucson, AZ, dally symptoms,
medication use, and ventllatory function
were studied 1n adults with asthma, allergies,
or airway obstructive disease (ADD) for an
11-month period In 1979 and 1980; 1-hr maximum
concentrations of 03 (CHEM), NOZ, CO, and
dally levels of TSP, allergens, and weather
variables were monitored at central stations
within % mile of each cluster of subjects.
In adults with AOD, 03 and TSP were signifi-
cantly associated with peak flow (Wright
Peak Flow Meter) after adjusting for covart-
ables; however, no interaction for 03 + TSP
with peak flow. In adults with asthma, 03
was not significantly related to peak flow
after adjusting for covarlables; however.
there was a significant Interaction for 03
+ temperature with peak flow and symptoms.
Small number of subjects actually studied and
Interaction with other environmental condi-
tions limit the quantitative Interpretation
of these studies.
Lebowitz et aj.
1982a D
Lebowltz, 1984
0.001-0.127
max 1-hr
Ozone Association of 03 exposure with the probabi-
lity of asthma attacks 1n subjects (aged 7-55
yrs) residing In two Houston communities during
May-Oct., 1981. Maximum hourly averages for
03 (CHEM), N02> CO, S02, temperature, and rh;
daily 12-hr averages for fine (<2.5 p) and
coarse (2.5-15 u) particles, aldehydes and
aeroallergens; dally 24-hr averages for TSP.
Fixed-rate monitoring within 2.5 miles of sub-
jects residence; exposure estimates developed
using microenvironment-speclf1c relationships.
Increased probability of an asthma attack was
associated with the occurrence of a previous
attack and with exposure to increased 03 con-
centration and decreased temperature; only
suggested Importance of pollen. Magnitude of
the 03 effect varies with the levels of the other
covariates; however, other stimuli may be Involved
Including S02 and particulates which were not
analyzed. In addition, uncertainties about the use
of a logistic regression model to estimate exposure
limits the usefulness of this study for developing
quantitative exposure-response relationships.
Holgujn et al.,
1985°; Contant
et al. , 1985°
Reviewed 1n U.S. Environmental Protection Agency (1978).
See text for discussion.
-------
PRELIMINARY DRAFT
most groups. Pollen was positively associated with sneezing in hay fever
patients. Sulfate levels were not consistently associated with symptoms.
Although it suggests a relationship between ambient ozone exposure and
symptom prevalence, the study does not allow quantitative inference as to
pollution exposures of individual subjects, largely because the distances
between monitoring sites and respective homes and workplaces were not reported.
Also, interpretation is limited by the fact that the dependent variable, symptom
prevalence, ignores the potential dependence of present day's symptom on
previous day's symptoms. Use of incidence, or adjustment for previous day's
symptoms, would have been more appropriate than use of prevalence. Furthermore,
the regression models were not clearly described, and thus the appropriateness
of statistical corrections can not be assessed with confidence.
Whittemore and Korn (1980) applied multiple logistic regression analysis
to asthma panel data collected in six southern California communities during
1972 through 1975. The panels were recruited by the U.S. Environmental Protection
Agency (EPA) as part of the Community Health Environmental Surveillance System
(CHESS). Subjects with physician-diagnosed, active asthma kept symptom diaries
in which they were asked to report the presence or absence of an asthma attack
each day for 34 weeks. Each diary contained information for one week; diaries
not returned after 16 days were excluded from analysis. The EPA data sets
used have undergone quality control to ensure accurate coding of health re-
sponses. There were 16 period- and community-specific panels. In selecting
panelists, preference was given to prospective subjects reporting frequent
asthma attacks; local physicians were consulted before final selection.
Concentrations of TSP, RSP, SO., and NO., were measured by EPA in each
community. Because a large proportion of EPA ozone measurements were missing,
total oxidant measurements made by the Los Angeles Air Quality Control District
were used instead. Measurements of N0? and S0? were not used in data analysis
because many such measurements were missing. The average distance between
subjects' homes and monitoring stations was 3 miles (range 1 to 8 miles). The
aerometric data were arranged into 24-hour periods (midday to midday). Daily
maximum hourly oxidant levels were used in analysis; panel-specific medians of
these ranged from 0.03 to 0.15 ppm. Because RSP, SO., and NO., were highly
correlated with TSP, TSP was the only particulate pollutant included in analysis.
Logistic regression analysis was applied to data from 444 person-periods,
?31 male and 213 female. Seventy-two percent of the males' reporting periods
were supplied by males under 17 years old; the corresponding percentage of
019DCD/A 12-26 8/19/85
-------
PRELIMINARY DRAFT
females'reporting periods was 44 percent. It was possible for an individual's
data to be analyzed more than once, since some asthmatics participated in more
than one panel. The dependent variable was the individual's presence or absence
of an asthma attack on a given day. Independent variables were the same day's
oxidant and TSP levels, minimum temperature, relative humidity, average wind-
speed, day of study, and day of week, as well as the individual's presence or
absence of an asthma attack on the previous day (autocorrelation variable).
Present day's attack status was most closely associated with the autocor-
relation variable, and was also significantly associated with all pollution
and weather variables except windspeed. The results suggested high inter-
individual variability in response to environmental and meteorologic factors.
The model estimated that a panelist having a baseline attack probability of
0.10 following an attack-free day and a probability of 0.41 on the day after
an attack day would have these probabilities raised to 0.13 and 0.44, respec-
tively, if the oxidant level increased by 0.2 ppm. The model also estimated
an increase of less than 0.01 when the oxidant level rose by 0.1 ppm.
The Whittemore and Korn (1980) analysis suggests an effect of ambient
oxidants on asthma attack rate. The analysis also offers the major advantages
of adjusting for previous day's status and confining the individual's model-
estimated attack probability to the realistic range of zero to one. These
results cannot, however, be considered quantitative. Oxidant measurements, not
ozone measurements, were used, and some subjects' homes were distant from
aerometric sites. The independent variable was a subjective measure, subject
to potential bias. Information on relevant covariates, such as daily medication
use, emotional stress, exercise level, acute respiratory infection, and other
environmental pollutants and pollen counts, was not collected. Shy and Muller
(1980) have also stated that a repeated-measures analysis of variance would
have allowed evaluation of a group-time interaction, and reduced occurrences
of individual subjects in more than one panel.
Lebowitz et al. (1982a, 1983) and Lebowitz (1984) conducted serial studies
of Tucson, AZ, adults with asthma, with reported chronic symptoms of airway
obstructive disease (ADD), with reported allergies, and without reported
symptoms. Subjects were drawn from 117 Anglo-white families from a stratified
sample of families in three geographic clusters in a community study population.
Subjects were followed for two years with daily symptom and medication diaries
®
and Mini-Wright peak flow measurements. All families gave information on
their home structure, heating, cooling, appliances, and smoking in the house-
019DCD/A 12-27 8/19/85
-------
PRELIMINARY DRAFT
hold. Telephone checks and visits ensured proper use of diaries, and visits
were made to calibrate peak flow meters.
Measurements of air pollutants, pollen, bacilli, fungi, and algae were
made in and directly around a random cluster sample of 41 study households
(Lebowitz et al., 1984). Pollen and TSP (high-volume samplers) were measured
simultaneously in the center of each geographic cluster. Air pollutants were
also measured regionally in the Tucson basin (see discussion in previous
section for details). Indoor pollution was classified according to indoor
smoking and gas-stove use for homes in which indoor monitoring was not done.
Indoor particle and pollen concentrations were 100- to 200-fold lower than
those outdoors. Scanning electron microscopy showed structural differences
between indoor and outdoor dust.
A total of 35 asthmatics provided daily peak flows. For each study
group, a given day was included in analysis only if more than five people had
provided data on that day. There were 353 such days for asthmatics, 544 for
the AOD group, 494 for the allergy group, and 312 for the asymptomatic group.
A sex-, age-, and height-specific z-score was computed for each-subject's peak
flow. Symptom rates per 100 person-days were calculated separately for asth-
matics and non-asthmatics. Asthmatics' attack incidence could not be analyzed
because there were only 75 newly incident asthma attacks in 3820 person-days.
The data were analyzed by multivariate analysis of variance and regression
analysis. When appropriate, models were adjusted for differences among indivi-
duals' person-days of observation. Of the variables considered, smoking was
most strongly related to peak flow. In the AOD group, 0, and TSP were both
significantly related to symptoms (p <0.01) after adjustment for gas-stove
use, smoking, and relative humidity.
In 23 asthmatics in the geographic cluster where indoor monitoring was
most complete, 0., and temperature had a significant interaction in relation to
peak flow; high temperature had an effect when temperature was low, and 0, had
an effect only at low temperatures. Ozone alone, however, was not independently
related to peak flow after adjustment for other pollutants and covariates.
There was also a temperature-0, interaction on these asthmatics' symptom
prevalence; 0., had an effect (not statistically significant) only in the
high-temperature range. Ozone was associated with rhinitis in asthmatics
living in homes with gas stoves (p <0.015). Daily medication correlated
highly with asthmatics' symptom exacerbations.
019DCD/A 12-28 8/19/85
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PRELIMINARY DRAFT
The authors speculated that CL effects in asthmatics were occurring
mainly at levels of 0.052 ppm or greater, but that 0, appeared to be acting as
a surrogate for other oxidants or in conjunction with other environmental
factors. These studies included good quality control of health data and
unusually extensive environmental monitoring. Like the studies discussed
previously, they suggest an effect of ozone in persons with pre-existing
respiratory illness. Their results are not truly quantitative, however,
largely because sample sizes were often small in relation to the number of
covariates, and because not all individuals' pollution exposures were known in
detail.
Javitz et al. (1983) reanalyzed a study of 286 persons with asthma,
chronic bronchitis, or pulmonary emphysema in Houston, TX (Johnson et al.,
1979, unpublished report). Over 114 days from May to October 1977, all subjects
were asked to complete daily symptom diaries, and about one-third of the
subjects underwent weekly spirometric testing at home. Air pollutants were
measured at nine fixed stations in the Houston area. The symptom data were
analyzed by logistic regression models, which estimated that the incidence of
chest discomfort, eye irritation, and malaise would increase as the PAN concen-
tration increased up to 0.012 ppm. The models also estimated that the incidence
of combined nasal symptoms, combined respiratory symptoms, and medication use
would increase by 6.0, 3.4, and 5.2 percent, respectively, as the 0, level
3
increased up to 412 ug/m (0.21 ppm). The models estimated no increase in any
specific nasal or respiratory symptoms with increasing 0, exposure.
The spirometric data were analyzed by linear regression models, which
estimated decreases in FVC and FEV, of 2.8 percent and 1.6 percent, respec-
3
lively, as daily maximum 1-hr 0., levels rose 412 ug/m (0.21 ppm). These
models estimated somewhat larger decreases in lung function with rising total
oxidant (CL and PAN) levels. The model-estimated changes in lung function
were of questionable statistical significance.
These results suggest a limited effect of ozone on symptoms and lung
function in persons with pre-existing lung disease, but substantial
limitations in data quality render the results inconclusive. Many aerometric
data points were missing, so that individuals' pollution exposures could not be
assessed at all confidently. Over one-third of the subjects reported respira-
tory symptoms on 100 or more days, and over two-thirds reported nasal symptoms
on 10 or fewer days. Such skewing of symptom behavior yielded a relatively
insensitive test for pollution effects in the study group.
019DCD/A 12-29 8/19/85
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PRELIMINARY DRAFI
In a preliminary presentation, Holguin Pt al. (1985) have evaluated the
association of 0., exposure with the probability of an asthma attack in Houston,
TX, during May to October 1981. The study population of 51 subjects was carefully
selected from individuals residing in the neighborhoods of Clear Lake and
Sunnyside. The subjects were medically diagnosed as probable, uncomplicated
extrinsic asthmatics, since all had elevated IgE levels, pulmonary function tests
consistent with reversible airway disease, and no evidence of other chronic
cardiopulmonary disease. Baseline pulmonary function status, however, was not
described in detail. Ages of the subjects ranged from 7 to 55 yr but the median
age was 13 yr and 41 of the subjects were under 20 yr ot age. All subjects
completed log forms twice daily providing 12-hr daytime (7 a.m. to 7 p.m.) and
12-hr nighttime (7 p.m. to 7 a.m.) records of hourly symptoms, activities, and
location. Pulmonary function measurements of peak flow were also made during
(s)
the morning and evening reporting times using a Mini-Wright peak flow meter.
Symptoms, medication use, and peak flow data were examined for patterns that
fit the clinical description of asthma and that represented deviations from
an individuals' baseline profile. Using this information, a specific defini-
tion of an asthma attack was derived for each subject.
Fixed-site monitors within 2.5 miles of the subjects residences in each
of the two neighborhoods provided: maximum hourly averages for 03 (CHEM),
N02, CO, SO-, temperature, and relative humidity (rh); daily 12-hr averages
for fine (<2.5 pro MMAD) and coarse (2.5-15 |.im MMAD) particles, aldehydes, and
aeroallergens; and daily 24-hr averages for total suspended particulates.
Mobile monitoring of indoor/outdoor concentrations of the same pollutants was
collected in 12 residences for 1 week. Detailed measurements of personal 0,
exposure were also obtained by means of portable monitors in 30 of 51 study
subjects. An exposure model that weighted indoor and outdoor location patterns
as well as fixed-site values was used to estimate individual exposures to 0.,
and other aerometric variables. Over the 12-hr symptom period, the time-weighted
1-hr maximum CL concentrations ranged from 2 to J51 pg/m (O.OOL to 0.077 ppm)
3
with a mean concentration of 37 |.ig/m (0.019 ppm). Values for the other environ-
mental variables were not reported.
Logistic regression analysis was, applied to 4? subjects, each with more
than five attacks. The analysis adjuster! for autocorrelation of present
day's attack probability with the attack probability en the previous day.
Regression coefficients were found to be significantly related to a previous
attack, to increasing 0, concentration, and to decreasing ambient temperature.
019DCD/A .12-30 8/19/85
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PRELIMINARY DRAFT
Elevated concentrations of pollen in September and October increased the
probability of an attack in some asthmatics, but this was not statistically
significant for the group. There was no association between attack probability
and N0? or rh.
The utilization of a time-weighted exposure model, employing data from
fixed-site as well as mobile monitors, provides an unusually good estimate of
actual exposures. Personal exposure data, however, were used to assess the
validity of the estimates of individual exposures determined by the model but
were not used in the development of the exposure estimate model itself. There
are still some uncertainties associated with this approach since results from
this comparison indicated that exposure estimates obtained from the model
underestimated actual personal exposures by approximately 10 ppb (Contant et
al., 1985).
The data analysis by Holguin et al. (1985) provides a means of estimating
the increasing probability of an asthma attack on the basis of a previous
attack, a 40 ppb increase in 03, an 8°C increase in ambient temperature, and a
combination of these factors. Although the authors estimate the increased
attack probabilities associated with incremental 0~ increases from given
baseline probabilities, it would be difficult to quantitate these probabilities
at any given 0, concentration since the magnitude of the effect varies as the
levels of the other covariates vary. While confounding variables such as N0?,
pollen, and rh were taken into account, other pollutants such as S02, total
suspended particulates, and inhalable particles (<15 urn MMAD) were not consid-
ered in the analysis. The role of other pollutants, particularly the fine
inhalable particles, in combination with 0.,, temperature, and pollen needs to
be evaluated before the results of this study can be used quantitatively.
12.3.1.5 Incidence of Acute Respiratory Illness. Table 12-6 describes studies
relating oxidant levels with the incidence of acute respiratory illnesses.
These studies, however, did not meet the criteria necessary for developing
quantitative exposure-response relationships for ambient oxidant exposures.
12.3.1.6 Physician, Emergency Room, and Hospital Visits. Earlier studies
reviewed in the 1978 EPA criteria document for ozone and other photochemical
oxidants (U.S. Environmental Protection Agency, 1978) were not able to relate
oxidant concentrations to hospital admission rates or clearly separate oxidant
effects from effects of other pollutants (Table 12-7). The effects of social
factors, which produce day-of-week and weekly cyclical variations, and holiday
and seasonal variations, were rarely removed (and then with possible loss of
019DCD/A 12-31 8/19/85
-------
PRELIMINARY DRAFT
TABLE 12-6. INCIDENCE OF ACUTE RESPIRATORY ILLNESS ASSOCIATED WITH PHOTOCHEMICAL OXIDANT POLLUTION
Concentration(s)
ppm
<0.23 avg cone
10 a.m. -3 p.m.
0.08-0.23
max 1-hr/day
Pollutant Study description
Oxldant Absentee rates from two elementary
schools In Los Angeles throughout
the 1962-63 school year; oxidant
(KI) concentrations measured by
LA-APCD within 2-4.5 miles from
each school.
Oxidant Retrospective study on the Inci-
dence and duration of Influenza-
like Illness from December 1968
to March 1969 among 3500 elementary
school children residing 1n five
Southern California communities.
Results and comments Reference
Absence rates were highest during the Wayne and Wehrle, 1969a
winter when oxidant levels were lowest;
no consistent association between oxidant
oxidant level and absenteeism. Other
pollutants were not considered.
No relationship between photochemical Pearlman et al . , 1971a
oxidant gradient and Illness rates
during an Influence epidemic occurring
in a low- oxidant period; all the
communities had similar levels. Other
pollutants were not considered.
(Not reported)
r\j
I
CO
N)
Oxidant Health service visits for respira-
tory Illness 1n students at five Los
Angeles and two San Francisco
colleges during the 1970-71 school
year peak oxidant and mean S02,
N02, NO, NO , CO, HC, PM, and
weather variables were monitored
within 5 miles of each university.
Pharyngitis, bronchitis, tonslHtis,
colds, and sore throat associated
primarily with oxidant, S02, and N02 levels
on same day and on 7 preceding days;
stronger associations In Los Angeles
than 1n San Franslcso.
Durham, 1974
0.066 and 0.079
avg of dally maxima
£0.195 maximum
(undefined)
Oxidant Health Insurance records from two
locations in Japan during July-
September 1975; maximum oxidant
and S02 levels and weather
variables were monitored dally.
No relationship between oxidant levels and
new acute respiratory diseases. Other
pollutants beside S02 were not considered.
Nagata et al., 1979a
Reviewed 1n U.S. Environmental Protection Agency (1978).
-------
PRELIMINARY DRAFT
TABLE 12-7. HOSPITAL ADMISSIONS IN RELATION TO PHOTOCHEMICAL OXIDANT POLLUTION
Concentratlon(s)
ppn
Pollutant
Study description
Results and comments
Reference
0.11 and 0.28
avg max 1-hr during
low and high periods,
respectively.
0x1 dant Comparison of admissions to Los Angeles
County Hospital for respiratory and
cardiac conditions during smog and smog-
free periods from August to November 1954.
No consistent relationship between admissions
and high smog periods; however, statistical
analyses were not reported.
California Depart-
ment of Public
Health, 1955a,
1956 , 1957a
0.12 avg cone
6 a.m.-1 p.m.
Ox I dant Respiratory and cardiovascular admissions
to Los Angeles County Hospital for resi-
dents living within 8 miles of downtown LA
between August and December, 1954.
Inconclusive results; partial correlation
coefficients between total oxidants and
admissions were variable. Method of patient
selection was not given. Other pollutants
were not considered.
Brant and Hill,
1964a;
Brant, 1965
(Not reported)
Oxldant Admissions of Blue Cross patients to
Los Angeles hospitals with >100 beds
between March and October 1961; dally
average concentrations of oxidant, 03,
CO, S02, N02. NO, and PM by LA-APCDs.
NJ
U)
UJ
Correlation coefficients between admissions
for allergies, eye Inflammation, and acute
upper and lower respiratory infections and
all pollutants were statistically significant;
correlations between cardiovascular and other
respiratory diseases were significant for
oxidant, 03, and S02; significant positive
correlations were noted with length of
hospital stay for S02, N02, and NO .
Correlations were not significant Tor tempera-
ture and relative humidity or for pollutants
with other disease categories.
Sterling et al.
1966, 1967a
(Not reported)
Oxidant Admissions for all adults and children with
acute respiratory Illness In 4 Hamilton,
Ontario hospitals during the 12 months from
July 1, 1970 to June 30, 1971; city-average
pollution monitoring for Ox(KI), S02, PM,
COH, CO, NO , HC, and temperature, wind
direction arid velocity, relative humidity,
and pollen.
Correlation between number of admissions and
an air pollution index for S02 and COH; negative
correlation between temperature and admissions.
No correlation was found with concentrations of
Ox, CO, HC, and NO or with pollen, relative
humidity, wind direction, and velocity.
Levy et al., 1977
(Not reported)
Ozone Emergency room visits for cardiac and
respiratory disease 1n two major hospitals
In the city of Chicago during April 1977
to April 1978; 1-hr concentrations of 03,
S02, N02, NO, and CO from an EPA site close
to the hospital, 24-hr concentrations of
TSP, S02, and NOZ from the Chicago A1r
Sampling Network.
No significant association between admissions
for any disease groups and 03, CO, or TSP;
S02 and NO accounted for part of the variation
of ER visits for respiratory and cardiovascular
admissions. Questionable study design and
analysis Including lack of control for con-
founding and weak exposure assessment.
Namekata et al.,
1979B
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PRELIMINARY DRAFT
TABLE 12-7 (continued). HOSPITAL ADMISSIONS IN RELATION TO PHOTOCHEMICAL OXIDANT POLLUTION
Concentratlon(s)
ppm
Pollutant
Study description
Results and comments
Reference
0.07 and 0.39
avg max 1-hr
during low and high
periods, respectively
Ozone Emergency room visits and hospital
admissions for children with asthma
symptoms during periods of high and
low air pollution 1n Los Angeles from
August 1979 to January 1980; dally
maximum hourly concentrations of 03,
S02, NO, N02, HC, and COM; weekly _
maximum hourly concentrations of S04
and TSP; biweekly allergens and dally
meterologlcal variables from regional
monitoring stations.
Asthma positively correlated with COH, HC, N02,
and allergens on same day and negatively
correlated with 03 and S02; asthma positively
correlated with N02 on days 2 and 3 after
exposure; correlations were stronger on day
2 for most variables; nonsignificant correla-
tions for SO, and TSP. No Indication of
Increased symptoms or medication use during
high pollution period; however, peak flow
decreased (no differentiation of pollutants).
Factor analysis suggested possible synerglsm
between NO, N02, rh, and wlndspeed; 03, 502,
and temperature; and allergens and wlndspeed.
Presence of confounding variables, lack of
definitive diagnoses for asthma and question-
able exposure assessment limit the quantita-
tive Interpretation of this study.
Richards et al.
1981b
0.03 and 0.11
avg max 1-hr for
low and high areas,
respectively
Oxldant Dally hospital emergency room admissions
In four Southern California communities
during 1974-1975. Maximum hourly average
concentrations of oxidant, NC2, NO, CO,
S02, COH;_24-hr average concentrations of
PH and S0<; and dally meteorological
conditions from monitoring sites <8 km
from the hospitals.
Admissions associated with oxidant in Azusa
(the highest oxidant pollution), S0< in
Long Beach and Lennox but not Riverside
(the highest sulfate pollution), and with
temperature In all locations. Lack of
sufficient exposure analysis and subject
characterization limit the quantitative use
of this study.
Goldsmith et al.
1983°
0.03-0.12 avg of
max 1-hr/day
for 15 stations
Ozone Admissions to 79 acute-care hospitals 1n
Southern Ontario for the months of January,
February, July, and August In 1974,
1976-1978. Hourly average concentrations
of partlculate (COH), 03, S02, N02, and
dally temperature from 15 air sampling
stations within the region.
Excess respiratory admissions associated
with S02, 03, and temperature during July
and August with 24 and 48 hr lag; only
temperature was associated with excess
respiratory admissions and total hospital
admissions for January and February. Lack
of sufficient exposure analysis limits the
quantitative use of this study.
Bates.and Sizto,
1983b
Reviewed 1n U.S. Environmental Protection Agency (1978).
See text for discussion.
-------
PRELIMINARY DRAFT
sensitivity). Relating time of visit to time of exposure was also very difficult.
Studies of visits to medical facilities in the United States usually lack
appropriate denominators since data on the number of individuals at risk are
generally not available and the catchment area (total population)
is unknown. In addition, with the increased use of the emergency room as a
family practice center, visits are becoming less associated with acute exposure
or attack than they once were. Also, emergency room data, like hospital record
data, often lack information on patients' smoking habits, ethnic group, social
class, occupation, and even other medical conditions.
Whether changes in hospital use reflect changes in either illness experi-
ence or illness perception and behavior is still uncertain. People may behave
differently according to individual perceptions of environmental challenges.
The response of the medical-care system is also determined by several factors,
including insurance and availability of physicians, beds, and services (Bennett,
1981; Ward and Moschandreas, 1978). Artifacts may arise from changing defini-
tions of classifications and varying diagnostic or coding practices as well.
Another frequent problem is that repeated admissions or attendance by a small
number of patients can cause tremendous distortions in the data (Ward and
Moschandreas, 1978). Furthermore, interpretation of hospital admissions data
is hindered because hospital statistics often lack reliability and validity
such that determining disease incidence is difficult; insufficient clinical
data are available for diagnostic classification and grading of severity; and
a number of potential subclassifications of patients may require separation
and attention in the analysis (Ward and Moschandreas, 1978).
Namekata et al. (1979) found no significant association between 0, levels
and emergency room visits for cardiac and respiratory diseases in two Chicago
hospitals during 1977-1978. This study, however, must be considered inadequate
because information collected from the medical records was insufficient for
identifying sources of variability in the data and for controlling confounding
factors of the types noted above. In addition, the 0., data were insufficient
and incomplete and the linear models used could not determine effect levels of
the pollutant.
Richards et al. (1981) evaluated the relationship between asthma emergency
room visits and hospital admissions and indices of air pollution, meteorolog-
ical conditions, and airborne allergens. Questionnaire data were obtained on
all children presenting to the Emergency Room of Childrens Hospital of Los
019DCD/A 12-35 8/19/85
-------
PRELIMINARY DRAFT
Angeles for symptoms associated with asthma during a 6-month period (August
I, 1979 to January 31, 1980), encompassing both high and low periods of air
pollution. Air pollution and meteorological data were obtained from monitoring
stations located in the geographical area and weighted according to the density
of patients residing near the monitoring stations. The weighted averages were
used to calculate an average exposure representative of the entire geographical
area. Univariate correlation analyses demonstrated a number of positive and
negative correlations of asthma with air pollutants (Table 12-9); however,
when asthma morbidity was regressed on the combined factor scores, 30 percent
of the total variation could be explained by air pollution or meteorological
conditions. Other variables such as restriction of outdoor activity or
exposure to other irritants that were not measured could also have affected
asthma morbidity. In addition, this study suffers from many of the problems
enumerated above. There was difficulty establishing a definitive diagnosis of
asthma retrospectively in the patients, inadequate exposure assessment, no
clear differentiation of 0., effects from the effects of other pollutants, and
the presence of multiple confounding variables.
Goldsmith et al. (1983) studied emergency room visits in four Southern
California communities (Long Beach, Lennox, Azusa, and Riverside) during
1974-1975. Logbook data on total admissions were taken from two hospitals in
each of the first three communities and from three hospitals in the fourth.
The hospitals were < 8 km from Southern California Air Quality Management
District stations monitoring TSP, 0 , CO, NO, NOp, SO-, sulfate (S04), and
coefficient of haze (COM). Catchment areas and air monitoring data for resi-
dential and work sites were unknown for the subjects included in the study.
The data were adjusted for day-of-the-week and long-term trends, but not for
seasonal trends. Maximum hourly averages of oxidants and temperature were
reported to be associated with daily admissions in the high-oxidant area
(Azusa) after correction for other variables using correlation coefficients
from path analysis (although the more complete path analysis explained less
variance than the standard regression model). Unfortunately, the lack of
population denominators and characteristics, the lack of admission character-
istics, 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, Canada (i.e., the whole catchment area of 5.9 million
people) for the months of January, February, July, and August in each of
019DCD/A 12-36 8/19/85
-------
PRELIMINARY DRAFT
6 years (1974, 1976-1978, and 1979-1980). Air pollution data for CO, N02, 03,
and particles (COH) were obtained from 15 stations located mostly along the
prevailing wind direction. Temperature was controlled. In July and August,
highly significant assocations (Pearson r, 1-tailed, P < 0.001) were found
between excess (percent deviations from day-of-week and seasonal means) respira-
tory admissions and average maximum hourly S0? and 0, concentrations, and
temperature (with 24- and 48-hr lags between the variables). Nonrespiratory
admissions showed no relation to pollution. Temperature was independently
important (-5.3°C average on winter days in study). Admissions, and admission
correlations with pollutants, were consistent from year to year. Further
analysis showed that asthma was the most significant respiratory problem
driving the admissions up, especially in younger people. Bronchitis and
pneumonia admissions were not significantly related to pollutants. The authors
state that it was difficult to differentiate between the effects of temperature,
sulfate, and ozone. With data extended through 1980 (Bates, 1985), however,
there is preliminary information that sulfate levels accounted for a high
percentage of explained variations for all respiratory complaints, but that
ozone was still independently associated with asthma. Since the number of
separate people admitted was unknown, a "sensitive" subpopulation could have
affected the results. In addition, actual exposure information can only be
approximated in this type of study so that only qualitative associations can
be drawn between ambient pollutants and morbidity increases in the population.
12.3.1.7 Occupational Studies. Studies of acute effects from occupational
exposure are summarized in Table 12-8. These studies did not meet the criteria
necessary for developing quantitative exposure-response relationships for
ambient oxidant exposures.
12.3.2 Trends in Mortality
The possible association between acute exposure to photochemical oxidants
and increased mortality rates has been investigated a number of times (Table
12-9) and the results have been reviewed at length in previous documents
(National Research Council, 1977; U.S. Environmental Protection Agency, 1978;
World Health Organization, 1978; Ferris, 1978). As yet, no convincing associ-
ation has been demonstrated between daily mortality and daily oxidant concen-
trations. High oxidant levels were usually associated with high temperatures
that sufficient to account for any excess mortality found in these studies.
019DC2/A 12-37 8/19/85
-------
PRELIMINARY DRAFT
TABLE 12-8. ACUTE EFFECTS FROM OCCUPATIONAL EXPOSURE TO PHOTOCHEMICAL OXIDANTS
Concentratlon(s)
ppm
(Not reported)
Pollutant Study description Results and comments Reference
Ozone Health complaints of workers 1n a test Reports of thoracic cage constriction, 1n- Truche, 1951
laboratory of a factory for electric
Insulators.
splratlon difficulty, and laryngeal Irrita-
tion. Other pollutants were not controlled.
NJ
UJ
CO
0.25-0.80 peaks
(undefined)
0.2-0.3 means
Ozone Clinical findings and symptoms 1n welders
using Inert gas-shield consumable elec-
trodes 1n three plants with ozone measured
at breathing zones.
Increase In chest constriction and throat
Irritation at 1-hr concentrations of 0.3 to
0.8 ppm; no complaints or clinical findings
below 0.25 ppm. Nitrogen dioxide and total
suspended partlculate matter were not measured
or controlled.
Klelnfeld et al.,
1957
0.8-1.7 peaks Ozone Symptoms 1n 14 hello-arc welders.
(undefined)
Upper respiratory symptoms 1n 11 of 14 welders
exposed dally to 0.8 to 1.7 ppm ozone, which
disappeared with exposure to 0.2 ppm. Nitrogen
dioxide was present, but not studied.
Challen et al. ,
1958
Ozone Lung function 1n seven welders using
argon-shield. 03 measured by rubber
cracking.
No changes 1n function. Nitrogen dioxide was
probably present, but not controlled.
Young et al., 1963
0.56-1.28
(interval not
specified)
Ozone Symptoms 1n welders and nearby workers
(controls) ages 25-35, with less than
5 years employment.
More frequent complaints of respiratory Irri-
tation, headache, fatigue, and nosebleeds In
welders; exams were normal. Carbon monoxide
and nitrogen dioxide were below permissible
levels. Total suspended partlculate matter
was not studied.
Polonskaya, 1968
0.01-0.36 peaks
(undefined)
Ozone Illness in 61 welders, 63 pipefitters, 61
plpecoverers, and 94 new pipefitters,
measured by questionnaires, pulmonary
function, partial physicals, and X-rays.
Lung function obstruction In smokers 1n first
two groups; third group had restrictive func-
tion. Otherwise, no differences were observed.
Many pollutants were also Involved.
Peters et al., 1973
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PRELIMINARY DRAFT
TABLE 12-8 (continued). ACUTE EFFECTS FROM OCCUPATIONAL EXPOSURE TO PHOTOCHEMICAL OXIDANTS
Concentratlon(s)
ppm
Pollutant
Study description
Results and comments
Reference
0.05-0.5
workshlft avg
0.16-0.29
workshlft avg
Ozone Pulmonary function In workers In a plastic
bag factory (31 exposed and 31 controls
of same age, height, smoking habits).
Ozone Extrapulmonary effects 1n 33 workers
In a plastic bag factory.
Decreased expiratory flow In 8 of 31 subjects
during workshlft. Lower flows In exposed
smokers than control smokers. Acute changes
to acetylchollnesterase, peroxldase, and
lactate dehydrogenase. Other pollutants,
Including formaldehyde (0.18 to 0.20 ppm)
were not controlled.
Altered serum enzyme levels 1n 22 subjects;
peroxldase activity of peripheral leucocytes
Increased at the end of the workshlft but
returned to normal after a holiday.
Fabbrl et al., 1979
Sarto et al.
1979a,b
0.08
workshlft avg
<1.0 peaks
(undefined)
Ozone Health effects 1n male German metallur-
gical plant workers, as measured by
questionnaire, absenteeism. Insurance
records, vital capacity measures,
plethysmographlc measures, blood pressure,
and airway resistance. Ozone, nitrogen
oxides, and sulfur oxides were sampled.
Group exposed to high ozone had more absenteeism
and more episodes of bronchitis and pneumonia,
more cough and phlegm, and higher airway resis-
tance than did controls. However, high total
suspended partlculate matter levels and
temperature-Induced volatilized metals obscured
effects of ozone.
von Nledlng and
Wagner, 1980
0.01-0.15 avg
personal exposure
Ozone Changes In Immune responses of 30 workers
(average age = 34 yr) exposed an average
of 4.3 yr to 03 when compared to a control
group of ore miners.
Levels of alpha-l-ant1tryps1n and transferrln
Increased after exposure. Comparisons of
relative numbers of changes In serum and
plasma proteins and 1n the Imnunologlcal
responses of peripheral lymphocytes In both
groups Indicates considerable Interlndlvldual
variability.
Ulrlch et al., 1980
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PRELIMINARY DRAFT
TABLE 12-9. DAILY MORTALITY ASSOCIATED WITH EXPOSURE TO PHOTOCHEMICAL OXIDANT POLLUTION
Concentratlon(s)
ppm
<1.0 peak
(undefined)
Pollutant Study description
Oxldant Relationship between dally concentrations
of photochemical oxldants and dally
mortality among residents of Los Angeles
County aged 65 yrs and over the periods
August-November 1954 and July-November 1955.
Results and comments
Heat had a significant effect on mortality;
no consistent association between mortality
and high oxidant concentrations In the
absence of high temperature.
Reference
Ca 1 1 f orn 1 a Depart-
ment of Public
Health. 1955,
19563, 1957a
<0.38 max l-hr(?)/day Oxldant
Data extended to Include the period from
1956 through the end of 1959.
Tucker, 1962
(Not reported) Oxldant
0.10-0.42 Ozone
(undefined) for
148 days of 1949
Relationship between dally maximum
oxidant concentrations and dally
cardiac and respiratory mortality 1n
Los Angeles for the periods 1947-1949,
August 1953 through December 1954, and
January 1955 through September 1955.
Positive relationship between dally maximum
oxidant concentrations and mean dally death
rates on high-smog v_s. low-smog days.
Questionable exposure analysis Including use
of the "SRI smog Index."
Mills, 1957aa,ba
M
I
(Not reported)
Oxldant Comparison of dally mortality 1n two
Los Angeles County areas similar In
temperature but with different levels
of dally maximum and mean oxidant
levels (KI); S02 and CO concentrations
were also measured.
No significant correlations between differences
In mortality and differences 1n pollutant
levels.
Massey et al.-, 196-1
0.05-0.21
monthly avgs
Oxldant Relationship between dally maximum oxidant
concentrations (KI) and dally mortality
from cardiac and respiratory diseases 1n
Los Angeles for the years 1956 through
1958.
No significant correlations between pollutants
and mortality for cardloresplratory diseases;
no correlation for a 1-4 day lag In exposure
and mortality.
Hechter and
Goldsmith, 1961a
(Not reported)
Oxldant Relationship between dally total mortality
from all causes and three Los Angeles heat
waves occurring In 1939, 1955, and 1963;
comparison with mortality during the same
season In 1947 without a heat wave.
High photochemical oxidant concentrations do
not augment the effect of high temperature
on mortality; however, no statistical
relationship was determined between mortality
and oxidant exposure.
Oechsll and
Buechley, 1970
0.003-0.128
max 1-hr/day
Ozone Relationship between dally mortality and
dally 1-hr maximum concentrations of 03
1n Rotterdam, The Netherlands during the
months of July and August of 1974 and 1975.
No significant correlation between Oo concen- Blersteker and
tratlon and mortality 1n the absence of high Evendljk, 1976
temperature; no augmentation of mortality
due to Increased temperature during heat waves.
Reviewed In U.S. Environmental Protection Agency (1978).
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PRELIMINARY DRAFT
12.4 EPIDEMIOLOG1CAL 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 the association of symp-
toms, lung function, chromosomal effects, or mortality rates and average
annual levels of photochemical oxidants; or comparisons of chronic effects in
populations residing in low- or high-oxidant areas. The inability to relate
chronic effects with chronic exposure to specific levels of pollutants is a
major limitation of these studies. In addition, given the long periods of
time known to be required for the development of chronic diseases, it is
unlikely that any of these studies can be used to develop quantitative exposure-
response relationships for ambient oxidant exposures. Further study of well-
defined populations over long periods of time is required before any relation-
ship between photochemical oxidants and the progression of chronic diseases
can be conclusively demonstrated from population studies.
12.4.1 Pulmonary Function and Chronic Lung Disease
Studies of chronic respiratory morbidity are summarized in Table 12-10.
While some of these studies (Detels et al., 1979, 1981; Rokaw et al., 1980;
Hodgkin et al., 1984) suggest an increase in the prevalence of respiratory
symptoms or possibly impairment of pulmonary function in high-pollutant areas,
the results do not show any consistent relationship with chronic exposure to
ozone or other photochemical oxidants. In addition, as discussed above, these
studies are generally limited by insufficient information about individual
exposures and by their inability to control for the effects of other environ-
mental factors. They do not provide information useful for quantitative
exposure-effect assessment. Thus, to date, insufficient information is avail-
able in the epidemiological literature on possible exposure-effect relationships
between 0., or other photochemical oxidants and the prevalence of chronic lung
disease. These relationships will need further study.
One of the largest investigations of chronic 0, exposure has been the
series of population studies of chronic obstructive respiratory diseases in
communities with different air pollutant exposures, reported by Detels and
colleagues of the University of California at Los Angeles (UCLA) (Detels et al.,
1979, 1981; Rokaw et. al., 1980). The areas studied were characterized by high
levels of photochemical oxidants (Burbank and Glendora, CA); high levels of S0x,
particulates, and HCs (Long Beach, CA); and low levels of gaseous pollutants (Lan-
caster, CA). The prevalence of symptoms was reported to be increased in the
019DC2/A 12-41 8/19/85
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PRELIMINARY DRAFT
TABLE 12-10. PULMONARY FUNCTION EFFECTS ASSOCIATED WITH CHRONIC PHOTOCHEMICAL OXIDANT EXPOSURE
Concentration(s)
ppm
Pollutant
Study description
Results and comments
Reference
<1.0 peak
(undefined)
Oxldant Comparison of weekly surveys of Illness
and Injury rates between population samples
from Los Angeles County and the rest of
California during 17 weeks from August
through November 1954.
No relationship between Incidence of Illness
and area In the young. Elderly showed some
Increases In Los Angeles but Investigators
did not adjust for dfferences in population
density, ethnic characteristics, and socio-
economic level. Pollutants other than ozone
were also higher.
Callfornia Depart-
ment of Public
Health 1955 ,
19563, 1957a
(Not reported)
Oxidant Prevalence of Illness 1n survey of 3545
households throughout California. Chronic
pulmonary disease studied four times,
1957-1959.
Higher prevalence rates in Los Angeles and
San Diego. No quantitative oxidant data.
Questionable study design and data analysis.
Hausknecht and
Breslow, 1960 ;
Hausknecht, 1962a
fo
I
(Not reported)
Oxfdant Symptoms, measured by questionnaire and
ventllatory function. In outdoor tele-
phone workers 40-59 years of age In San
Francisco and Los Angeles.
Respiratory symptoms were more frequent In the
older age group (50-59 yrs) of Los Angeles but
pulmonary function was similar. No differences
1n symptom prevalence between cities In the
younger group (40-49 yrs), although participate
concentrations were about twice as high in Los
Angeles. No aerometrlc data.
Deane et al.
Goldsmith and
Deane, 1965a
1965"
0.07 and 0.12
avg max 1-hr for
low and high areas,
respectively
Oxidant Comparison of pulmonary function 1n
nonsmoking Seventh Day Adventlsts (aged
45-64 yrs) residing 1n high-oxidant
(San Gablel Valley) and low-oxidant
(San Diego) areas of California in
January 1970; average maximum oxidant
concentrations were obtained from
September 1969 and January 1970; TSP,
RSP, and S02 were also measured.
No significant difference In prevalence of
respiratory symptoms or 1n measurements of
pulmonary function; however, the findings
are limited by the similarity of annual
average ambient levels of oxldants In the
two areas.
Cohen et al., 1972
0.15 and 0.33
max 1-hr for the
low and high areas,
respectively
Oxidant Respiratory symptoms and function in
insurance company workers in Los Angeles
and San Francisco during the Spring and
Summer of 1973; median concentrations of
oxidant, N02, S02, CO, TSP, and weather
were measured from 1969 to 1972 at
central-city monitoring stations.
Sex-specific pulmonary function measurements
were similar 1n all tests; no difference in
chronic respiratory symptom prevalence between
cities. More frequent reports of nonperslstent
(<2 years) production of cough and sputum by
women in Los Angeles. Different populations and
different aerometrlc characteristics complicate
the analysis.
Linn et al., 1976
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PRELIMINARY DRAFT
TABLE 12-10 (continued). PULMONARY FUNCTION EFFECTS ASSOCIATED WITH CHRONIC PHOTOCHEMICAL OXIOANT EXPOSURE
Concentratlon(s)
ppm
Pollutant
Study description
Results and comments
Reference
0.07 and 0.09 annual
means of max 1-hr/day
for Lancaster and
Burbank, respectively
0.04, 0.07, and 0.09
annual means of max
1-hr/day for Long
Beach, Lancaster, and
Burbank, respectively
0.07 and 0.12 annual means
of max 1-hr/day for
Lancaster and Glendora,
respectively
0x1dant UCLA population studies of the prevalence
of symptoms of chronic obstructive respira-
tory disease (CORD) and of functional
respiratory Impairment 1n residents of
California communities with differing
photochemical oxldant concentrations.
Dally maximum hourly average concen-
trations of oxldant, 03, NO , S02, CO,
and HC; 24-hr_average concentrations
of TSP and S04 from regional SCAQMD
and CARB monitoring stations within 1
to 3 miles of the subjects residential
zone.
Increased prevalence of respiratory symptoms 1n
the residents of high-pollution areas; pulmonary
functon tests of small airways showed little or
no differences between areas while results of
large airway function suggest that long-term
exposure to high concentrations of pollutants
(oxldants, S02, N02, PM, and HC) may result In
measurable Impairment. Difficulty 1n judging
ambient pollution exposure and lack of control
for confounding environmental conditions, migra-
tion, smoking history, and occupational exposure
restrict the quantitative Interpretation of these
studies.
Detels et al., 1979U
Rokaw et al., 1980
Detel et al. , 1981
NJ
(Not reported)
Oxldant Prevalence of respiratory symptoms 1n
nonsmoking Seventh Day Adventtsts
residing for at least 11 yrs 1n high
(South Coast) and low (San Francisco,
San Diego) photochemical air pollution
areas of California; CARB regional air
basin monitoring data for_ox1dants,
N02> S02, CO, TSP, and SO., from 1973
to 1976.
Slightly Increased prevalence of respiratory
symptoms 1n high pollution area; after adjusting
for covaHables, 15% greater risk for COPD due
to air pollution (not specific to oxldants);
past smokers had greater risk than never
smokers; when past smokers were excluded,
risk factors were similar. Use of symptoms
as risk for COPD without FEV, data Is question-
able. In addition, Insufficient exposure
assessment and confounding by environmental
conditions limit the quantitative use of this
study.
Hodgkln et al.
1984
(Not reported)
Oxidant Respiratory symptoms and function 1n 360
wives and daughters of shipyard workers In
Long Beach, CA compared to a reference popu-
lation from Michigan.
Increased prevalence of chronic bronchitis,
reduced expiratory air flow, and altered gas
distribution 1n the Long Beach cohort; all
subjects 1n this cohort had family exposure
to asbestos and 31/238 wives and 3/122
daughters had clinical signs of asbestosls.
Questionable effects of smoking and other
pollutants; no oxldant exposure data were
presented.
Ktlburn et al.
1985
Reviewed In U.S. Environmental Protection Agency (1978).
See text for discussion.
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PRELIMINARY DRAFT
residents of the highest-polluted area (Glendora). Lung function was general-
ly better among residents of the low-pollution areas, as indicated by FEV,,
FVC, maximum expiratory flow rates, closing volume, thoracic volume, and
airway resistance. Maximal mid-expiratory flow rate, considered to be sensitive
to changes in small airways, was similar in the residents of all three areas,
while the mean AN? was slightly higher among residents of the high-pollution
areas. Although the results suggest that adverse effects of long-term exposure
to photochemical oxidant pollutants may occur primarily in the larger airways,
the usefulness of these studies is limited by a number of problems. For example,
testing in different communities occurred at different times over a 4-year period.
Also, the authors presented no information on such matters as self-selection and
migration in and out of these areas.
Additional comparisons between mobile laboratory and hospital laboratory
test results did not always show adequate reproducibility. The study popula-
tions had mixed ethnic groups, and completion rates were approximately 70 to
79 percent in the three areas. Comparisons of participants with census infor-
mation were fairly close. Analysis of the comparisons of the three communi-
ties for symptoms and pulmonary function results used age- and sex-adjusted
data only from white residents who had no history of change of occupation or
residence because of breathing problems. Those with occupations that may have
involved significant exposure were not necessarily excluded. Analyses were
often made by smoking status and compared means or proportions that fell above
or below certain levels.
A major difficulty in the analyses is that the exposure data presented
are not adequate. Control of migration effects on chronic exposure was insuf-
ficient, and recent exposure information was provided only by ambient levels
from only one monitor, located as far as 3 mi away. A further problem is
that, as in most geographical comparisons, analysis of results assumes no
differences by place, date, or season. This assumption is especially important
since the study periods in each community were different. Furthermore, over
the 4-year period of the study there were many changes, including amounts and
types of cigarettes smoked, respiratory infection epidemics, and other undeter-
minable influences that could have affected the results. Also, the numbers of
subjects changed from one report to another and from one analysis to another.
Interpretation of the UCLA lung function data is complicated by the fact
that fewer smokers had abnormal lung function than might be expected. Also,
some of the tests employed, e.g., flow rates at low lung volumes and single-
019DC2/A 12-44 8/19/85
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PRELIMINARY DRAFT
breath nitrogen tests, require stringent measures to avoid observer bias. It
is not clear whether such measures were taken in the UCLA studies.
To test for health effects of air pollution, the investigators often
compared the lower ends (three to five standard deviations below the means) of
the distributions of the study communities' health measurements. It is very
difficult to interpret such comparisons unless the other portions of the
distributions are also presented. Also, numbers of cases were sometimes
relatively small, and some results, e.g., those of the single-breath nitrogen
test, suggested improving lung function with increasing pollution exposure.
It is not clear whether covariates were appropriately treated in data analysis.
Thus, this work is not sufficiently quantitative for air quality standard-
setting purposes.
12.4.2 Chromosomal Effects
The importance of chromosomal damage depends on whether the effect is
mutagenic or cytogenetic. For example, translocations and trisomies are im-
portant forms of genetic damage, whereas minor chromosomal breakage (such as
that associated with caffeine) and chromatid aberrations are of questionable
significance. Interest in the existence and extent of chromosomal damage in
populations exposed to Cu derives from ut vitro cell studies and HI vivo
animal studies (Chapter 10). Findings from j_n vivo human studies are
conflicting, but generally negative (Chapter 11).
Chromosomal changes in humans exposed to 0, have been investigated in
four epidemiological studies, none of which found any evidence that Cu affects
peripheral lymphocytic chromosomes in humans at the reported ambient concentra-
tions. For example, Scott and Burkart (1978) studied chromosome lesions in
peripheral lymphocytes of students exposed to air pollutants in Los Angeles.
In their study of 256 college students, who were followed continuously, chromo-
somal changes found were almost entirely of the simple-breakage type and were
no more numerous than the predicted incidence for a population.
Magie et al. (1982) studied chromosomal aberrations in peripheral lympho-
cytes of college students in Los Angeles: 209 nonsmoking freshmen at a campus
3
with higher smog levels (>0.08 ppm 07; >160 ug/m ) and 206 freshmen at a
3
campus with lower smog levels (<0.08 ppm 0.,; <160 ug/m ). Students were
enrolled in the study after completing questionnaires, and were assigned to
groups on the basis of campus location and previous residence. Blood samples
and medical histories (obtained at the beginning of the school year, in Novem-
019DC2/A 12-45 8/19/85
-------
PRELIMINARY DRAFT
ber, in April, and at the beginning of the next school year) were analyzed for
chromosome and chromatid aberrations, but no significant effects on chromosomal
structure were found in peripheral lymphocytes.
Bloom (1979) studied military recruits before and after welding training.
No chromosomal aberrations were seen in peripheral lymphocytes (CL levels were
negligible and N0? was high). Fredga et al. (1982) studied the incidence of
chromosomal changes in men occupationally exposed to automobile fuels and exhaust
gases in groups of drivers, automobile inspectors, and a control group matched
with respect to age, smoking habits, and length of job employment. Chromosome
preparations from lymphocytes were made and analyzed by standardized routine
methods. Analysis of the data gave no evidence of effects from occupational
exposure.
12.4.3 Chronic Disease Mortality
Two studies previously reviewed in the 1978 EPA criteria document for
ozone and other photochemical oxidants (U.S. Environmental Protection Agency,
1978) were not able to establish conclusively a relationship between oxidant
exposure and mortality from chronic respiratory diseases and lung cancer.
Buell et al. (1967) studied mortality rates among members of the California
Division of the American Legion for the 5-year period from 1958 through 1962.
Long-term residents of Los Angeles County had slightly lower age- and smoking-
adjusted lung cancer rates than residents of the San Francisco Bay area and
San Diego County. Rates of mortality resulting from chronic respiratory
diseases other than lung cancer were higher in Los Angeles than in San Francisco
or San Diego, but the rates were highest in the other less urbanized counties.
Mahoney (1971) reported higher total respiratory disease mortality rates in
inland, downwind sections of Los Angeles than in coastal, upwind sections;
however, variables such as smoking, migration within the city, and variation
among zones in population density were not considered. In fact, socioeconomic,
demographic, and behavioral variables were not fully controlled in either the
Buell et al. (1967) or Mahoney (1971) studies and mortality rates were not
related to actual pollution measurements.
12.5 SUMMARY AND CONCLUSIONS
Field and epidemiological studies offer a unique view of health effects
research because they involve the real world, i.e., the study of human popula-
019DC2/A 12-46 8/19/85
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PRELIMINARY DRAFT
tions in their natural setting. These studies have attendant limitations,
however, that must be considered in a critical evaluation of their results.
One major problem in singling out the effects of one air pollutant in field
studies of morbidity in populations has been the interference of other environ-
mental variables that are critical. Limitations of epidemiological research
on the health effects of oxidants include: interference by other air pollutants
or interactions between oxidants and other pollutants; meteorological factors
such as temperature and relative humidity; proper exposure assessments, includ-
ing determination of individual activity patterns and adequacy of number and
location of pollutant monitors; difficulty in identifying oxidant species
responsible for observed effects; and characteristics of the populations such
as hygiene practices, smoking habits, and socioeconomic status.
The most quantitatively useful information of the effects of acute exposure
to photochemical oxidants presented in this chapter comes from the field studies
of symptoms and pulmonary function. These studies offer the advantage of
studying the effects of naturally-occurring, ambient air on a local subject
population using the methods and better experimental control typical of
controlled-exposure studies. In addition, the measured responses in ambient
air can be compared to clean, filtered air without pollutants or to filtered
air containing artificially-generated concentrations of CL that are comparable
to those found in the ambient environment. As shown in Table 12-11, studies by
Linn et al. (1980, 1983) and Avol et al. (1983, 1984, 1985a,b) have demonstrated
that respiratory effects in Los Angeles area residents are related to 0.,
concentration and level of exercise. Such effects include: pulmonary function
decrements seen at 0, concentrations of 282 ug/m (0.144 ppm) in exercising healthy
adolescents; and increased respiratory symptoms and pulmonary function decrements
3
seen at 0, concentrations of 300 ug/m (0.153 ppm) in heavily exercising athletes
3
and at 0, concentrations of 341 pg/ni (0.174 ppm) in lightly exercising normal
and asthmatic subjects. The light exercise level is probably the type most
likely to occur in the exposed population of Los Angeles. The observed effects
are typically mild, and generally no substantial differences were seen in
asthmatics versus persons with normal respiratory health, although symptoms
lasted for a few hours longer in asthmatics. Many of the normal subjects,
however, had a history of allergy and appeared to be more sensitive to 0., than
"non-allergic" normal subjects. Concerns raised about the relative contribution
to untoward effects in these field studies by pollutants other than 0, have been
diminished by direct comparative findings in exercising athletes (Avol et al. ,
019DC2/A 12-47 8/19/85
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PRELIMINARY DRAFT
TABLE 12-11. SUMMARY TABLE: ACUTE EFFECTS OF OZONE AND OTHER PHOTOCHEMICAL OXIDANTS IN FIELD STUDIES WITH A MOBILE LABORATORY*
Mean ozone
concentration
(jg/m3 ppm
282 0.144
300 0.153
306 0. 156
323 0.165
341 0.174
Measurement '
method
UV,
UV
UV,
UV
UV,
NBKI
UV,
NBKI
UV,
NBKI
Exposure Activity
duration level (V£)
1 hr CE(32)
1 hr CE(53)
1 hr CE(38)
1 hr CE(42)
2 hr IE(2 x R)
@ 15-mln
Intervals
Observed effect(s)
Small significant decreases 1n FVC (-2. IX), FEV0 75
(-4.0%). FEVi.o (-3.7X), and PEFR (-4.4%) relative
to control with no recovery during a 1-hr post-
exposure rest; no significant Increases In
symptoms .
Mild Increases In lower respiratory symptom scores
and significant decreases In FEV, (-5.3%) and
FVC; mean changes In ambient air were not statisti-
cally different from those 1n purified air contain-
ing 0. 16 ppm 03.
No significant changes for total symptom score or
forced expiratory performance 1n normals or
asthmatics; however, FEV, remained low or
decreased further (-3%) 3 hr after ambient air
exposure 1n asthmatics.
Small significant decreases 1n FEV, (-3.3%) and
FVC with no recovery during a 1-hr postexposure
rest; TLC decreased and AN2 Increased slightly.
Increased symptom scores and small significant
decreases In FEV, (-2.4X), FVC, PEFR, and TLC
In both asthmatic and healthy subjects however,
25/34 healthy subjects were allergic and "atypi-
cal ly" reactive to 03.
No.
of subjects Reference
59 healthy Avol et al., 1985a,b
adolescents
(12-15 yr)
50 healthy Avol et al . , 1984
adults (compe-
titive bicy-
clists)
48 healthy Linn et al., 1983;
adults Avol et al. , 1983
50 asthmatic
adults
60 "healthy" L1nn et al., 1983;
adults Avol et al. , 1983
(7 were
asthmatic)
34 "healthy" Linn et al . , 1980, 1983
adults
30 asthmatic
adults
Ranked by lowest observed effect level for 03 1n ambient air.
Measurement method: UV = ultraviolet photometry.
cCa!1brat1on method: UV = ultraviolet photometry standard; NBKI = neutral buffered potassium Iodide.
Minute ventilation reported In L/m1n or as a multiple of resting ventilation. CE = continuous exercise, IE = Intermittent exercise.
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PRELIMINARY DRAFT
1984) showing no differences in response between chamber exposures to oxidant-
3
polluted ambient air with a mean 07 concentration of 294 ug/m (0.15 ppm) and
purified air containing a controlled concentration of generated 0, at 314 ug/m
(0.16 ppm). The relative importance of exercise level, duration of exposure,
and individual variations in sensitivity in producing the observed effects
remains to be more fully investigated, although the results from field studies
relative to those factors are consistent with results from controlled human
exposure studies (Chapter 11).
Studies of the effects of both acute and chronic exposures have been
reported in the epidemiological literature on photochemical oxidants. Investi-
gative approaches comparing communities with high 03 concentrations and communi-
ties with low 0., concentrations have usually been unsuccessful, often because
actual pollutant levels have not differed enough during the study, or other
important variables have not been adequately controlled. The terms "oxidant"
and "ozone" and their respective association with health effects are often
unclear. Moreover, information about the measurement and calibration methods
used is often lacking. Also, as epidemiological methods improve, the incorpor-
ation of new key variables into the analyses is desirable, such as the use
of individual exposure data (e.g., from the home and workplace). Analyses
employing these variables are lacking for most of the community studies
evaluated.
Studies of effects associated with acute exposure that are considered to
be qualitatively useful for standard-setting purposes include those on irritative
symptoms, pulmonary function, and aggravation of existing respiratory disease.
Reported effects on the incidence of acute respiratory illness and on physician,
emergency room, and hospital visits are not clearly related with acute exposure
to ambient 0.. or oxidants and, therefore, are not useful for deriving health
effects criteria. Likewise, no convincing association has been demonstrated
between daily mortality and daily oxidant concentrations; rather, the effect
correlates most closely with elevated temperature.
Studies on the irritative effects of 03 have been complicated by the
presence of other photochemical pollutants and their precursors in the ambient
environment and by the lack of adequate control for other pollutants, meteoro-
logical variables, and non-environmental factors in the analysis. Although 0.,
does not cause the eye irritation normally associated with smog, several studies
in the Los Angeles basin have indicated that eye irritation is likely to occur
in ambient air when oxidant levels are about 0.10 ppm. Qualitative associations
019DC2/A 12-49 8/19/85
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PRELIMINARY DRAFT
between oxidant levels in the ambient air and symptoms such as eye and throat
irritation, chest discomfort, cough, and headache have been reported at
>0.10 ppm in both children and young adults (Hammer et al., 1974; Makino and
Mizoguchi, 1975; Okawada et al., 1979). Discomfort caused by irritative
symptoms may be responsible for the impairment of athletic performance reported
in high school students during cross-country track meets in Los Angeles (Wayne
et al., 1967; Herman, 1972) and is consistent with the evidence from controlled
human exposure studies indicating that exercise performance may be limited by
exposure to 0., (Chapter 11). Although several additional studies have shown
respiratory irritation apparently related to exposure to ambient 0- or oxidants
in community populations, none of these epidemiological studies provide satis-
factory quanti-tative data on acute respiratory illnesses.
Epidemiological studies in children and young adults suggest an association
of decreased peak flow and increased airway resistance with acute ambient air
exposures to daily maximum 1-hr 0., concentrations ranging from 20 to 294 (jg/m
•3
(0.01 to 0.15 ppm) over the entire study period (Kagawa and Toyama, 1975;
Kagawa et al., 1976; Lippmann et al., 1983; Lebowitz et al., 1982a, 1983;
Lebowitz, 1984; Bock et al., 1985; Lioy et al., 1985). None of these studies
by themselves can provide satisfactory quantitative data on acute effects of
0~ because of methodological problems along with the confounding influence of
other pollutants and environmental conditions in the ambient air. The aggre-
gation of individual studies, however, provides reasonably good qualitative
evidence for an association between ambient 0_ exposure and acute pulmonary
function effects. This qualitative association is strengthened by the consis-
tency between the findings from the epidemiological studies and the results
from the field studies in exercising adolescents (Avol et al., 1985a,b) which
have shown small decreases in forced expiratory volume and flow at 282 pg/m
(0.144 ppm) .of 0- in the ambient air; and with the results from the controlled
human exposure studies in exercising children which have shown small decrements
3
in forced expiratory volume at 235 ug/m (0.12 ppm) of 0, (Section 11.2.9.2).
In studies of exacerbation of asthma and chronic lung diseases, the major
problems have been the lack of information on the possible effects of medica-
tions, the absence of records for all days on which symptoms could have occurred,
and the possible concurrence of symptomatic attacks resulting from the presence
of other environmental conditions in ambient air. For example, Whittemore and
Korn (1980) and Holguin et al. (1985) found small increases in the probability
of asthma attacks associated with previous attacks, decreased temperature, and
019DC2/A 12-50 8/19/85
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PRELIMINARY DRAFT
with incremental increases in oxidant and CL concentrations, respectively.
Lebowitz et al. (1982a, 1983) and Lebowitz (1984) showed effects in asthmatics,
such as decreased peak expiratory flow and increased respiratory symptoms, that
were related to the interaction of CL and temperature. All of these studies
have questionable effects from other pollutants, particularly inhalable particles.
There have been no consistent findings of symptom aggravation or changes in
lung function in patients with chronic lung diseases other than asthma.
Only a few prospective studies have been reported on morbidity, mortality,
and chromosomal effects from chronic exposure to 0., or other photochemical
oxidants. The lack of quantitative measures of oxidant exposures seriously
limits the usefulness of many population studies of morbidity and mortality
for standards-setting purposes. Most of these long-term studies have employed
average annual levels of photochemical oxidants or have involved broad ranges
of pollutants; others have used a simple high-oxidant/low-oxidant dichotomy.
In addition, these population studies are also limited by their inability to
control for the effects of other factors that can potentially contribute to
the development and progression of respiratory disease over long periods of
time. Thus, insufficient information is available in the epidemiological
literature on possible exposure-response relationships between ambient (L
or other photochemical oxidants and the prevalence of chronic lung disease
or the rates of chronic disease mortality. None of the epidemiological studies
investigating chromosomal changes have found any evidence that ambient CL or
oxidants affect the peripheral lymphocytes of the exposed population.
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Shishido, M.; Suguta, K.; Higuchi, F. ; Ogihara, A. (1974) Effects of photo-
chemical smog on respiratory function: observation with the flow volume
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(1966) Urban morbidity and air pollution. A first report. Arch. Environ.
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Sterling, T. D. ; Pollack, S. V.; Phair, J. H. (1967) Urban hospital morbidity
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Tashkin, D. P.; Coulson, A. H.; Simmons, M. S.; Spivey, G. H. (1983) Respira-
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To evaluate the health effects documented and described in the preceding
chapters, relevant effects and the identification of potentially-at-risk
individuals and groups are discussed at length in this chapter. In addition,
inherent biological characteristics or personal habits and activities that may
attenuate or potentiate typical responses to ozone and other oxidants are dis-
cussed. The environmental factors that determine potential or real exposures
of populations or groups are presented, as well, including known ambient air
concentrations of ozone, of other related photochemical oxidants, and of these
combined oxidants.
The issues discussed in subsequent sections are enumerated below:
1. Concentrations and patterns of ozone and other photochemical oxidants,
including indoor-outdoor gradients, relevant for exposure assessment.
2. Symptomatic effects of ozone and other photochemical oxidants.
3. Effects of ozone on pulmonary function in the general population, at
rest and with exercise and other stresses.
4. Influence on the effects of ozone of age, sex, smoking status,
nutritional status, and red-blood-cell enzyme deficiencies.
5. Effects of repeated exposure to ozone.
6. Effects of ozone on lung structure and the relationship between
acute and chronic effects from ozone exposure.
7. Effects of ozone related to resistance to infections, i.e., host
defense mechanisms.
8. Effects of ozone on extrapulmonary tissues, organs, and systems.
9. Effects of ozone in individuals with pre-existing disease.
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 groups.
13. Demographic information on potentially at-risk groups.
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
019JSA/A 13-3 11/18/85
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PRELIMINARY DRAFT
of individuals and of populations. In this section, air monitoring data are
summarized as background information for relating the concentrations at which
effects have been observed in health studies to the occurrence of ozone and
other oxidants, 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 from precursor emissions
is limited to daylight hours since the chemical reactions in the atmosphere
are driven by sunlight. Because of the intensity of sunlight necessary and
the other meteorological and climatic conditions required, the highest concen-
trations of ozone and other photochemical oxidants usually occur during the
second and third quarters of the year, i.e., April through September. The
months of highest ozone concentrations depend, however, upon local or regional
weather patterns to a considerable degree, so that the 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 concen-
trations than April, and therefore the 6-month period of highest average ozone
concentrations appears typically to be May through October in many California
cities and conurbations.
In nonurban areas, most peaks in ozone concentrations occur during day-
light hours, but peak concentrations in the early evening and at night are not
uncommon. The occurrence of nighttime peaks appears to be the result of
combined induction time and transport time for urban plumes, coupled with the
lack of nitric oxide (NO) sources to provide NO for chemical scavenging of
ozone in the evening and early morning hours. Average ozone concentrations
are generally lower in nonurban than in urban areas, but it is not unusual to
encounter peak concentrations higher than those found in urban and suburban
areas; but such peak concentrations, though sometimes higher than in urban
areas, seldom remain elevated as long as in 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. In nonurban areas, early morning ozone concentrations are
higher and are near background levels (e.g., 0.02 to 0.04 ppm), since surface
019JSA/A 13-4 11/18/85
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PRELIMINARY DRAFT
scavenging rather than chemical scavenging by NO is the principal removal
mechanism in nonurban areas.
Quantitative data on ozone concentrations are briefly summarized here.
Figure 13-1 shows the frequency distribution of the three highest 1-hour ozone
concentrations aggregated for 3 years (1979 through 1981) (U.S. Environmental
Protection Agency, 1980, 1981, 1982). These three curves are based on data
obtained from predominantly urban monitoring stations. The frequency distri-
bution of the highest 1-hour concentrations measured at eight rural or remote
sites (Evans, 1985) is presented separately in Figure 13-1. These 1-hour
concentrations, recorded at sites of the National Air Pollution Background
Network (NAPBN) located in national forests across the country, have been
aggregated for the same 3-year period, 1979 through 1981. The present primary
and secondary national ambient air quality standards for ozone are expressed
as a concentration not to be exceeded on more than one day per year. Thus,
the second-highest value among daily maximum 1-hour ozone concentrations,
rather than the highest, is regarded as a concentration of potential signifi-
cance for the protection of public health and welfare. As demonstrated by
Figure 13-1, 50 percent of the data reported at the urban monitoring stations,
aggregated for 3 years, were ~ 0.12 ppm; 25 percent were ~ 0.15 ppm; and
10 percent were ~ 0.20 ppm. The frequency distribution of the daily maximum
(i.e., the highest) 1-hour concentrations measured at NAPBN sites shows that
50 percent of the concentrations were < 0.09 ppm; 25 percent were < 0.08 ppm;
and 10 percent were < 0.07 ppm.
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 occurs in
many, though not all, of the individuals studied. Thus, the potential for
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 5 for exposures to four different 1-hour concentrations to determine
their recurrence on 2 or more consecutive days in a 3-year period (see Tables
5-6 through 5-9). Those data are summarized for three cities in Table 13-1.
The data given in Table 13-1 are descriptive statistics based on aerometric
data from the respective localities for 1979, 1980, and 1981, and cannot be
used to predict the number of recurrences of high 1-hour concentrations of
ozone for any other period. The 1-hour ozone concentration at the Pasadena,
019JSA/A 13-5 11/18/85
-------
O
(J
LU
99.99
0.45
0.40
0.35
99.9 99.8 99 98 95 90 80 70 60 SO 40 30 20 10 5 21 05 0.2 01 0.05 001
a 0.30
0.25
0.20
O 0.15
O
0.10
0.05
HIGHEST
2nd HIGHEST
3rd HIGHEST
HIGHEST, NAPBN SITES
i i i i i i i i
i
i i
0.01 0.05 0.1 0.2 0.5 1 2 5 10 20 30 40 50 60 70 80 90 95 98 99 99.8 99.9
STATIONS WITH PEAK 1-hour CONCENTRATIONS < SELECTED VALUE, percent
9999
Figure 13-1. Distributions of the three highest 1-hour ozone concentrations at valid sites (906 station-years)
aggregated for 3 years (1979, 1980, and 1981) and the highest ozone concentrations at NAPBN sites aggre-
gated for those years (24 station-years).
Source: U.S. Environmental Protection Agency (1980, 1981. 1982).
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PRELIMINARY DRAFT
TABLE 13-1. NUMBER OF TIMES THE DAILY MAXIMUM 1-hr OZONE
CONCENTRATION WAS > 0.06, > 0.12, > 0.18, and > 0.24 ppm
FOR SPECIFIED CONSECUTIVE DAYS IN PASADENA, DALLAS, AND
WASHINGTON, APRIL THROUGH SEPTEMBER, 1979 THROUGH 1981
1 y ^ No. of occurrences of daily max. 1-hr 03 concns of:
consecutive days >0.06 ppm > 0.12 ppm > 0.18 ppm > 0.24 ppm
Pasadena
2
3
4
5
6
7
>8
Dallas
2
3
4
5
6
7
>8
Washington
2
3
4
5
6
7
>8
5a
0
2
2
0
2
10
10
6
5
8
3
5
11
10
6
2
2
0
2
5
10
8
4
7
2
0
14
4
2
0
1
0
0
0
1
0
0
0
0
0
0
9
10
6
3
4
1
7
0
0
0
0
0
0
0
0
0
0
0
0
0
0
13
!3
2
2
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
aNote: Data are not cumulative by row or by column. This is because an epi-
sode in which, for example, a 1-hour concentration of 0.18 ppm is exceeded
on each of 2 consecutive days is almost always part of a longer episode in
which a lower 1-hour concentration (e.g., 0.12 or 0.06 ppm) has been exceeded
on each day of an even longer consecutive-day period. Thus, the occurrences
of a 2-day episode at a higher concentration, for example, are a subset of
the occurrences of an n-day episode (e.g., >_ 3 days) tabulated under one or
more lower concentrations.
Source: SAROAD (1985a,b,c).
019JSA/A 13-7 11/18/85
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PRELIMINARY DRAFT
California, site reached a 1-hour concentration > 0.18 ppm for 4 consecutive
days six times and for 8 or more consecutive days seven times in the 3-year
period examined. A 1-hour concentration >_ 0.24 ppm was reached on 4 consecu-
tive days two times and 8 or more consecutive days one time in the 3 years.
Data for sites in Dallas, Texas, and Washington, D.C. , show no consecutive-day
recurrences of high 1-hour concentrations such as those sustained in Pasadena.
Data presented in Chapter 5 for a Pomona, California, site, also in the South
Coast Air Basin, show a pattern similar to that of Pasadena of consecutive-day
recurrences of high 1-hour ozone concentrations.
Potential exposures of nonurban populations, while not easily ascertained
in the absence of a suitable aerometric data base, can be estimated from
measurements made at selected sites known to represent agriculturally oriented
areas and at sites of special-purpose monitoring networks. Data from the
eight NAPBN national forest (NF) monitoring stations show that arithmetic mean
1-hour ozone concentrations at these sites, for the second and third quarters
of the year, ranged from a 5-year average of 25.8 ppb at Kisatchie NF, Louisiana
(1977-1980, 1982) to a 4-year average of 49.4 ppb at Apache NF, Arizona (1980-
1983) (Evans, 1985). (Data are weighted for the number of 1-hour concentra-
tions measured.) Data from Sulfate Regional Experiment (SURE) sites showed
mean concentrations of ozone for August through December 1977 at four "rural"
sites of 0.021, 0.029, 0.026, and 0.035 ppm at Montague, MA, Duncan Falls, OH,
Giles County, TN, and Lewisburg, WV, respectively. At five "suburban" SURE
sites (Scranton, PA; Indian River, DE; Rockport, IN; Ft. Wayne, IN; and Research
Triangle Park, NC), mean concentrations for the study period were 0.023,
0.030, 0.025, 0.02fl, and 0.025 ppm, respectively. Maximum 1-hour ozone concen-
trations 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
with surfaces of such materials as wall board, carpeting, and draperies (Chap-
ter 5). Ozone concentrations indoors depend also on those factors that affect
both reactive and nonreactive pollutants: concentrations outdoors, temperature,
humidity, air exchange rates, presence or absence of air conditioning, and
019JSA/A 13-8 11/18/85
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PRELIMINARY DRAFT
mode of air conditioning (e.g., 100 percent fresh-air intake versus recircula-
tion of air). Estimates in the literature on indoor-outdoor ratios (I/O,
expressed as percent) of ozone concentrations range from just over 0 percent
to 100 percent for residences (Stock et a!., 1983), and from 29 percent
(Moschandreas et al., 1978) to 80 ± 10 percent (Sabersky et al., 1973) for
office buildings. Variations in estimated I/O for buildings are attributable
to the diversity of structures monitored, their locations, and their heating,
ventilating, and air-conditioning systems. Measurements made inside automobiles
show inside ozone concentrations ranging from about 30 percent (Peterson and
Sabersky, 1975) to about 56 percent (Contant et al., 1985) of outside concen-
trations. Again, outside concentrations and mode of air conditioning or
ventilation are among the factors determining the inside concentrations.
Along with small-scale spatial variations in ozone concentrations, such
as indoor-outdoor gradients, large-scale variations exist, such as those that
occur with latitude and altitude. Latitudinal variations have little effect
on potential exposures within the contiguous United States, since the conti-
guous states all fall within latitudes where photochemical oxidant formation
is favored (Logan et al., 1981; U.S. Environmental Protection Agency, 1978).
The increases in ozone concentrations with increase with altitude (Viezee
et al., 1979; Seiler and Fishman, 1981) have no physiological significance for
the general population, since the concentration gradient is significant only
in the free troposphere, well above inhabited elevations. Data presented in
Chapter 5 for Denver show, in fact, that ozone concentrations are lower there
than in many metropolitan areas of comparable size. These altitudinal gradients
could be of possible consequence, however, for certain high-altitude flights,
as reported in the field studies documented in Chapter 12.
Even though ozone is a regional pollutant, intermediate-scale spatial
variations in concentrations occur, nevertheless, that are of potential conse-
quence for designing and interpreting epidemiological studies. For example,
data from a study of ozone formation and transport in the northeast corridor
(Smith, 1981) showed that in New York City an appreciable gradient existed, at
least for the study period (summer, 1980), between ozone concentrations in
Brooklyn and those in the Bronx. The maximum 1-hour ozone concentration
measured at the Brooklyn monitoring site was 0.174 ppm, while that measured at
the Bronx monitoring site was 0.080 ppm.
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13.2.2 Potential Exposures to Other Photochemical Oxidants
13.2.2.1 Concentrations. Concentrations in ambient air of four photochemical
oxidants other than ozone have been presented in Chapter 5. Those data are
drawn upon here to examine the concentrations of these pollutants that might
be encountered in the United States, including "worst-case" situations, in
order to determine both the minimum and maximum additive concentrations of
these pollutants with ozone that could occur in ambient air. The four photo-
chemical oxidants for which concentration data were given in Chapter 5 are
peroxyacetyl nitrate (PAN), peroxypropionyl nitrate (PPN), hydrogen peroxide
(HpOo), and formic acid.
Although they co-occur to varying degrees with ozone, aldehydes are not
photochemical oxidants. Since they are not oxidants and are not measured by
methods that measure oxidants, their role relative to public health and welfare
is not reported in this document. The reader is referred to a recent compre-
hensive review by Altshuller (1983) for a treatment of the relationships in
ambient air between ozone and aldehyde concentrations.
Few health effects data or aerometric data on formic acid exist. Those
ambient air concentrations that are given in the literature, however, indicate
that formic acid occurs at trace concentrations, i.e., <0.015 ppm, even in
high-oxidant areas such as the South Coast Air Basin of California (Tuazon et
al., 1981). No data are available for other urban areas or for nonurban
areas. Given the known atmospheric chemistry of formic acid, concentrations
in the South Coast Air Basin are expected to be higher than in other urban
areas of the country (Chapter 3).
The measurement methods (IR and GC-ECD) for PAN and PPN are specific and
highly sensitive, and have been in use in air pollution research for nearly
two decades. Thus, the more recent literature on the concentrations of PAN
and PPN confirm and extend, but do not contradict, earlier findings reported
in the two previous criteria documents for ozone and other photochemical
oxidants (U.S. Department of Health, Education, and Welfare, 1970; U.S. Environ-
mental Protection Agency, 1978).
Concentrations of PAN are reported in the literature from 1960 through
the present. The highest concentrations reported over this extended period
were those found in the 1960s in the Los Angeles area: 70 ppb (1960), 214 ppb
(1965), and 68 ppb (1968) (Renzetti and Bryan, 1961; Mayrsohn and Brooks,
1965; Lonneman et al., 1976, respectively).
019JSA/A 13-10 11/18/85
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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 con-
centrations 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 concentration there was 0.5 ppb and the maximum was 11 ppb during
a study done from September 1978 through May 1980. Studies outside California
from the early 1970s through 1978 showed average PAN 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 concentra-
tions 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).
The highest PPN concentration reported in studies from 1963 through the
present was 6 ppb in Riverside, California, in the early 1960s (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 (Singh et al., 1982) to 3.1 ppb at Staten Island, New York, in
1981 (Singh et al., 1982). California concentrations fell within this range.
Average PPN concentrations at the respective sites for the more recent data
ranged from 0.05 ppb at Denver and Pittsburgh to 0.7 ppb at Los Angeles in
1979 (Singh et al., 1981).
Altshuller (1983) has succinctly summarized the nonurban concentrations
of PAN and PPN by pointing out that they overlap the lower end of the range of
urban concentrations at sites outside California. At remote locations, PAN
and PPN concentrations are lower than even the lowest of the urban concentra-
tions (by a factor of three to four).
In urban areas, hydrogen peroxide (HJ)-) 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
/
019JSA/A 13-11 11/18/85
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PRELIMINARY DRAFT
concentrations ranged from 0.2 ppb near Boulder, Colorado, in 1978 (Kelly
et al., 1979) to < 7 ppb 54 km southeast of Tucson, Arizona (Farmer and Dawson,
1982). These nonurban data were obtained by the luminol chemiluminescence
technique (see Chapter 4). The urban data were obtained by a variety of
methods, including the luminol chemiluminescence, the titanium (IV) sulfate
8-quinolinol, and other wet chemical methods (see Chapter 4).
Although they appear in the published literature, these and other reported
H?(L concentrations must be regarded as inaccurate, since all wet-chemical
methods used to date are now thought to be subject to positive interference
from ozone. Evidence that reported H?0? concentrations have been in error is
provided not only by recent investigations of wet-chemical methods, but by the
fact that FTIR measurements of ambient air have not demonstrated the presence
of H,,0? even in the high-oxidant atmosphere of the Los Angeles area. The
limit of detection for a 1-knrpathlength FTIR system, which can measure H~0?
with specificity, is around 0.04 ppm (Chapter 4).
13.2.2.2 Patterns. The patterns of formic acid (HCOOH), PAN, PPN, and H202
can be summarized fairly succinctly. They bear qualitative but not quantita-
tive resemblance to the patterns already summarized for ozone concentrations.
Qualitatively, diurnal patterns are similar, with peak concentrations of each
of these occurring in close proximity to the time of the ozone peak. The
correspondence in time of day is not exact, but is close. As the work of
Tuazon et al. (1981) at Claremont, California, demonstrates (see Chapter 5)
ozone concentrations return to baseline levels faster than the concentrations
of PAN, HCOOH, or H^ (PPN was not measured).
Seasonally, winter concentrations (first and fourth quarters) of PAN are
lower than summer concentrations (second and third quarters). The winter
concentrations of PAN are proportionally higher relative to ozone in winter
than in summer. Data are not available on the seasonal patterns of the other
non-ozone oxidants.
Indoor-outdoor data on PAN are limited to one report (Thompson et al.,
1973), which confirms the pattern to be expected from the known chemistry of
PAN; that is, it persists longer indoors than ozone. Data are lacking for the
other non-ozone oxidants.
019JSA/A 13-12 11/18/85
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PRELIMINARY DRAFT
13.2.3 Potential Combined Exposures and Relationship of Ozone and Other
Photochemical Oxidants
Data on concentrations of PAN, PPN, and hLO,, indicate that in "worst-case"
situations these non-ozone oxidants together could add as much as about 0.15
ppm of oxidant to the ozone burden in ambient air. The highest of the "second-
highest" ozone concentration measured in the United States in 1983 was 0.37
ppm, in the Los Angeles area. (For the definition of the "second-highest"
1-hour value see Chapter 5). In the presence of that concentration of ozone,
the addition of a "worst-case" concentration of non-ozone oxidants (0.15 ppm
total) would bring the total oxidant concentration to around 0.52 ppm, provided
the maximum concentrations of ozone and non-ozone oxidants were reached at the
same time. It should be noted that such "worst-case" concentrations are not
viewed as typical.
Data from recent years for the Los Angeles Basin indicate that average
concentrations of PAN and PPN together would add 0.014 ppm (14 ppb) to the
average nxidant burden there (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 not only on average or "worst-case"
concentrations, however, but on the answers to at least several other questions,
e.g.:
1. Do PAN, PPN, or H^O-, singly or in combination, elicit adverse or
potentially adverse responses in human populations?
2. Do any or all of these non-ozone oxidants act additively or syner-
gistically in combination with ozone to elicit adverse or poten-
tially adverse responses in human populations? Do any or all act
antagonistically with ozone?
3. What is the relationship between the occurrence of ozone and these
non-ozone oxidants? Can ozone serve as a surrogate for these other
oxidants?
The first two questions are addressed by health effects data presented in
Chapters 10 through 12 and in Section 13.6 of the present chapter. The third
question has been addressed in detail by Altshuller (1983). His conclusion is
019JSA/A 13-13 11/18/85
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PRELIMINARY DRAFT
that "the ambient air measurements indicate that 0., may serve directional ly,
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 CL could serve as an abatement surrogate for all
photochemical products, including those not relevant to effects data examined
in this document. For example, the products he reviewed relative to ozone
included aldehydes, aerosols, and nitric acid. Nevertheless, his conclusions
appear to apply to the subset of photochemical products of concern here: PAN,
PPN, and H^.
The most straightforward evidence of the lack of a quantitative, monotonic
relationship between ozone and the other photochemical oxidants is the range
of PAN-to-0., and, indirectly, of PAN-to-PPN ratios presented in the review by
Altshuller (1983) and summarized in Table 13-2 and in Chapter 5.
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
PAN/O^ %
of study
West Los Angeles, CA, 1978
Claremont
Claremont
Riverside
Riverside
Riverside
Riverside
Houston,
, CA
, CA
, CA
, CA
, CA
, CA
TX,
New Brunswick
, 1978
, 1979
, 1975-1976
, 1976
, 1977
, 1977
1976
, NJ, 1978-1980
Avg.
9
7
4
9
5
4
4
3
4
At 03 peak
6
6
4
5
4
4
NAa
3
2
Reference
Hanst
Tuazon
1981b)
Tuazon
Pitts
Tuazon
Tuazon
Singh
et
et
et
and
et
et
et
Westberg
al. (1982)
al.
al.
(1981a,
(1981a)
Grosjean (1979)
al.
al.
al. (
et al
(1978)
(1980)
1979)
. (1978)
Brennan (1980)
Not available.
Source: Derived from Altshuller (1983).
Chapter 5.
For primary references, see
019JSA/A
13-14
11/18/85
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PRELIMINARY DRAFT
Certain other information presented in Chapter 5 bears out the lack of a
strictly quantitative relationship between ozone and PAN and its homologues.
Not only are ozone-PAN relationships not consistent between different urban
areas (e.g., Singh et al., 1982), but they are not consistent in urban versus
nonurban areas (e.g., Lonneman et al., 1976), in summer versus winter (e.g.,
Temple and Taylor, 1983), in indoor versus outdoor environments (Thompson et
al. , 1973), or even, as the ratio data show, in location, timing, or magnitude
of diurnal peak concentrations within the same city (e.g., Jorgen et al.,
1978). In addition, Tuazon et al. (1981) demonstrated that PAN persists in
ambient air longer than ozone, its persistence paralleling that of HNO.,, at
least in some localities. Reactivity data presented in the 1978 criteria
document for ozone and other photochemical oxidants indicate that all precur-
sors that give rise to PAN also give rise to ozone. Not all are equally
reactive toward both products, however, and therefore some precursors prefer-
entially give rise, on the basis of units of product per unit of reactant, to
more of one product than the other (U.S. Environmental Protection Agency,
1978).
It must be emphasized that information presented in Chapter 4 clearly
shows that no one method can quantitatively and reliably measure all four
oxidants of potential concern (ozone, PAN, PPN, and hydrogen peroxide), either
one at a time or in ambient air mixtures. This point was not clearly presented
in the 1978 criteria document but is given substantial discussion in Chapter 4
of this document.
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 adults acutely exposed in
environmental chambers to 0^ (Chapter 11) or to ambient air containing 0^ as
the predominant pollutant (Chapter 12). This association holds for both the
time-course and magnitude of effects. Insofar as cough and chest pain or
irritation may interfere with the maximal inspiratory or expiratory efforts,
such associations between symptoms and function might be expected. In a
comparison of adults exposed to both oxidant-polluted ambient air and purified
air containing only 0., (Avol et. al. , 1984), no evidence was found to suggest
019JSA/A 13-15 11/18/85
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PRELIMINARY DRAFT
that any pollutant other than CL contributed to the symptom increases associated
with decrements in lung function. Studies on children and adolescents exposed
to CL or ambient air containing CL under similar conditions have found no
significant increases in symptoms despite significant changes in pulmonary
function (Avol et al., 1985a,b; McDonnell et al., 1985b,c).
To date, while epidemiological studies have attempted to compare the
incidence of acute, irritative symptoms associated with exposure of communities
to varying concentrations of photochemical oxidants, they have not been designed
specifically to test the comparative frequency or magnitude of response of
symptoms versus functional changes. In addition, epidemiological studies have
been complicated by the presence of other photochemical pollutants and their
precursors in the ambient environment and the lack of adequate control for
other pollutants, meteorological variables, and non-environmental factors in
the analysis. Which type of effect is more likely to occur within the polluted
community is therefore uncertain and of limited use for quantifying exposure-
response relationships.
The symptoms found in association with controlled exposure to 0, and with
exposure to photochemical air pollution are similar but not identical. Eye
irritation, one of the commonest complaints associated with photochemical
pollution, is not characteristic of controlled exposures to 0., alone or to
ambient air containing predominantly CL, even at concentrations of the gas
several times higher than any likely to be encountered in ambient air. Other
components of photochemical air pollution, such as aldehydes and PAN, are held
to be chiefly responsible (National Air Pollution Control Administration,
1970; Altshuller, 1977; National Research Council, 1977; U.S. Environmental
Protection Agency, 1978; Okawada et al., 1979).
There is limited qualitative evidence to suggest that at low concentra-
tions of Ov 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 CL is the sole pollutant administered in the chamber studies.
The symptoms may be indicative of either upper or lower respiratory tract
irritation. For example, in epidemiological studies, qualitative associations
between oxidant levels and symptoms such as throat irritation, chest discomfort,
cough, and headache have been reported at > 0.10 ppm in both children and
young adults (Hammer et al. , 1974; Makino and Mizoguchi, 1975; Okawada et al.,
1979). While some individual subjects have experienced cough, shortness of
019JSA/A 13-16 11/18/85
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PRELIMINARY DRAFT
breath, and pain upon deep inspiration at CL concentrations as low as 0.12 ppm
during controlled exposure (McDonnell et al., 1983), the group mean symptom
response was significant only for cough. However, as noted above, it is not
clear if the symptoms reported in epidemiological studies could have been
induced by other pollutants in the ambient air. Above 0.12 ppm 0.,, a variety
of both respiratory and non-respiratory symptoms have been reported in con-
trolled exposures. They include throat dryness, difficulty or pain in inspiring
deeply, chest tightness, substernal soreness or pain, cough, wheeze, lassitude,
malaise, headache, and nausea (DeLucia and Adams, 1977; Kagawa and Tsuru,
1979b; McDonnell et al., 1983; Adams and Schelegle, 1983; Avol et al., 1984;
Gibbons and Adams, 1984; Folinsbee et al., 1984; Kulle et al. , 1985). Most
"symptom scores" have been positive at concentrations of 0.2 ppm 03 and above.
Symptoms tend to remit within hours after exposure is ended. Relatively few
subjects have reported persistence of symptoms beyond 24 hours.
Many variables could possibly explain differences in symptomatic effects
reported in epidemiological and controlled human studies. They include dif-
ferent subject populations, pollutant mixtures, and exposure patterns utilized
in each study, factors affecting the perception of symptoms in one type of
study compared to the other, or differences in the methods used to assess
symptoms. Alternatively, the presence of highly reactive chemical species in
polluted ambient air might be chiefly responsible for the symptoms or might
interact synergistically with 0, to initiate the symptoms, although recently
published data show no excess response to oxidant-polluted air containing
predominant 0, and particulates (Avol et al., 1984).
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, there has
been a good association between changes in symptoms and objective functional
tests at OT concentrations > 0.15 ppm. Symptoms are therefore considered as
useful adjuncts in assessing the effects of 03 and photochemical pollution,
particularly if combined with objective measurements of pulmonary function.
019JSA/A 13-17 11/18/85
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PRELIMINARY DRAFT
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). Other flow-
derived variables, such as the maximal expiratory flow at 50 percent 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
certain individuals at 0.75 ppm 0., (Bates et al., 1972; Silverman et al.,
1976). Small increases in airway resistance (R < 17 percent) were reported
6W
at concentrations greater than 0.5 ppm (Bates et al., 1972; Golden et al.,
1978). Specific tests of lung mechanical properties generally exhibited a
lack of significant effects. Static compliance (C .) remained virtually un-
changed, whereas dynamic compliance (C. ) and the maximum static elastic
recoil pressure of the lung (P. max) showed some borderline effects (Bates et
al., 1972). Ventilatory (VT, fD, Vc) and metabolic (V00, V.-/00) responses to
lot c. t i.
ozone, even at 0.75 ppm level, were not significantly altered (Folinsbee et
al., 1975). The only non-spirometric test reported to be significantly affected
by ozone inhalation was a bronchial response. Post-ozone (0.6 ppm for 2 hr)
challenge with histamine showed significant enhancement of airway responsive-
ness in every tested subject. Premedication with atropine blocked only tran-
siently ozone-induced hyperreactivity of airways (SR ) to histamine (Golden
3W
et al., 1978). Breathing 0.6 to 0.8 ppm 0, for 2 hr reduced markedly diffusion
O
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
increases as the inhomogeneity in the distribution of ventilation increases,
was not significantly altered by 0^ inhalation (Silverman et al. , 1976).
More recent at-rest ozone exposure studies basically confirmed previously
reported findings. Results from exposures to concentrations at and above 0.5
ppm have demonstrated decrements in forced expiratory volume and flows
(Folinsbee et al., 1978; Horvath et al., 1979). Airway resistance was not
019JSA/A 13-18 11/18/85
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PRELIMINARY DRAFT
significantly affected at these CL concentrations while static lung volume
changes (increase in RV and decrease in TLC) were only suggestive (Shephard et
al., 1982). Metabolic and cardiopulmonary effects were also minimal (Horvath
et al., 1979). At concentrations below 0.5 ppm ozone, the effects assessed by
commonly used pulmonary function tests were small and inconsistent (Folinsbee
et al., 1978; Horvath et al., 1979). Reports, however, of ozone-induced
symptoms and functional effects well exceeding the group mean response indicate
that even under resting exposure conditions some subjects are more responsive
to ozone (Kbnig et al, 1980; Golden et al., 1978).
13.3.2.2 Exposures with Exercise. Minute ventilation (VV) is considered to be
one of the principal modulators of the magnitude of response to 0^. The most
convenient physiological procedure for increasing VF is to exercise exposed
individuals either on a treadmill or bicycle ergometer. Consequent increase
in frequency and depth of breathing will increase the overall volume of inhaled
pollutant. Moreover, such a ventilatory pattern also promotes penetration of
ozone into peripheral lung regions. Thus, a larger amount of ozone will reach
tissues most sensitive to injury. These processes are further enhanced at
higher workloads (VV > 35 L/min), since the mode of breathing will change from
nasal to oronasal or oral only (Niinimaa et al., 1980). As the ventilation
increases, an increasingly greater portion of the total minute volume is
inhaled orally, bypassing scrubbing capacity of the nose and nasopharynx
(Niinimaa et al., 1981) and further augmenting ozone dose to the lower airways
and parenchyma.
Even in well-control led experiments on an apparently homogeneous group of
subjects, physiological responses to the same work and pollutant loads vary
widely among individuals (Chapter 11). Under strenuous exposure conditions
(Vp = 45-51 L/min at 0.4 ppm) the least responsive subjects showed FEV, decre-
ments of less than 10 percent, while the most responsive yet apparently healthy
individuals had severely impaired lung function (FEV, = 40 percent of control);
the average decrement was 26 percent (Haak et al., 1984; Silverman et al.,
1976). Some factors, such as the mode of ventilation (oral versus nasal) and
the pattern of breathing (shallow rapid versus slow deep) contribute but
cannot account totally for the commonly observed heterogeneous responses of an
otherwise homogeneous group of subjects. Implementation of strict subject
selection criteria including restrictions on age and sex in most of the studies
narrowed only slightly the distribution of responses. Attempts to determine
019JSA/A 13-19 11/18/85
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PRELIMINARY DRAFT
predisposing factors responsible for increased or decreased CL responsiveness
utilizing nonspecific tests were unsuccessful (Hazucha, 1981). Undoubtedly,
individual responsiveness is a function of many factors. Previous exposures
of individuals to other pollutants (Hackney et al., 1976, 1977b), nutritional
deficiencies and/or latent infection(s) known to be relevant in animals (Chapter
10) might be among contributing factors. The individual responsiveness appears
to be maintained relatively unchanged for as long as 10 months. Generally,
within-individual variability in response is considerably smaller than the
variations reported between subjects (McDonnell et al., 1985a; Gliner et al.,
1983).
The changes in pulmonary function resulting from exposure to clean air or
near zero ozone concentrations are small and uniformly distributed. As the
ozone concentration increases, the distribution widens and becomes skewed
towards larger decrements in pulmonary function, the largest changes respresent-
ing the most responsive subjects (McDonnell et al., 1983; Kulle et al., 1985).
Reported retrospective classification of subjects into "responders/sensitives"
and "non-responders/nonsensitives" varies from study to study. Some subjects
were classified as "responders" by medical history and previous exposures/
testing results (Hackney et al., 1975); others had to show more than 10 percent
post-exposure decrements (Horvath et al., 1981) or decrements exceeding two
standard deviations of the control (Haak et al., 1984). The term "hyperreactor"
or "hyperresponder" has been arbitrarily used to describe the 5 to 20 percent
of the population that is most responsive to ozone exposure. There are no
clearly established criteria to define "reactive" or "nonreactive" subjects.
Nevertheless, it is important to identify criteria to define the "reactive"
portion of the population since they may represent a subgroup of the popula-
tion which can be considered "at risk".
Intermittent exercise augments physiological response to 0-,. Moderate
exercise (Vj- = 24-43 L/min) in 0.4 ppm ozone for 2 hr reduced the FEV, of
healthy subjects by an average of 11 percent. In contrast, rest under the
same environmental conditions decreased FEV, by only 3 percent (Haak et al.,
1984), while very heavy exercise (VV > 64 L/min) reduced FEV, by 17 percent on
the average (5 to 50 percent) (McDonnell et al. , 1983). Even low 0, concentra-
tions (0.12 ppm) induced measurable changes in lung function of more responsive
individuals; the average decrements in FVC, FEV,, and FEF?[-_7(- were 3, 4.5,
and 7.2 percent from control, respectively (McDonnell et al., 1983). The
019JSA/A 13-20 11/18/85
-------
PRELIMINARY DRAFT
maximum changes were observed within 5 to 10 minutes following the end of each
exercise period (Haak et al., 1984). During subsequent rest periods, however,
the response is not maintained and partial improvement in lung function can be
observed despite continuous inhalation of ozone (Folinsbee et al., 1977b).
Functional recovery from a single exposure with exercise appears to progress
in two phases: during the initial rapid phase, lasting between 30 min and 3
hr, improvement in lung function exceeds 50 percent; this is followed by a
much slower recovery phase usually completed within 24 hr (Bates and Hazucha,
1973). There are some individuals, however, whose lung function did not reach
the pre-exposure level even after 24 hrs. Despite apparent functional recovery
of most of the subjects, 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).
The magnitude of functional changes assessed by spirometry is positively
associated with 0-, concentration. Exposure of intermittently exercising
subjects (VE > 63 L/min) for 2 hr to 0.4 ppm reduced significantly (p <0.005)
FVC by 12 percent, FEV, by 17 percent, and FEF?I- 7c by 27 percent on the
average. At lower 0., concentrations (0.18 to 0.24 ppm) the respective decre-
ments (FVC 4 to 11 percent, FEVj^ 6 to 14 percent, FEF25_?5 12 to 23 percent)
were still statistically significant (McDonnell et al., 1983). The same
ventilation in 0.12 to 0.15 ppm 03 atmosphere elicited spirometric changes (1
to 7 percent) of only borderline significance (McDonnell et al., 1983; Kulle
et al., 1985).
Similar positive associations have been reported between lung function
decrements and the level of ventilation. Intermittent exercise (V.. > 68
L/min) in 0.3 ppm 0., decreased FVC, FEV.. , and FEF?[._7C. by 7, 8, and 10 percent,
respectively. A lower intensity of exercise (Vp ~ 32 L/min) in the same G..
atmosphere induced proportionally smaller changes; the respective mean decre-
ments were 2, 5, and 8 percent (Folinsbee et al. , 1978).
More recently, the relationship between ventilation, exposure time, 0.,
concentration, and functional response has been examined in a more general
way. The response has been evaluated as a function of an "effective rate"
(Colucci, 1983), an "effective dose" (Colucci, 1983; Folinsbee et al., 1978;
Silverman et al., 1976) and 0~ concentration (Kulle et al., 1985). The concept
of defining ozone exposure in terms of an "effective dose" (the product of
concentration, ventilation, and time) is relatively simplistic from a modelling
019JSA/A 13-21 11/18/85
-------
PRELIMINARY DRAFT
point of view. A major weakness of this concept, however, is that the same
dose/rate may induce quantitatively different responses which limits the
general applicability of the model for standard-setting (Silverman et al.,
1976; Folinsbee et al., 1978). Moreover, the small data base(s) and the
limited statistical evaluation of almost all of these models further precludes
their quantitative applications and limits their qualitative application(s) to
a similarity of conditions at which the models were derived.
The effects of intermittent exercise and (k concentration on the magnitude
of average pulmonary function response (e.g., FEV,) during 2-hr exposures are
illustrated in Figures 13-2 through 13-6. The data sets on which the predictive
models are based have been limited to studies utilizing intermittent exercise
and 2-hr exposure protocols. In addition to single exposure studies, data
obtained on the first exposure day of sequential exposure studies and following
repetitive exposures of the same cohort to a range of concentrations, or the
same concentration but different levels of exercise if separated by at least 7
days, have been included in the data base. To minimize further inhomogeneity
of data, studies conducted under unique environmental conditions (high relative
humidity and temperature), or on known hyperreactive groups of subjects, were
not included in this analysis. Neither were data from resting and continuous
exercise studies included in the calculations.
The selected set of 25 studies represents data obtained on 320 subjects
studied between 1973 and 1985, in 8 different laboratories (Table 13-3). Since
minute ventilation is one of the most important determinants of response to
ozone, the data have been categorized by reference to exercise level, as
defined by minute ventilation. Based on a distribution pattern of VV during
exercise, four subgroups were identified: light exercise (VV < 23 L/min),
moderate (VV = 24 to 43 L/min), heavy (Vp = 44 to 63 L/min), and very heavy
exercise group (VV > 64 L/min). Although basic second-order functions were
considered in modeling the concentration-response relationship, the pure
quadratic function with no intercept was found to be the simplest and most
suitable model since this is the only function which passes through a minimum
(no response) at zero CL concentration. The relative contribution of each
0
data point was adjusted by weighing it by the number of subjects. Scatter
plots with superimposed best-fit curves and 95 percent confidence limits for
FEV, at each exercise level show clearly differentiated response curves with
high correlation coefficients (r = 0.89 to 0.97). A strong and statistically
019JSA/A 13-22 11/18/85
-------
ro
OJ
0)
a
5
3
—I
O
>
oc
O
<
a
a
x
LU
a
UJ
O
OC
O
u.
O
100
• 23
80
70
60
LIGHT EXERCISE
(s=23 L/min)
r = 0.92
I I
I
I
I
0.2
0.4
0.6
0.8
OZONE CONCENTRATION, ppm
Figure 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. Individual means (± standard error) are given in
Table 13-3 along with specific references.
-------
I
r\>
-P.
ffl
2
O
Q.
LU
O
>
tr
O
oc
X
LJ
Q
UJ
U
tr
O
u.
u
111
CO
110
100
11
80
70
60
13
• 13
MODERATE EXERCISE
(24-43 L/min)
r = 0.94
I
I
0.2
0.4
0.6
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.
-------
110
100
CO
I
ro
ui
O
>
flC
o
QC
Q.
X
O
cc
o
u.
u
01
w
80
70
60
19
HEAVY EXERCISE
(44-63 L/min)
r = 0.97
I I
0.2
0.4
0.6
0.8
OZONE CONCENTRATION, ppm
Figure 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. Individual means (± standard error) are
given in Table 13-3 along with specific references.
-------
110
ro
CTl
2
3
O
>-
oc
O
<
oc
a!
X
O
oc
O
1L.
O
LLI
V)
100
70
60
• 5
r VERY HEAVY EXERCISE
(^64 L/min)
r-0.89
0.2 0.4
OZONE CONCENTRATION, ppm
0.6
0.8
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 error)are
given in Table 13-3 along with specific references.
-------
110
100
o>
a
90
oc
o
OC
0.
o
ui
O
CC
O
u.
O
UJ
(A
80
70
60
VERY HEAVY X EXERCISE
EXERCISE
'••-. LIGHT EXERCISE
MODERATE
EXERCISE
0.2 0.4
OZONE CONCENTRATION, ppm
0.6
0.8
Figure 13-6. Group mean decrements in 1-sec forced expiratory volume during 2-
hr ozone exposuresowith different levels of intermittent exercise: light ($g ^ 23
L/min); moderate (Vg = 24-43 L/min); heavy (Vg = 44-63 L/min); and very heavy
(VE ^ 64 L/min). Concentration-response curves are taken from Figures 13-2
through 13-5.
-------
PRELIMINARY DRAFT
TABLE 13-3. EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC
FORCED EXPIRATORY VOLUME DURING 2-hr EXPOSURES
Ozone .
concentration Measurement '
|jg/m3
LIGHT
1470
1470
0
1470
1470
0
510
^ 1156
uo
1
rsj
00
490
725
980
784
784
490
1098
0
0
725
725
1470
1470
ppm method
EXERCISE (V < 23 L/min)
0.75 MAST. NBKI
0.75
0.00 MAST, NBKI
0.75
0.75 CHEM, NBKI
0.00 CHEM, NBKI
0.26
0.599
0.25 CHEM, NBKI
0.37
0.50
0.4 CHEM, NBKI
0.4
0.25 MAST, NBKI
0.56
0.00 MAST, NBKI
0.00
0.37
0.37
0.75
0.75
Exposure
duration ,
mi n
120
120
120
120
120
125
125
125
120
120
120
135
135
120
120
120
120
120
120
120
120
Number of
subjects
10
10
3
3
11
21
21
21
6
5
7
6
9
3
3
6
6
6
6
6
6
Minute
venti lation
L/mi n
22.5
22.5
23.0
23.0
20.0
22.6
22.6
22.6
20.0
20.0
20.0
20.0
20.0
11.0
11.0
22.0
22.0
22.0
22.0
22.0
22.0
FEVj.o,'1
%
79.3 ± 2.7
76.6 ±2.7
104.9
69.7
77.2 ± 4.4
100.3 ± 0.8
96.9 ± 1.3
81.6 ± 2.7
100.3
97.7
95.3
99.5
95.5
95.7 ± 4.1
82.1 ± 13.2
101.4 ± 1.7
100.5 ±3.3
92.6 ± 2.3
96.1 ± 0.7
73.3 ± 6.8
72.4 ± 4.7
Reference
(1) Bates and Hazucha, 1973
(2) Bates et al. , 1972
(3) Folinsbee et al. , 1977a
(7) Gliner et al. , 1983
(9) Hackney et al. , 1975c
(10) Hackney et al. , 1976
(12) Hazucha, 1973
(14) Hazucha et al. , 1973
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PRELIMINARY DRAFT
TABLE 13-3 (continued). EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC
FORCED EXPIRATORY VOLUME DURING 2-hr EXPOSURES
Ozone ,
concentration Measurement '
(jg/m3
431
451
470
784
784
784
1215
1235
0
294
588
0
29 a
0
0
980
1470
725
941
1509
pom method
0.22 MAST, NBKI
0.23
0.24
0.40
0.40
C.40
0.52
0,53
0.00
0.15
0.30
0.00
0.15
0.00
0.00
0.50
C.75
0.37
0.48
0.77
Exposure
duration,
mi n
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
Number of
subjects
4
4
4
4
4
4
4
4
15
15
10
6
6
8
8
8
8
5
5
5
Minute
venti lation,
L/min
22.5
22.5
22.5
22.5
22.5
22.5
22.5
22.5
22.0
22.0
22.0
20.0
20.0
22.5
22.5
22.5
22.5
22.5
22.5
22.5
FEV,.,,.d
101.5
93.7 ± 1.4
96.0 ± 3. 1
93.9 ± 2.5
91.9 ± 5.9
89.5
88.0
86.0
100.9
100.3
100.1
93.3
94.3
102.8
101.9
98.2
86.0
94.6 ± 3.5
95.1 ± 1.9
79.8 ± 6.4
Reference
(15) Hazucha et al. , 1977
(17) Kagawa, 1984
(18) Kagawa and Tsuru. 1979b
(23) Shephard et al. , 1983
(24) Silverman et al., 1976
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PRELIMINARY DRAFT
TABLE 13-3 (continued). EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC
FORCED EXPIRATORY VOLUME DURING 2-hr EXPOSURES
Ozone
concentration
|.ig/m3
MODERATE
0
0
980
980
0
216
588
960
0
0
0
392
666
921
0
0
784
666
666
0
0
1176
1176
ppm
EXERCISE
0.0
0.0
0.5
0.5
0.00
0.11
0.30
0.49
0.00
0.00
0.00
0.20
0.34
0.47
0.0
0.0
0.4
0.34 .
0.34
0.0
0.0
0.6
0.6
Exposure
Measurement '" duration,
method min
(VE = 24-43 L/min)
CHEM, NBKI 118
118
118
118
CHEM, NBKI 120
120
120
120
CHEM. NBK] 135
135
135
135
135
135
CHEM, GPT 120
120
120
CHEM, NBK1 120
120
CHEM. NBKI 120
120
120
120
Number of
subjects
8
6
8
6
10
10
10
10
10
10
10
10
10
10
29
15
15
4
4
14
14
14
14
Minute
vent i 1 at ion,
L/min
36.0
35.0
33.3
39.2
32.6
32.3
31.0
32.1
32.0
30.0
31.0
31.0
32.0
30.0
35.0
35.0
35.0
24.0
24.0
35.0
35.0
35.0
35.0
, -,,„<
99.4 ± 2.7
96.4 ± 5.5
87.8 ± 6.4
81.9 ± 5.6
99.4 ± 13.1
101.9 ± 13.8
95.4 ± 16.0
87.3 ± 16.6
99.6 ± 4.3
100.6 ± 4.7
100.2 ± 5.1
101.3 ± 4.8
95.5 ± 4.3
91.3 ± 5.0
101.5 ± 2.6
99.7 ± 4.3
96.9 ± 5.5
91.7 ± 27.4
99.7 t 18. 1
97.9 ± 5.1
96.0 ± 6.7
78.8 ± 6.1
73.1 ± 6.5
Reference
(4) Folinsbee et al. , 1977b
(5) Folinsbee et al. , 1978
(6) Folinsbee et al . , 1980
(8) Haak et al. , 1984
(11) Hackney et al. , 1977b
(13) Hazucha, 1981
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PRELIMINARY DRAFT
TABLE 13-3 (continued). EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC
FORCED EXPIRATORY VOLUME DURING 2-hr EXPOSURES
Ozone , Exposure
concentration Measurement ' duration.
j.ig/m3
0
1058
0
921
HEAVY
0
196
588
980
0
0
0
784
0
1176
725
941
0
784
ppm method
0.00 UV, UV
0.54
0.00 UV, NBKI
0.47
EXERCISE (VE = 44-63 L/min)
0.00 CHEM, NBKI
0.11
0.30
0.49
0.0 CHEM, GPT
0.0
0.0
0.4
0.0 CHEM, NBKI
0.6
0.37 MAST, NBKI
0.48
0.0 CHEM, NBKI
0.4
min
125
125
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
Number of
subjects
24
24
11
11
10
10
10
10
15
15
15
15
20
20
5
5
10
12
Mi nute
venti lation
L/min
30.0
30.0
24.0
24.0
50.4
49.8
56.3
51.4
57.0
57.0
57.0
57.0
45.0
45.0
46.5
44.7
55.3
55.3
FEVl.0,d
99.7 ± 1.0
78.9 ± 3.0
100.8
88.7
100.8 ± 16.3
100.5 ± 16.2
93.7 ± 17.5
85.8 ± 19.5
99.4 ± 5.0
98.7 ± 4.1
101.9 ± 4.3
90.6 ± 4.9
102.5
71.6
94.3
84.4
98.8 ± 5.6
92.3 ± 4.8
(16)
(21)
(5)
(8)
(19)
(24)
(25)
Reference
Horvath et al. , 1981
Linn et al. . 1982b
Folinsbee et al . , 1978
Haak et al. , 1984
Ketcham et al. , 1977
Silverman et al., 1976
Stacy et al. , 1983
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PRELIMINARY DRAFT
TABLE 13-3 (continued). EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC
FORCED EXPIRATORY VOLUME DURING 2-hr EXPOSURES
Ozone3
concentration Measurement '
ug/m3
ppm method
Exposure
duration,
min
Number of
subjects
Minute
venti lation
L/mi n
FEV!.
%
d
0 i a
Reference
VERY HEAVY EXERCISE (V£ > 64 L/min)
0
216
588
960
0
235
353
470
588
784
0
196
294
392
490
0.00 CHEM, NBKI
0.11
0.30
0.49
0.00 CHEM, UV
0.12
0.18
0.24
0.30
0.40
0.0 UV, UV
0.10
0.15
0.20
0.25
120
120
120
120
125
125
125
125
125
125
113
113
113
113
113
10
10
10
10
22
22
20
21
21
29
20
20
20
20
20
66.8
71.2
68.4
67.3
66.2
68.0
64.6
64.9
65.4
64.3
70
70
70
70
70
99.7 ±
97.4 ±
92.3 ±
76.1 ±
98.9 ±
95.7 ±
93.6 ±
85.6 ±
83.2 ±
83.0 ±
101.3
101.0
99.4
96.7
93.3
13.7 (5) Folinsbee et al. , 1978
17.6
12.7
11.9
2.4 (22) McDonnell et al., 1983
3.2
3.4
3.4
3.8
3.7
(20) Kulle et al. , 1985
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); CHEM = 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.
P
Subjects exposed to 0.55 and 0.65 ppm ozone were reported as one group (Gliner et al. , 1983).
-------
PRELIMINARY DRAFT
significant (p <0.0001) positive association between decrements in FEV, and
ozone concentration for all levels of exercise is apparent. From the curves,
it can be determined with 95 percent confidence that light exercise in 0.2 ppm
atmosphere will decrease FEV, by 1.6 percent, moderate exercise by 2.4 percent,
heavy exercise by 2.8 percent, and very heavy exercise by 4.7 percent on the
average, respectively. Inversely, a 5 percent decrement in FEV, can be expec-
ted with light exercise in 0.36 ppm 0,, moderate exercise in 0.29 ppm 0.,,
heavy exercise in 0.27 ppm 0~, and very heavy exercise in a 0.21-ppm 0, atmos-
phere. Since the models are based on a large number of data and show highly
statistically significant differences of slope with narrow confidence bands,
they are acceptable for quantitative estimates of response. It is important
to note, however, that any predictions of average pulmonary function responses
to 0, only apply under the specific set of exposure conditions at which these
data were derived. Other pulmonary function variables analyzed in the same
manner, although not illustrated here, showed the same trend as the FEV.., but
as expected, changes differed in magnitude. For example, the decrements in
FVC were smaller, while decrements in FEF?[- 7r were greater, for a given 0,
concentration, than decrements in FEV,. The R showed a similar concentration-
J. u W
dependent, positively correlated response (r = 0.73).
Continuous exercise equivalent in duration to the sum of intermittent
exercise periods at comparable ozone concentrations and minute ventilation (V,-
>60 L/min) elicited greater changes in pulmonary function. The enhancement
ranged from several percent to more than a twofold augmentation of the effects
(Folinsbee et al., 1984; Avol et al., 1984). Others, however, reported group
mean responses in continuous exercise exposures that were similar to those
previously observed with comparable levels of intermittent exercise (Adams et
al., 1981; Adams and Schelegle, 1984). The lack of sufficient data, however,
on comparable levels of exercise in the same subjects prevents any quantitative
comparison of the effects induced by the two modes of exercise.
Exercise not only stresses the respiratory system but other physiological
systems, as well, particularly the cardiovascular and musculoskeletal systems.
Various compensatory mechanisms activated within these systems during physical
activity might facilitate, suppress, cr 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, 1980). In one study,
019JSA/A 13-33 11/18/85
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PRELIMINARY DRAFT
light intermittent exercise (V.- = 20-25 L/min) at a high ozone concentration
(0.75 ppm) reduced post-exposure maximal exercise capacity by limiting maximal
oxygen consumption (Folinsbee et al.. 1977a); submaximal oxygen consumption
changes were not significant (Folinsbee et al., 1975). The extent of ventila-
tory (V,, fR) and respiratory metabolic changes (V0?) observed during or
following the exposure appears to have been related to the magnitude of pul-
monary function impairment. Whether such (metabolic) changes are consequent
to respiratory discomfort or are the result of changes in lung mechanics or
both is still unclear and needs to be elucidated.
13.3.2.3 Environmental Stresses. Environmental conditions such as heat and
relative humidity (rh) may contribute to symptoms and physiological impairment
during and following 0., exposure. A hot (31 to 40°C) and/or humid (85 percent
rh) environment, combined with exercise in the 0, atmosphere, has been shown
to reduce forced expiratory volume more than similar exposures at normal room
temperature and humidity (25°C, 50 percent rh) (Folinsbee et al. , 1977b;
Gibbons and Adams, 1984). Modification of the effects of C> by heat or humidity
stress may be attributed to increased ventilation associated with elevated
body temperature but there may also be an independent effect of elevated body
temperature on pulmonary function (VC).
13.3.3 Other Factors Affecting Pulmonary Response to Ozone
13.3.3.1 Age. Although age has been postulated as a factor capable of modi-
fying responsiveness to 0~, studies have not been designed to test specifically
for effects of 03 in different age groups. Greater responsiveness of the
young to 0, exposure has been suggested from epidemiological studies reporting
an association between decreased lung function and exposure to oxidant-polluted
ambient air (Kagawa and Toyama, 1975; Kagawa et al. , 1976; Lippmann et al. ,
1983; Lebowitz et al., 1982, 1983; Lebowitz, 1984; Bock et al., J985; Lioy et
al., 1985). It is not clear, however, if the observed effects are attributable
to 0., alone since these studies have considerable methodological problems,
including the inability to adjust adequately for the confounding influence of
other pollutants and environmental conditions in ambient air (see Chapter 12).
Controlled-exposure studies, however, on children and adolescents exposed to
0^ or ambient air containing predominantly 0^ (Avol et al., 1985a,b; McDonnell
et al., 1985b,c) have indicated that the effects of 03 on lung spirometry were
very similar to those found in adults exposed under similar conditions except
019JSA/A 13-34 11/18/85
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PRELIMINARY DRAFT
that no significant increases in symptoms were found. Therefore, based on the
limited pulmonary function data available, young children and adolescents do
not appear to respond any differently to CL than adults. Further research is
needed to confirm these preliminary findings in the young and also to determine
if older subjects have altered responsiveness to 0,.
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 et al. (1983), and Crapo et al.
(1984) studied pulmonary function and morphometry of the proximal alveolar
region in neonatal (1-day-old) and young adult (6-week-old) rats exposed to
0.08, 0.12, or 0.25 ppm ozone for 12 hr/day, 7 days/week for 6 weeks. A few
different responses were observed in the neonates and adults, but they were
not major. Generally, neonates and young adults were about equally responsive,
which is consistent with the human studies summarized above.
Animal studies of lung antioxidant metabolism and oxygen consumption
(Lunan et al. , 1977; Tyson et al., 1982; Elsayed et al., 1982) indicate that
the stage of development at initiation of short-term exposure determines the
response to 0^. Generally, the direction of the effect differs before and
after weaning. Suckling neonates (5 to 20 days old) exhibited a decrease in
antioxidant enzyme activities; as the animals grew older (up to 180 days old),
enzyme activities increased progressively, reached a plateau at 35 days of
age, and persisted after cessation of exposure. This response may be attri-
buted to morphological changes in the lung demonstrating a similar age-related
pattern in the progression of centriacinar lesions in rats exposed to 0.,
before and after weaning (Stephens et al., 1978). Thus, further research is
needed to determine if the young differ markedly from adults in their response
to03.
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). One additional study (Gibbons and
Adams, 1984) compared 0., effects in women with the results from male subjects
previously studied in the same laboratory. Lung function of women, as assessed
by changes in FEV, .,, may have been affected more than that of men under
similar exercise and exposure conditions, but the results are not conclusive.
019JSA/A 13-35 11/18/85
-------
PRELIMINARY DRAFT
Field and epidemiological studies of children and adolescents exposed to
ambient air have also tended to show greater effects in girls, but the differ-
ences were either not tested statistically (Bock et al., 1985) or were not
significant (Avol et al., 1985a,b). Further research is needed to determine
whether there are systematic differences in response that are related to sex,
and what factors might be responsible.
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).
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 smoking histories are not documented well. Hazucha
et al. (1973) and Bates and Hazucha (1973) appear to have demonstrated greater
responses (FVC, MMFR) in nonsmokers at 0.37 ppm 0.,, but the responsiveness was
reversed at 0.75 ppm (RV, FEVr Vmax50, and MMFR). Kerr et al. (1975) observed
greater responses (FVC, SG , R. , FEV-, and symptoms) in nonsmokers at 0.5 ppm
3W L J
0., for 6 hr. DeLucia et al. (1983) also observed greater responses in non-
smokers for VC, FEV MMFR, t" , and VT at 0.3 ppm 0, (1 hr, CE). Kagawa and
_L D I O
Tsuru (1979a) stated that the 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 had a greater response (SG ) to 0.15 ppm
oW
(2 hr, IE). Shephard et al. (1983) found a slower and smaller change in
spirometric variables in smokers at 0.5 and 0.75 ppm (2 hr, IE). While none
of these controlled studies have examined the effects of different amounts of
smoking, the general trend suggests that smokers are less sensitive than
nonsmokers. The reasons for these differences are not known; however, smokers
have an altered lung function and an increase in mucus, both of which could
influence the dosimetry of 0,. to regions of the lung.
019JSA/A 13-36 11/18/85
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PRELIMINARY DRAFT
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 ID vitamin
F. 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, hemo-
globin, glutathione concentration, acetylcholinesterase, glucose-6-phosphate
dehydrogenase, and lactic acid dehydrogenase activities. Pulmonary function
and symptoms also showed no differences between the vitamin E and placebo
groups (Hackney et al., 1981).
Hamburger et al. (1979) studied the effects of ozone exposure on the
agglutination of human erythrocytes by the lectin concanavalin A. Pre-incuba-
tion with malonaldehyde, an oxidation product of polyunsaturated fatty acids,
decreased concanavalin A agglutination of red cells exposed j_n vitro to ozone.
Red cells obtained from 29 subjects receiving 800 ID vitamin E 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
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. Rats maintained on a basal vitamin E diet had the typical
centriacinar lesions found as a result of 0, exposure (Stephens et al., 1974;
Schwartz et al., 1976). Lesions were generally worse, however, in vitamin
019JSA/A 13-37 11/18/85
-------
PRELIMINARY DRAFT
E-deficient or marginally supplemented rats when compared to highly supple-
mented rats (Plopper et al., 1979; Chow et al., 1981), supporting the finding
from mortality (Donovan et al., 1977) and biochemical studies that vitamin E
is protective.
The difference in response between animals and man with regard to the
protective effects of vitamin E against ozone toxicity may lie in the pharma-
cokinetics of vitamin E distribution in the body. Redistribution of vitamin E
from extrapulmonary stores to the lung is slow. Short exposures to ozone may
not allow adequate time for redistribution and for a protective effect to be
observed. Animal exposures in which the striking effects of vitamin E on
ozone toxicity were observed were generally conducted over longer exposure
periods (often 1 to 2 weeks). Human subjects were exposed for shorter times
and lower concentrations because of ethical considerations. Thus, the protec-
tive effects of vitamin E might likewise be demonstrated in man, but might
require longer times and higher ozone exposures. In addition, animal studies
have demonstrated that vitamin E-deficient rats are subject to increased
toxicity from (L when compared to supplemented groups, while animals on basal
vitamin E diets are afforded little if any protection from CL. The respective
human group would very likely not have had a substantial deficiency to show
any effect. Thus, the antioxidant properties of vitamin E in preventing
ozone-initiated peroxidation HI vitro are well demonstrated and the protective
effects _i_n vivo are clearly demonstrated in rats and mice. No evidence indi-
cates, however, that man would benefit from increased vitamin E intake relative
to ambient ozone exposures. 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 toxi-
city.
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 pero-
xidase 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.,-initialed polyunsaturated fatty acid peroxidation (see
Section 13.5.1). Therefore, Calabrese etal. (1977) has postulated that
individuals with a hereditary deficiency of G-6-PD may be at-risk to signifi-
cant hematologica! effects from 0., exposure. However, there have been too few
studies performed to reliably document this possibility. Most ozone studies
019JSA/A 13-38 11/18/85
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PRELIMINARY DRAFT
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
such as 0.,. This group has suggested the use of the C57L/J strain of mice and
the Dorset sheep as better animal models for hematological studies since these
species have levels of G-6-PD closer to those in man, especially those levels
found in G-6-PD-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 j_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 03 intermediates, but that G-6-PD-deficient human erythrocytes
were considerably more susceptible. Even if 0., or a reactive product of
CL-tissue interaction were to penetrate the RBC after i_n vivo exposure, it is
unlikely that decrements in reduced glutathione levels leading to chronic
hemolytic anemia would be of functional significance for the affected individ-
ual .
13.3.4 Effects of Repeated Exposure to Ozone
13.3.4.1 Introduction. Attenuated response 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"; other terms have also been
used to describe this phenomenon (Chapter 10, Section 10.3.5). The distinc-
tion, if any, among these terms with respect to 0, and its effects has never
been established in a clear, consistent manner.
The following sections describe the nature of observed alterations in
responsiveness to 0., and discuss possible interrelationships for those observed
changes in responsiveness.
13.3.4.2 Development of Altered Responsiveness to Ozone. Successive daily
brief exposures of human subjects to 0., (< 0.7 ppm for ~ 2 hrs) induce a
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PRELIMINARY DRAFT
typical temporal pattern of response (Chapter 11, Section 11.3). Maximum
functional changes that occur on the first exposure day assessed by plethys-
mographic and bronchial reactivity tests (Farrell et al., 1979; Dimeo et a!.,
1981) or the second exposure day (assessed by spirometry) become progressively
attenuated on each of the subsequent days (Horvath et al., 1981; Kulle et al.,
1982b; Linn et al., 1982b). By the fourth day of exposure, the average effects
are not different from those observed following control (air) exposure.
Individuals need between 3 and 7 days 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., 1982b),
while partial attenuation might persist for up to 2 weeks (Horvath et al.,
1981). Although the severity of symptoms generally correlates with the magni-
tude of the functional response, partial attenuation of symptoms appears to
persist longer, for up to 4 weeks (Linn et al., 1982b). Ozone concentrations
inducing few or no functional effects (< 0.2 ppm) elicited no significant
changes in pulmonary function on consecutive exposures (Folinsbee et al.,
1980). 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 might
modify the response. Most notably, other pollutants may interact with ozone
during more protracted ambient exposures to induce changes at concentrations
lower than those reported from control led-laboratory studies. 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., 1983a).
13.3.4.3 Conclusions Relative to Attenuation with Repeated Exposures. The
attenuation of acute effects of 03 after repeated exposure, such as changes in
lung function, have been well documented in controlled human exposure studies.
There are no practical means at present, however, of assessing the role of
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altered responsiveness to 0-, in human populations chronically exposed to
ozone. No epidemiological studies have been designed to test whether attenua-
tion of symptoms, pulmonary function, or morbidity occurs in association with
photochemical air pollution. It might be added that the proposition would be
difficult to test epidemiologically. Thus, scientists must rely mainly on
inferences and qualitative extrapolations from animal experimentation.
Attenuation of response to 0., may be viewed as a process exhibiting some
concentration/response characteristics. Concentrations of 0., that have little
or no effect do not appear to influence measurably the response invoked by
subsequent exposures to higher 0, concentrations. Over some higher range (0.2
to 0.8 ppm) of exposure, recovery occurring after repeated exposure is virtually
complete within several days. Insofar as this generalization is valid, it
suggests that photochemical air pollution may induce altered responses only in
individuals who previously responded to exposure. Above this range, persistent
or progressive damage is most likely to accompany repeated exposure. The
attenuation, however, of the functional changes (and the time course of atten-
uation) following repeated exposure to 0~ does not necessarily follow the
morphological or biochemical pattern of responses nor does it necessarily
imply that there is attenuation of the morphological or biochemical responses
to 03.
Responses to 0.,, whether functional, biochemical, or morphological, have
the potential for undergoing changes during repeated or continuous exposure.
There is an interplay between tissue inflammation, hyperresponsiveness, ensuing
injury (damage), repair processes, and changes in response. The initial
response followed by its attenuation may be viewed as sequential states in a
continuing process of lung injury and repair.
13.3.5 Mechanisms of Responsiveness to Ozone
The time course, type, and consistency of changes of such indices as
symptoms, lung volumes, flows, resistances, and bronchial reactivity strongly
implicate vagal sensory receptors in substantially modulating responsiveness
to 03.
A growing body of evidence from both animal (Roum and Murlas, 1984; Lee
et al., 1979; Gertner et al., 1983a,b) and human studies (Golden et al., 1978;
DiMeo et al., 1981; Beckett et al., 1985) indicates that a post-ozone exposure
increase in bronchial smooth muscle tone is mediated, at least in part, by
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increased tonic vagal activity consequent to stimulation of muscarinic recep-
tors. Beckett et al. (1985) demonstrated that pretreatment of subjects with
atropine (bronchodilator; cholinergic blocker) prevented an increase in SR
aw
and partially blocked decrease in FEV,; both tests are used clinically as
indirect indices of bronchoconstriction. Atropine, however, did not prevent
the reduction in FVC, increase in frequency of breathing (fn), or decrease in
tidal volume (VT). Inhalation of other types of bronchodilators (isoproterenol,
metaproterenol ; adrenoreceptor agonists) immediately post-exposure relaxed
constricted airways while elevated R and SR returned rapidly to baseline
J aw aw K J
values (Golden et al., 1978; Beckett et al., 1985). Such a pattern of response
strongly suggests involvement of vagal sensory receptors (irritant, stretch
and J-receptors) since stimulation of these receptors will generally elevate
bronchomotor tone, increase fg and decrease V' These findings show that
ozone-induced increases in airway resistance are caused primarily by a reflex
constriction of airway smooth muscle. The afferent pathways of this reflex
originate at different receptor sites, but the (increased) efferent activity
seems to be vagally mediated. Besides direct excitation of afferent end-organs
(receptors, nerve endings), other factors may influence this (afferent) dis-
charge. Enhanced sensitivity of receptors (Lee et al., 1977) and mucosal
inflammation (Holtzman et al. , 1983a,b) leading to increased epithelial permea-
bility (Davis et al., 1980) are some of the proposed mechanisms. On the
effector's side, sensitization of muscarinic receptors (Roum & Murlas, 1984)
and mucosal hypersecretion may be contributing factors.
Because of the physical interaction of lung structure, increased R may
aw
be expected to reduce FVC and increase RV. However, the lack of a significant
association between individual changes in R and FVC (McDonnell et al., 1983)
uW
and the disparate effects of bronchodilator agents on airway diameter indicate
the presence of more than one mechanism for CL-induced changes in pulmonary
function. At 0., concentrations of 0.5 ppm and less, decrements in FVC have
been related to decreases in 1LC without changes in RV or TGV (Hackney et al.,
1975c; Folinsbee et al., 1977b, 1978; Kulle et al. , 1985). The consequent
decrease in TLC most likely results from inhibition of maximal inspiration, as
indicated by the reduced 1C reported at higher (0.75 ppm) 0^ concentrations
(Bates et al., 1972). Whether such an inhibition of maximal inspiration is
voluntary (due to discomfort) or involuntary (due to reflex pathways or altered
lung mechanics) is unclear and awaits further experimentation. It is highly
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probable, however, that most of the decrements in lung volume reported to
result from 0, exposure of greatest relevance to standard-setting (<_ 0.3 ppm)
are due to inhibition of full inspiration rather than changes in airway dia-
meter. The lack of any reported changes in the FEV,/FVC ratio also supports
the restrictive nature of this mechanism (Farrell et al., 1979; Kagawa, 1984).
Among the non-vagal components of the functional response, the release of
mediators is one of more plausible mechanisms suggested (Lee et al. , 1979).
None of the experimental evidence, however, is definitive. Additional investi-
gation is needed to elucidate, assess the relative importance of, and determine
the overall contribution of the mechanisms associated with ozone exposure.
Recent experiments by Gertner et al. (1983a,b,c) may provide additional
information on possible mechanisms. They demonstrated that even a brief
exposure of the peripheral airways of dogs to ozone triggered a functional
response that, depending on 0^ concentration, could be mediated through reflex
and/or humoral pathways. The reflex-mediated response was subject to attenua-
tion after repeated exposure, whereas the response mediated humorally was not.
Experimental evidence in laboratory animals also suggests a close rela-
tionship between the cellular response to 0,-induced injury, as measured by
the appearance of neutrophils in the airway epithelium of dogs exposed to 0.,,
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 hydroxy-
urea (O'Byrne et al., 1983), the (neutrophilie) infiltration after ozone
exposure was depressed (Fabbri et al., 1983), and no increase was seen in
airway responsiveness.
Ozone toxicity, in both humans and laboratory animals, may be mitigated
through altered responses at the cellular and/or subcellular level. At present
the mechanisms underlying altered responses are unclear and the effectiveness
of such mitigating factors in protecting the long-term health of the individual
against 0, is still uncertain (Bromberg and Hazucha, 1982). Since cellular
mechanisms are difficult if not impossible to investigate in humans, animal
studies become essential to provide confirmatory evidence. Numerous basic
metabolic processes in humans and animals appear to be similar; mechanisms
underlying these processes may indeed provide some clues on possible mechanisms
in humans (Mustafa and Tierney, 1978; Boushey et al., 1980). It has been shown
that human and animal leukocytes, pulmonary macrophages, and neutrophils produce
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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 Keisari,
1981). Excessive production of radicals without adequate scavenging will
injure the supporting tissues, while the attenuation of response to successive
stimuli suppresses the release of free oxygen radicals and depresses the
chemotactic responsiveness of the cells (Mustafa and Tierney, 1978; Bhatnagar
et al., 1983). Accumulation of 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
inflammation and injury. Perturbation of lung collagen metabolism seen HI
vivo in animals exposed to 0, (see Section 10.3.3.6) could be involved in the
inflammatory response. Furthermore, the attenuation of prolyl hydroxylase (a
key enzyme in collagen synthesis) activity (Hussain et al., 1976a,b), and
concurrent changes in 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 changes in responsiveness to
0-,. However, even though the prolyl hydroxylase activity returns to control
levels, the product of the originally increased metabolism (collagen) remains.
The glutathione peroxidase system also increases after 0., exposure, thereby
providing another line of defense against oxidant toxicity (Chow, 1976; Chow
et al., 1976).
With time, there is a reduction in 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 0^ pulsations may be in influencing the induction and remission
of the inflammatory reaction. The latter issue has potential significance for
public health, since exposure to ambient air pollution is essentially intermit-
tent. The timing and intensity of exposure within the community, and conse-
quently 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 variability.
13.3.6 Relationship Between Acute and Chronic Ozone Effects
Understanding the relationship between acute effects that follow 0.,
exposure of man or animals and the effects that follow long-term exposures of
man or animals is crucial to the evaluation of the full array of possible
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human health effects of oxidant pollutants. Most of the acute responses to 03
described in animals and man tend to return towards control (filtered air)
values with time after the exposure ends. While effects of longer periods of
exposure have been documented in laboratory animals (Chapter 10), long-term
exposures of human beings have not been done because of ethical and logistical
considerations. In fact, little is known about the long-term implications of
acute damage or about the chronic effects of prolonged exposure to 07 in man.
o
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 Q~ 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 0., 6 hr/day, 5 days/week for 62 exposures. The latter change was
related to decreased airway stiffness or to narrowing of the airway lumen.
Raub et al. (1983), in neonatal rats exposed to 0.12 or 0.25 ppm 03 12 hr/day
for 42 days, observed significantly lower peak inspiratory flows during spon-
taneous respiration, in addition to the increased lung volumes noted above.
While Yokoyama and Ichikawa (1974) did not find changes in lung static pressure-
volume curves of rats exposed to 0.45 ppm 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
OT 7 hr/day, 5 days/week for 6 weeks.
Wegner (1982) studied pulmonary function in bonnet monkeys exposed to
0.64 ppm 0- 8 hr/day, 7 days/week for up to 1 year. After 6 months of exposure,
significant increases in pulmonary resistance and in the frequency dependence
of pulmonary compliance were reported. In the monkeys exposed 1 year, Wegner
(1982) reported significantly increased pulmonary resistance and inertance and
decreased flows during forced expiratory maneuvers at low lung volumes and
decreased volume expired in 1 second (FEV,). These findings were interpreted
as indicating narrowing of the peripheral airways. This observation was
confirmed using morphometric techniques by Fujinaka et al. (1985), who reported
respiratory bronchioles of the bonnet monkeys exposed for 1 year had smaller
internal diameters and thicker walls. Following a 3-month postexposure period,
static lung compliance tenaed to decrease in both exposed and control monkeys,
but the decrease in exposed monkeys was significantly greater than that for
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control monkeys. No other significant differences were measured fallowing the
3-month recovery period, although values for 0.,-exposed animals remained
substantially different from those for control animals. Wegner (1982) inter-
preted these differences as an indication that full recovery was not complete.
Morphological alterations in both rats and monkeys tend to decrease with
increasing duration of exposure to CL, 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 al., 1983;
Crapo et al., 1984), monkeys (Eustis et al., 1981; Fujinaka et al., 1985), and
dogs (Freeman et al., 1973). While repair, as indicated by DMA 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 0., for 42 to 180 days includes damage to
ciliated cells and centriacinar alveolar type 1 cells; hyperplasia of noncili-
ated bronchiolar and alveolar type 2 cells, with extension of nonciliated
bronchiolar cells into more distal structures than in unexposed controls;
accumulation of intraluminal and intramural inflammatory cells; and in rats,
but not reported in monkeys, thickening of interalveolar septa (Boorman et al.,
1980; Moore and Schwartz, 1981; Eustis et al., 1981; Barry et al., 1983; Crapo
et al., 1984). Lungs from the bonnet monkeys studied by Wegner (1982) were
evaluated morphologically and morphometrically by Fujinaka et al. (1985). At
the end of the 1-year exposure to 0.64 ppm 0~ for 8 hr/day, a significant
increase was found in the total volume of respiratory bronchioles in the lung,
but their lumens were smaller in diameter because of thickened epithelium and
other wall components. The reduction in diameter of the first generation
respiratory bronchioles correlates with the results of the pulmonary function
tests performed by Wegner (1982). Cuboidal bronchiolar epithelial cells in
respiratory bronchioles were hyperplastic. Walls of respiratory bronchioles
contained significantly more macrophages, lymphocytes, plasma cells, and
neutrophils. Neither the numbers of fibroblasts nor amount of stainable
collagen was increased significantly, but there was more amorphous intercellu-
lar material. There was also a significant increase in arteriolar media and
intima.
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Lung collagen content was increased after short-term exposure to less
than 1.0 ppm 03 (Last et al., 1979; Last et al., 1981). This change continued
during long-term exposure (Last and Greenberg, 1980; Last et al., 1984b).
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 1 year (Last et al., 1984b). Some of the weanling
rats and their controls were examined after a 6-week postexposure period in
clean air following the 6-week exposure to 0.,. During this postexposure
period, the differences in lung collagen content between exposed and pair fed
controls increased rather than decreased. Thus, with respect to this biochem-
ical alteration, the postexposure period was one of continued damage rather
than recovery.
Continuation of the centriacinar inflammatory process during long-term 0.,
exposures is especially important, as it appears to be correlated with remodel-
ing of the centriacinar airways (Boorman et al., 1980; Moore and Schwartz,
1981; Fujinaka et al., 1985). There is morphometric (Fujinaka et al., 1985),
morphologic (Freeman et al., 1973), and functional evidence (Costa et al.,
1983; Wegner, 1982) of distal airway narrowing. Continuation of the inflamma-
tion also appears to be correlated with the increased lung collagen content
(Last et al., 1979; Boorman et al. , 1980; Moore and Schwartz, 1981; Last
et al., 1984b) that morphologically appears predominantly in centriacinar
regions of the lung.
The distal airway changes described in the above studies of ozone-exposed
animals have many similarities to those reported in lungs from cigarette
smokers (Niewoehner etal., 1974; Cosio etal., 1980; Hale etal., 1980;
Wright et al., 1983). Even though cigarette smoking has been linked with
emphysema in humans, however, there is no evidence of emphysema in the lungs
of animals exposed to 0,. The previous criteria document for 0., (U.S. Environ-
mental 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 Ov
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13.3.7 Resistance to Infection
Normally the mammalian respiratory system is protected from bacterial and
viral infections by the integrated activity of the mucociliary, phagocytic,
and immunological defense systems. Animal models and isolated cells have been
used to assess the effects of oxidants on the various components of these lung
defenses and to measure the ability of these systems to function as an inte-
grated unit in resistance against pulmonary infections. In these studies,
short-term (3 hr) exposure to 0, at concentrations of 0.08 to 0.10 ppm can in-
•J
crease the incidence of mortality from bacterial pneumonia (Coffin et al.,
1967; Ehrlich et al., 1977; Miller et al., 19"/8a). Subchronic exposure to 0.1
ppm caused similar effects (Aranyi et al., 1983). Following short-term expo-
sures to 0~, a number of alterations in lung defenses have been shown, such as
(1) impairment in the ability of the lung to inactivate bacteria and viruses
(Coffin et al., 1968; Coffin and Gardner, 1972; Goldstein et al., 1974, 1977;
Ehrlich et al., 1979); (2) reduced effectiveness of mucociliary clearance
(Phalen et al., 1980; Frager et al., 1979; Kenoyer et al., 1981; Abraham et
al. , 1960); (3) immunosuppression (Campbell and Hilsenroth, 1976; Aranyi et
al., 1980; Thomas et al., 1981b; Fujimaki et al., 1984); (4) a significant
reduction in number of pulmonary defense cells (Coffin et al., 1968; Alpert et
al., 1971); and (5) impaired macrophage phagocytic activity, less mobility,
more fragility and membrane alterations, and reduced lysosomal enzymatic
activity (Dowell et al. , 1970; Hurst et al. , 1970; Hurst and Coffin, 1971;
Goldstein et al., 1971a,b, 1974, 1977; Hadley et al., 1977; McAllen et al.,
1981; Witz et al., 1983; Amoruso et al., 1981). Such effects on pulmonary
host defense have been reported in a variety of species of animals following
either short-term and subchronic exposure to 0_ in combination with other
airborne chemicals (Gardner et al., 1977; Aranyi et al., 1983; Ehrlich, 1980,
1983; Grose et al., 1980, 1982; Phalen et al., 1980; Goldstein et al., 1974).
Studies have also indicated that the activity level of the test subject is an
important variable that can influence the determination of the lowest effective
concentration of the pollutant (Illing et al., 1980).
The major problem remaining is the assessment of the relevance of these
animal data to humans. If animal models are to be used to reflect the toxicol-
ogical response occurring in humans, then the end point for comparison of such
studies should be morbidity rather than mortality. A better comparison in
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humans would be the increased prevalence of respiratory illness in the com-
munity. Such a comparison is proper since both mortality (animals) and mor-
bidity (humans) result from a loss in pulmonary defenses. Ideally, studies of
pulmonary host defenses should be performed in man using epidemiological or
volunteer methods of study. Unfortunately, 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 are similar in animals
and man. Green (1984) recently delineated the many similarities between the
rodent and human antibacterial defenses. Both defenses consist of the same
defense components which together act to maintain the lung free of bacteria.
The effects seen in animals represent alterations in basic biological systems.
One may 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 that different exposure levels may be required to produce similar
responses in humans. The concentrations of 0, at which effects become evident
can be influenced by a number of factors, such as preexisting disease, dietary
factors, combinations with other pollutants, and/or the presence of other
environmental stresses. Although not confirmed by experimental data, one
could hypothesize that humans exposed to CL could experience decrements in
host defenses, but at the present time one cannot predict the exact concentra-
tion at which effects may occur in man or the severity of the effect.
13.3.8 Extrapulmonary Effects of Ozone
Because of the high degree of reactivity of 0., with biological tissue, it
is not clear whether 0., reaches the circulation. Results from mathematical
modeling (Miller et al., 1985) suggest that only a small fraction of CU can
penetrate the air-blood barrier. 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 and
enzymatic activity, as well as cytogenetic effects in circulating lymphocytes,
have been reported in man and laboratory animals. Other organ systems of the
body may also be involved. Exposure to 0, may have central nervous system
•J
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effects, since subjective limitations 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, along with changes in endocrine function; but the implica-
tions of these findings for human health are difficult to judge. More recent
studies in laboratory animals have shown that hepatic metabolism of xenobiotic
compounds may be impaired by 0-, inhalation. While some of these systemic
effects, such as decrements in exercise and vigilance performance, may be
attributed to odor perception or respiratory irritation, the others are more
difficult to conceptualize. "Ihese effects may result from direct contact with
0, or more likely from contact with a reactive product of 03 that penetrates
to the blood and is transported to the other organs.
Cytogenetic and mutational effects of ozone are controversial. In cells
in culture, a significant increase in the frequency of sister chromatid ex-
changes 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 DMA of mouse peritoneal exudate cells were measurable
after a 24-hr exposure to 1 ppm ozone (Chaney, 1981). Gooch et al. (1976)
analyzed the bone marrow samples from Chinese hamsters exposed to 0.23 ppm of
0., for 5 hr and the leukocytes and spermatocytes from mice exposed for up to
2 weeks to 0.21 ppm of 0,. No effect was found on either the frequency of
chromatid or chromosome aberrations, nor were there any reciprocal transloca-
tions in the primary spermatocytes. Small increases observed in chromatid
lesions in peripheral blood lymphocytes from humans exposed to 0.5 ppm ozone
for 6 or 10 hr were not significant because of the small number (n=6) of
subjects studied (Merz et al., 1975). Subsequent investigations, however,
with more human subjects exposed to ozone at various concentrations and for
various times have failed to show any cytogenetic effect considered to be the
result of ozone 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 potential chromosomal effects in humans exposed to 03
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PRELIMINARY DRAFT
is needed. Evidence now available, however, fails to demonstrate any cytoge-
netic or mutagenic effects of ozone in humans when exposure schedules are used
that are representative of exposures that the population at large might actually
experience.
With the exception of peripheral blood lymphocytes, the potential genotoxic
effects of ozone for all of the other body tissues are unknown. It is surpris-
ing that no cytogenetic investigations have been conducted on the respiratory
tissues of animals exposed to ozone. These tissues are exposed to the highest
concentrations and are also the target of most of the toxic manifestations of
ozone. Clearly, one cannot extrapolate ozone-induced genotoxicity data from
peripheral blood lymphocytes to other organs, such as the lungs or reproductive
organs.
Ozone exposure produces a number of hematological and serum chemistry
changes both in rodents and man, but the physiological significance of these
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
monkey RBCs (Clark et al., 1978) at concentrations of 0.4 to 0.75 ppm and
times as short as 2.75 hr in man or 4 hr/day for 4 days in monkeys. Loss of
RBC acetylcholinesterase could either be mediated by membrane peroxidation or
by loss of acetylcholinesterase thiol groups at the active site. Dorsey
et al. (1983) observed that the deformabi1ity of CD-I mouse RBCs decreased on
exposure to 0.7 and 1 ppm for 4 hr. Deformabi1ity also decreased at 0.3 ppm,
but was not statistically significant. These data also support the concept of
membrane damage to circulating RBCs, which appears to be similar in most
species of animals studied and in normal human RBCs exposed to 0.,.
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13.4 HEALTH EFFECTS IN INDIVIDUALS WITH PRE-EXISTING DISEASE
13.4.1 Patients with Chronic Obstructive Lung Disease (COLD)
Patients with mild COLD have not shown increased responsiveness to 0., in
controlled human exposure studies. For example, Linn et al. (1982a, 1983b)
and Hackney et al. (1983) showed no changes in symptoms or function at 0.12,
0.18, or 0.25 ppm 0, (1 hr with intermittent light exercise). Likewise, Solic
et al. (1982) and Kehrl et al. (1983, 1985) found no significant changes in
symptoms or function at 0.2 or 0.3 ppm 0., (2 hr with intermittent moderate
exercise). 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 with intermittent moderate exercise) on day 1 of exposure and upon
reexposure at day 9 (fourth day following cessation of repeated daily expo-
sures); these subjects were less responsive to 0, than healthy nonsmokers.
There is suggestive evidence that bronchial reactivity is increased in
some subjects with COLD (two of three) following exposure to 0.1 ppm 03 (Kbnig
et al., 1980). Small decreases in arterial 0, saturation (S 09) have also
c. 3 c.
been observed in COLD subjects exercising at 0.12 ppm 0., for 1 hr (Linn et
al., 1982a; Hackney et al., 1983) and at 0.2 ppm 03 for 2 hr (Solic et al.,
1982). These changes were seen at higher 0-, concentrations but were not
significant (Linn et al. , 1983b; Kehrl et al., 1985). Interpretation of small
differences in S 09 or their physiological and clinical significance is there-
a £
fore uncertain. In addition, since many of the COLD subjects were smokers,
the interpretation of small changes in S 00 is complicated. Further studies
cl L.
are needed to resolve this issue, particularly on COLD subjects exposed to 0.,
at higher exercise levels.
One difficulty in attempting to characterize the responsiveness of patients
with COLD is that they exhibit a wide diversity of clinical and functional
states. These range from a history of smoking, cough, and minimal functional
impairment to chronic disability that is usually combined with severe defects
in blood gases or respiratory mechanical behavior. The chief locus of damage
may also vary: either the bronchi (chronic bronchitis) or parenchyma (emphy-
sema) may dominate the clinical picture. Finally, the mixture of acute and
chronic inflammatory processes may vary considerably among patients. Even
with strict selection criteria, however, it may be very difficult to sort out
many of these manifestations of COLD in the design of pollutant-exposure
studies.
019C13/A 13-52 11/18/85
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13.4.2 Asthmatics
There is as yet no definitive laboratory evidence demonstrating that mild
asthmatics are functionally more responsive than healthy individuals to (L.
Linn et al. (1978) found no significant changes in lung function, as indicated
by forced expiratory spirometry or the nitrogen washout test, when a hetero-
geneous group of adult asthmatics with mild to moderate bronchial obstruction
was exposed to 0.20 ppm CL for 2 hr with intermittent light exercise; increased
symptom scores were noted, however. Silverman (1979) found minimal changes in
forced expiratory spirometry following 2-hr exposures of adult asthmatics to
0.25 ppm 0^ while at rest. Although group mean changes were not statistically
significant, one third of the subjects who rested for 2 hr while inhaling
0.25 ppm 0, demonstrated a greater than 10 percent decrement in lung function.
Changes of this magnitude have not been reported in normal subjects under
these conditions. In laboratory field studies with ambient air containing an
average concentration of 0.17 ppm 0,, Linn et al. (1980) found small but
statistically significant decrements in forced expiratory measures in both
healthy and asthmatic adults, following 2-hr exposures with intermittent light
exercise. The magnitude of functional responses in both groups did not differ
statistically. Finally, Koenig et al. (1985) found no significant changes in
pulmonary function or symptoms when a group of adolescent subjects with atopic,
extrinsic asthma were exposed at rest to 0.12 ppm 0~ for 1 hr.
The studies reported above are not considered definitive since major
limitations leave open the question of whether the pulmonary function of
asthmatics is more affected by 0., than that of healthy subjects. Intake of
medication was not controlled in several of the studies, and some subjects
continued to use oral medication when being tested. Adequate characterization
of subjects is lacking in most studies and, as a result, group mean changes
could not be detected because of the large variability in responses from such
heterogeneous groups. For example, some of the subjects in one study (Linn
et al.. 1978) showed evidence of chronic obstructive lung disease in addition
to asthma. Most of the normal subjects (70 percent) in the Linn et al. (1980)
study, in which asthmatics were compared to normals, had a history of allergy
and appeared atypically reactive to the 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
proportionately with the intensity of exercise, in determining the response to
0,, additional testing at higher levels of exercise should be undertaken.
019C13/A 13-53 11/18/85
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PRELIMINARY DRAFT
The specific measurements of pulmonary function and the exposure protocols
employed in the above studies may be inappropriate for ascertaining pulmonary
effects in asthmatic subjects. Asthma is essentially cnaracterized by broncho-
constriction. Compared to airway resistance, some measures of forced expiratory
spirometry are less sensitive to bronchoconstriction, since fairly severe
bronchoconstriction must occur in order to affect decrements in these measures.
McDonnell et al. (1983), reporting on healthy subjects exposed to levels of CL
as low as 0.12 ppm with heavy intermittent exercise, attributed small decrements
in forced expiratory spirometry to a reduced inspiratory capacity resulting
from stimulation or sensitization of airway receptors by CL. They also observed
that there was no correlation between changes in airway resistance and forced
expiratory spirometry for individual subjects, which prompted them to postulate
two different mechanisms of action. It may be that the sensitivity of the
mechanism affecting inspiratory capacity is the same in asthmatics and normals,
while the mechanism affecting airway resistance is different.
Epidemiological findings provide only qualitative evidence of exacerbation
of asthma at ambient concentrations of 0-. below those generally associated
with symptoms or functional changes in healthy adults. Whittemore and Korn
(1980) and Holquin et al. (1985) found small increases in the probability of
asthma attacks associated with previous attacks, decreased temperature, and
incremental increases in oxidant and 0, concentrations, respectively. Lebowitz
et al. (1982, 1983) and Lebowitz (1984) also showed effects in asthmatics,
such as decreased peak expiratory flow and increased respiratory symptoms,
that were related to the interaction of 0., and temperature. All of these
studies have questionable effects from other pollutants, particularly inhalable
particles. The major problem in epidemiological studies, therefore, has been
the lack of definitive information on the effects of 0... alone, since there is
confounding by the presence of other environmental conditions in ambient air.
Other factors leading to inconsistencies between epidemiological and controlled-
laboratory studies include (1) differences in the pulmonary function tests
employed, (2) differences in study subjects, since the general population
contains individuals with more severe disease than can be studied in controlled
human exposures, (3) insufficient clinical information in most of these studies,
or (4) the lack of data on other, unmeasured, pollutants and environmental
conditions in ambient a'r.
019C13/A 13-54 11/18/85
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PRELIMINARY DRAFT
13.4.3 Subjects with Allergy, Atopy, and Ozone-Induced Hyperreactivity
Allergic or hypersensitivity disorders may be recognized by generalized
systemic reactions as well as localized reactions in various sites of the
body. The reactions can be acute, subacute, or chronic, immediate or delayed,
and may be caused by a variety of physical and chemical stimuli (antigens).
Although many hypersensitive individuals in the population have a family
history of allergy, a true allergic reaction is one that is classically elicited
through an immunological mechanism (i.e., antigen-antibody response), thereby
distinguishing allergic responses from simple chemical or pharmacologic reac-
tions. There are also some individuals with family histories who develop
natural or spontaneous allergies, defined generally as atopy. Determination
of the specific allergens (antigens) responsible for these disorders is often
difficult, but clinical history, physical examination, skin tests, and selective
diets are very useful. A more definitive evaluation can be provided by pulmo-
nary function tests (e.g., airway reactivity), serum IgE levels, and nasal
cytology. The information available on the responsiveness of these individuals
to ozone, i.e., whether they differ from normal non-allergic, non-atopic
individuals, is sparse.
Hackney et al. (1977a) found decreases in spirometric function among
atopic individuals exposed to 0.5 ppm 0, with light intermittent exercise.
Neither Folinsbee et al. (1978), in a controlled laboratory exposure, nor Linn
et al. (1980), in a field study in the Los Angeles area, distinguished between
the responses of normal subjects and allergic non-asthmatic subjects. In the
latter study, spirometric function was reduced and symptoms were increased in
association with an average ambient 0., concentration of 0.17 ppm. Similarly,
O
Lebowitz et al. (1982, 1983) reported that 0., and TSP were independently
associated with peak flow in adults with airway obstructive disease, after
adjusting for other covariables.
Some healthy subjects with no prior history of respiratory symptoms or
allergy demonstrate increased nonspecific airway sensitivity resulting from 03
exposure (Golden et al., 1978; Holtzman et al., 1979; Kb'nig et al. , 1980;
Dimeo et al. , 1981; Kulle et al., 1982b). Airway responsiveness is typically
defined by changes in specific airway resistance produced by a provocative
bronchial challenge to drugs like acetylcholine, methacholine, or histamine,
administered after 0, exposure. In one study (Holtzman et al., 1979), in
which subjects were classified as atopic or nonatopic based on medical history
019C13/A 13-55 11/18/85
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PRELIMINARY DRAFT
and allergen skin testing, the induction and time course of increased bronchial
reactivity after exposure to CL were unrelated to the presence of atopy. An
association of (L-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 0,
(Sielczak et al., 1983). Little is known, however, about this relationship in
animals at lower 0, concentrations (<0.5 ppm), and the possible association
between 0.,-induced inflammation and airway hyperresponsiveness in human subjects
has not been explored systematically.
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
potential value 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 would be reasonable to infer that
some element present in all mammalian species, including man, was susceptible
to ozone. A commonality 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 polyunsaturated fatty acids and the oxidation of thiols or amino
acids in tissue proteins or small-molecular-weight peptides. Thus, since the
affected molecules are identical across all species, then any differences in
the observed responses between species would be a function of species differ-
ences in delivered doses or of subsequent processes of injury and repair. For
example, a likely target site for 0., toxicity is the cellular membrane, such
as the membrane of cells like the Type 1 and ciliated cell which cover a large
surface area of the respiratory tract. Since there are no major interspecies
differences in cell membranes and membranes are composed of proteins and
lipids, then both proposed molecular mechanisms of 0., toxicity could occur at
the cellular membrane. In fact, the two proposed mechanisms most likely occur
simultaneously. The consequent toxic impact on the membrane, the cell, and
surrounding tissue would be influenced by species differences in antioxidant
019C13/A 13-56 11/18/85
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PRELIMINARY DRAFT
defenses or repair mechanisms. A commonly accepted hypothesis is that if
ozone causes an effect in several animal species, it can cause a similar
effect in man. This does not imply, however, that the concentrations at which
man might experience the common effect are the same as those for experimental
animals.
The health data base for ozone consists of hundreds of studies with about
eight species, and even more strains, of laboratory animals. Generally, for a
given effect, whether it be on lung morphology, physiology, biochemistry, or
host defenses, all species tested have been responsive to ozone, albeit some-
times at different concentrations. The few studies of several species having
at least two points of identity for comparison will be discussed.
Morphological examinations of the lungs of several species have been
conducted after ozone exposure. Of the groups studied, there are significant
differences in lung structure. Man, nonhuman primates, and dogs have both
nonrespiratory and respiratory bronchioles, while respiratory bronchioles are
either absent or poorly developed in mice, rats, and guinea pigs. Additional
differences exist. Nonetheless, a characteristic ozone lesion occurs at the
junction of the conducting airways and the gaseous exchange tissues, whatever
the species specifics of the structure. The typical effect in all the species
examined is damage to ciliated and Type I cells and hyperplasia of nonciliated
bronchiolar cells and Type 2 cells. An increase in inflammatory cells is also
observed. Such changes were observed after a 7-day intermittent 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 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 is
likely to 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 0^ concentrations as low
as 0.22 ppm produces rapid, shallow breathing. Similar changes in respiration
019C13/A 13-57 11/18/85
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PRELIMINARY DRAFT
have been observed in man during exposure to comparable ozone concentrations,
as shown in Table 13-4. The onset of these effects is rapid and appears to be
related to the ozone concentration. In a literature review, Mauderly (1984)
compared changes in breathing patterns of humans and guinea pigs during and
after a 2-hr exposure to 0.7 ppm 0.,. The respiratory frequency increased and
tidal volume decreased with similar patterns 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 13-5). Short-term
exposure to 0., concentrations as low as 0.32 ppm increases airway responsive-
ness to provocative aerosols such as acetylcholine, carbachol, methacholine,
or histamine in sheep, dogs, and humans. However, the time course of this
response may be species specific. A maximum response is obtained immediately
after exposure in man but appears to be delayed by 24 hr in sheep and dogs.
Mauderly (1984) has also compared the effect of 2-hr CL 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.
Species comparisons of host defense against infection are theoretically
possible, given the abundance of information describing the effect of exposure
to photochemical oxidants. For example, as a surrogate for humans, the rodent
models relating to the physiologic interaction between infectious agents and
host antibacterial defense systems have a number of virtues. Green's 1984
review paper delineates the similarities of rodent's and man's antibacterial
defenses. Both defense systems consist of an aerodynamic filtration system,
fluid lining layer covering the respiratory membranes, active transport mecha-
nism for removal and inactivation of viable microorganisms, pulmonary cells
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TABLE 13-4. COMPARISON OF THE ACUTE EFFECTS OF OZONE ON BREATHING PATTERNS IN ANIMALS AND MAN
Ozone3
concentration
ug/mj
392
686
431
804
1568
470
588
784
588
588
588
588
980
666
1333
2117
2646
725
980
1470
980
1100
1470
ppm
0.20
0.35
0.22
0.41
0.8
0.24
0.30
0.40
0.3
0.3
0.3
0.3
0.5
0.34
0.68
1.08
1.35
0.37
0.50
0.75
0.5
0.56
0.75
Measurement
method
UV
CHEM
CHEM
MAST
UV
UV
CHEM
NBKI
MAST
NBKI
CHEM
MAST
Exposure
duration
1 hr
(mouthpiece)
2 hr
2.5 hr
1 hr
(mouthpiece)
1 hr
(mouthpiece)
1 hr
2 hr
2 hr
2 hr
2 hr
2 hr
2 hr
Activity0
level (V£)
CE(77.5)
R
IE(65)
CE(34.7, 51)
CE(66)
CE(55)
IE(31,50,67)
R
IE(29)
R
R
IE
Observed effects(s)
Increased f. and decreased V..
Concentration-dependent increase in f_ for
all exposure levels.
Increased f. and decreased V..
Increased f., and decreased V,..
Increased f_ and decreased V,.
Increased fR and decreased V,.
Increased f~ and decreased V,
with time o* exposure; signi-
ficant linear correlations with
Increased f_ and decreased V-. during
exposure to all 03 concentrations.
Oose-dependent increase in f_ and decrease
in VT. "
Increased fR.
Abnormal, rapid, shallow breathing while
exercising on a treadmill after exposure.
Increased fR and decreased V, at maximum
workloads only.
Species Reference
Human Adams and Schelegle, 1983
Guinea pig Amdur et al. , 1978
Human McDonnell et al . , 1983
Human DeLucia et al., 1983
Human DeLucia and Adams, 1977
Human Gibbons and Adams, 1984
Human Folinsbee et al., 1978
Guinea pig Murphy et al., 1964
Human Folinsbee et al., 1975
Guinea pig Yokoyama, 1969
Dog Lee et al. , 1979
Human Folinsbee et al., 1977a
Ranked by lowest observed effect level.
Measurement method: MAST = Kl-Coulometric (Mast meter); CHEM = gas phase chemiluminescence; UV = ultraviolet photometry; NBKI = neutral buffered
potassium iodide.
Minute ventilation reported in L/min or as a multiple of resting ventilation. R = rest; IE = intermittent exercise; CE = continuous exercise.
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PRELIMINARY DRAFT
TABLE 13-5. COMPARISON OF THE ACUTE EFFECTS OF OZONE ON AIRWAY REACTIVITY IN ANIMALS AND MAN
Ozone3
concentration
ug/m3
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
Activity
level (V_)
R
IE(4-5xR)
IE(2xR)
R
IE(2xR)
R
R
R
Observed effects(s)
SR increased with ACh challenge.
dW
SG decreased with methachol ine;
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
metKacholine 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 Ktinig 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.
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PRELIMINARY DRAFT
(alveolar macrophages, polymorphonuclear leukocytes) and immune secretions of
lymphocytes and plasma cells. These similarities provide an ideal basis for
qualitative extrapolation, since in both species these components act in
concert to maintain the lung free of bacteria. The following conclusions are
therefore appropriate (Goldstein, 1984). First, similarity exists between the
major defense mechanisms in rodents and humans sufficient to permit the use of
the rat as a human surrogate. Second, the pulmonary antibacterial system is a
sensitive means of assessing potential toxicity. Third, pollutant-induced
abnormalities in the individual components of the host defense system permit
bacterial proliferation and disease. Fourth, extrapolation of results in
rodents to humans is qualitative. Although quantitative relationships may also
exist, the detailed information is not yet available for such extrapolation.
In addition, too few studies of antiviral host defenses after 0, exposure
exist to form any accurate conclusions.
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 acti-
vity was elevated to a roughly equivalent degree. Glutathione reductase
activity was increased in rats, but not monkeys. Chow et al. (1975) also
compared these species after exposure to 0.5 ppm ozone for 8 hr/day for 7
days. Antioxidant enzymes were increased in the rats, but not 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.
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For extrapulmonary effects, the only species comparison was made by
Graham et al. (1981). Female mice, rats, and hamsters had an increase in
pentobarbital-induced sleeping time after a 5-hour exposure to 1 ppm ozone.
Under the experimental conditions used, relative species responsivity cannot
be assessed.
An analysis of the animal toxicological data for ozone indicates that the
rat is the species most often tested. Other species often used include mice,
rabbits, guinea pigs, and monkeys. A few dog, cat, sheep, and hamster studies
exist. As has been noted above, very few species comparisons can be made due
to differences in exposure regimens and measurement techniques. Even when
direct comparisons are possible, interpretation is difficult. Statements
regarding responsiveness can be made, but statements about sensitivity (e.g.,
responses to an equivalent delivered dose) cannot be made until more dosimetry
and other types of data are available. Nonetheless, 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 experiences more types of effects than can be deduced from human
studies. Types of effects for which substantial animal data bases exist
include changes in lung structure, biochemistry, and host defenses. However,
the risks to man from breathing ambient levels of ozone cannot fully be deter-
mined until quantitative extrapolations of animal results are used in making
inferences about the likelihood of effects occurring in man.
13.5.2 Dosimetry Modeling
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 biological response given that the same dose of ozone is
delivered to a target site in different species. A coupling of these two
elements is required to be able to make quantitative interspecies comparisons
of toxicological results from different experiments.
Although additional research is needed on dosimetry and on species sensi-
tivity before quantitative extrapolations can confidently be inferred between
species, only dosimetry is sufficiently advanced for discussion here. Because
the factors affecting the transport and absorption of 0, are general to animals
and man, dosimetry models can be formulated that use appropriate species
019C13/A 13-62 . 11/18/85
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PRELIMINARY DRAFT
anatomical and ventilatory parameters to describe CL absorption. Thus far,
theoretical modeling efforts (McJilton et al., 1972; Miller et al., 1978b,
1985) 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
(Miller et al., 1979), and guinea pig (Miller et al. , 1979). To date, infor-
mation on nasopharyngeal removal of CL in man is not available. Since naso-
pharyngeal removal of 0, serves to lessen the insult to lower respiratory
tract tissue, an assessment of species differences in this area is critical to
interspecies comparisons of dosimetry.
Damage to all respiratory tract regions occurs in animals exposed to CL,
•J
with location and intensity dependent upon concentration and exposure duration.
When comparisons are made at the analogous anatomical site, the morphological
effects of CL on the lungs of a number of animal species are remarkably similar.
Despite inherent differences in the anatomy of the respiratory tract between
various experimental animals and man, the junction between the conducting
airways and the gas exchange region is most affected by 0., exposure in animals
(See 10.3.1). This finding is consistent with the inference that this region
is also most likely the principal site affected in man. Dosimetry model
simulations (Miller et al., 1978b) predict that the maximal tissue dose occurs
at the region of predominant morphological damage in animals. The overall
similarity of the predicted CL dose patterns in animal lungs studied thus far
(rabbits and guinea pigs) extends to the simulation of CL uptake in humans
(Miller et al., 1985) (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 quantitative extrapolations of effects from exposure to CL. Since
animal studies are the only available approach for investigating the full
array of potential disease states induced by exposure to 0,, quantitative use
•J
of animal data is in the interest of better establishing CL levels to which
man can safely be exposed.
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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 because of its relative abundance compared
with other photochemical oxidants. Still, the coexistence of other reactive
oxidants (Section 13.2.2) suggests that the potential effects of other ambient
oxidants should be examined. Not unexpectedly, however, animal and clinical
research has centered largely on 0,; very limited effort has been devoted to
studies of peroxyacetyl nitrate (PAN) and hydrogen peroxide (H,,0?). Field and
epidemiological studies evaluate health effects associated with exposure to
the ambient environment, making it difficult to single out the oxidant species
responsible for the observed effects.
13.6.1 Effects of Peroxyacetyl Nitrate
There have been too few controlled toxicological studies with the other
oxidants to permit a sound scientific evaluation of their contribution to the
toxic action of photochemical oxidant mixtures. The few animal toxicology
studies on PAN indicate that it is less acutely toxic than 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,
J
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 moderate exercise
(Smith, 1965; Drinkwater et al., 1974; Raven et al., 1974a,b, 1976; Gliner
et al., 1975). No significant effects were observed at PAN concentrations of
0.25 to 0.30 ppm, which are higher than the daily maximum concentrations of
PAN reported for relatively high oxidant areas (0.037 ppm). One study
(Drechsler-Parks et al., 1984) suggested a possible simultaneous effect of PAN
and 0,; however, there are not enough data to evaluate the significance of
this effect.
Field and epidemiological studies have found few specific relationships
between reported health effects and PAN concentrations. The increased preva-
lence of eye irritation reported during ambient air exposures has been asso-
ciated with PAN as well as other photochemical reaction products (National Air
019C13/A 13-64 11/18/85
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PRELIMINARY DRAFT
Pollution Control Administration, 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
discomfort was reported along with eye irritation as PAN concentrations in the
ambient air increased from 0 to 0.012 ppm (Javitz et al., 1983). However, the
significance of these symptomatic responses is questionable since functional
changes reported in this study for the subjects exposed to total oxidants (0~
and PAN) were similar to those found for 0, alone.
13.6.2 Effects of Hydrogen Peroxide
Toxicological studies on H«0~ have been performed at concentrations much
higher than those found in the ambient air (see Section 13.2). The majority
have been mechanistic studies using various jn vitro techniques for exposure.
Very limited information is available on the health significance of inhalation
exposure to gaseous HLCL in laboratory animals. No significant effects were
observed in rats exposed for 7 days to >95 percent H?0? gas with a concentration
of 0.5 ppm in the presence of inhalable ammonium sulfate particles (Last
et al. , 1982). Because H?tL 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). Unfortu-
nately, there have not been studies designed to look for possible effects in
this region of the respiratory tract.
A few in vitro studies have reported cytotoxic, genotoxic, and biochemical
effects of H?0? 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 0. with SC< NO^, 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
019C13/A 13-65 11/18/85
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mixtures of these pollutants. Studies reviewed in the previous 03 criteria
document (U.S. Environmental Protection Agency, 1978) suggested that mixtures
of SCL and CL at a concentration of 0.37 ppm are potentially more active than
would be expected from the behavior of the gases acting separately (Bates and
Hazucha, 1973; Hazucha and Bates, 1975). High concentrations of inhalable
aerosols, particularly HLSCK or ammonium sulfate, could have been responsible
for the results (Bell et al., 1977); however, subsequent studies of 0., mixtures
with SCL, 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, the exposure
design, and the measured variables. Additive and/or possibly syner,gistic
effects of 03 exposure in combination with NO,, have been described for increased
susceptibility to bacterial infection (Ehrlich et al., 1977, 1979; Ehrlich,
1980, 1983), morphological lesions (Freeman et al., 1974), and increased
antioxidant metabolism (Mustafa et al., 1984). Additive or possibly synergistic
effects from exposure to 0, and H?SO. have also been reported for host defense
mechanisms (Gardner et al., 1977; Last and Cross, 1978; Grose et al., 1982),
pulmonary sensitivity (Osebold et al., 1980), and collagen synthesis (Last et
al., 1983), but not for morphology (Cavender et al., 1977; Moore and Schwartz,
1981). Mixtures of 0, and (NH.)2SO. had synergistic effects on collagen
synthesis and morphometry, including percentage of fibroblasts (Last et al.,
1983, 1984a).
Combining 0, with other particulate pollutants produces a variety of
responses in laboratory animals, depending on the endpoint measured. Mixtures
of 0 Fe (S04) H SO and (NH^-SO. produced the same effect on clearance
rate of particles from the lung as exposure to 0.. alone (Phalen et al., 1980).
However, when measuring changes in host defenses, the combination of 0., with
N0£ and ZnS04 (Ehrlich et al., 1983) or 03 with S02 and (NH4)2S04 (Aranyi et
al., 1983) produced enhanced effects that can not be attributed to 0., only.
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
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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.
One of the major limitations 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 concentra-
tions has also limited the usefulness of these studies for standard-setting.
Concerns raised about the relative contribution to untoward effects by pollu-
tants other than CU have been diminished somewhat by direct comparative findings
in exercising athletes showing no differences in response between chamber
exposures to oxidant-polluted ambient air and purified air containing an
equivalent concentration of generated CL (Avol et al., 1984). 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 (Whittemore and Korn, 1980; Linn et al.,
1980, 1983a; Lebowitz et al., 1982, 1983; Lebowitz, 1984; Holguin et al.,
1985) and in children and young adults (Kagawa and Toyama, 1975; Kagawa et al.,
1976; Lippmann et al. , 1983; Lebowitz et al., 1982, 1983; Bock et al., 1985;
Lioy et al., 1985). Possible interactions between 0., and total suspended
particulate matter have been reported with decreased expiratory flow in chil-
dren (Lebowitz et al. , 1982, 1983; Lebowitz, 1984) and adults with symptoms of
airway obstructive disease (Lebowitz et al., 1982, 1983).
The effects of interactions between inhaled oxidant gases and other
environmental pollutants on the lung have not been systematically studied. In
fact, one of the major problems with the available literature on interaction
concerns the exposure design. Most of the controlled studies have not used
concentrations of combined pollutants that are found in the ambient environment.
It may be desirable to place greater research emphasis on characterizing
sequential patterns of air pollutant exposure which may have quite different
effects compared with continuous exposure to pollutant mixtures. An alterna-
tive approach 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.
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13.7 IDENTIFICATION OF POTENTIALLY AT-RISK GROUPS
13.7.1 Introduction
The identification of the population or group to be protected by a national
ambient air quality standard depends upon a number of factors, including
(1) the identification of one or more specific biological endpoints (effects)
that individuals within the population should be protected from; and (2) the
identification of those individuals in whom those specific endpoints are
observed (a) at lower concentrations than in other individuals, (b) with
greater frequency than in other individuals, (c) with greater consequences
than in other individuals, or (d) at various combinations of "effects levels,"
frequency, or consequences. In addition, other factors such as activity
patterns and personal habits, as well as actual and potential exposures to the
pollutant in question, must be taken into account when identifying one or more
groups potentially at risk from exposure to that pollutant.
In the following sections, biological and other factors that have been
found to predispose one or more groups to particular risk from exposure to
photochemical oxidants are discussed. It should be noted that these factors
are discussed in relation to ozone exposure only. There are too few controlled
studies with the other oxidants to permit a sound scientific evaluation of
their contribution to the toxic action of photochemical oxidant mixtures. The
following sections also include estimates of the number of individuals in the
United States that fall into certain categories of potentially at-risk groups.
It must be emphasized that the final identification of those effects that
are considered "adverse" and the final identification of "at-risk" groups are
both the domain of the Administrator.
13.7.2 Potentially At-Risk Individuals
All studies have shown that there is a wide variation in sensitivity to
ozone among healthy subjects. The factors suspected of altering sensitivity
to ozone are numerous. Those actually known to alter sensitivity, however,
are few, largely because few have been examined adequately to determine defini-
tively their effects on sensitivity. The discussion below presents information
on the factors that are thought to have the potential for affecting sensitivity
to ozone, along with what is actually known from the data regarding the impor-
tance 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.
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Sensitivity to a specified dose of an air pollutant may be greater or
less than normal. Changes in sensitivity may arise from some prior exposure
or may result from cross-reactivity to chemicals. Individual differences in
sensitivity or an unusual response upon exposure cannot be explained at the
present time. Statistical analysis is generally relied upon to establish the
range of normal responses for a particular biological endpoint, and to distin-
guish between normal responses and those that are indicative of either increased
or decreased sensitivity.
Susceptibility may be conferred by some predisposing host factor, such as
immunological or biochemical factors; or by some condition, such as preexisting
disease. Susceptibility may also result from some aspect of the growth or
decline of lung development (e.g., greater bronchomotor tone in childhood,
loss of lung function in the elderly), or some previous infectious or immunolog-
ical process (e.g., childhood respiratory trouble, prior bronchiolitis or
other lower respiratory tract infections, and prior asthma).
In most human studies, the complex diagnostic procedures needed to classify
study subjects properly are not performed, nor is the mechanism of response
usually determined or even examined (i.e., underlying immunological, biochem-
ical, or structural character). Furthermore, even diagnostic labels, such as
COLD, asthma, allergy, and atopy, are not usually based on sufficient clinical
evaluation nor standardized inclusion/exclusion criteria, so that differences
in such classifications within and between studies are bound to occur. For
example, there are few studies in which bronchoconstrictor challenges, skin or
blood antibody testing, or similar procedures were performed, let alone radio-
graphic studies, to characterize disease status. 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 identified as being susceptible or sensitive to 0,, will respond
dramatically to 0, exposure.
Airway reactivity is affected by a variety of pharmacologic and norrphar-
macologic stimuli. The degree to which different stimuli act in a given
individual is determined by a complex set of mechanisms which may vary from
subject to subject and from time to time. Unfortunately, little information
on these aspects of the study population is available so that reliance must be
placed on limited work-ups, non-standardized clinical evaluations and defini-
tions, and theoretical considerations. Thus, estimates of "at-risk" groups
are difficult to assess with any precision with presently available data.
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Anthropomorphic and demographic characteristics which have been used to
attempt to characterize susceptible individuals in the general population
include gender, age, race, ethnic group, nutritional status, baseline lung
function, and immunological status. Many of these factors have implications
for the acquisition and/or progress of infectious and chronic diseases. For
example, the very young and very old members of the population, individuals
with inadequate nutrition, individuals with depressed baseline lung function,
may all be predisposed to susceptibility or sensitivity to ozone. None of
these factors, however, has been sufficiently studied in relation to 0., exposure
to give definitive answers.
The most prominent modifier of response to 0., in the general population
O
is minute ventilation, which increases proportionately with increases in
exercise workload. Higher levels of exercise enhance the likelihood of in-
creased frequency of irritative symptoms and decrements in forced expiratory
volume and flow. However, even in well-controlled experiments on apparently
homogeneous groups of healthy subjects, physiological responses to the same
exercise levels and the same 0. concentrations have been found to vary widely
among individuals.
Exposure history may determine susceptibility or sensitivity. Smokers
are more susceptible to impaired defense against infection, have some chronic
inflammation in the airways, have cellular damage, and may have altered biochem-
ical/cellular responses (e.g., reduced trypsin inhibitory capacity, neutro-
philia, impaired macrophage activity). Likewise, those with "significant"
occupational exposures to irritants, sensitizers or allergens may have similar
predispositions. Furthermore, both groups show differential immunological
status, atopy, and, in some cases, bronchomotor tone. Despite these inferences,
there is some evidence to suggest that smokers may be less sensitive to 0,.
although the available data are not conclusive.
Social, cultural, arid 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
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immunoglobulin-E, possibly altered prostaglandin function and/or T-cell func-
tion) or cellular function (e.g., eosinophi1ia), may be expected to be poten-
tially more sensitive to 0,. Asthma, however, is not a specific homogeneous
disease and efforts to precisely define asthma have been unsuccessful. Like-
wise, allergic individuals, with a predisposing atopy, have altered immunolog-
ical responses, similar to those in asthmatics, and may have labile bronchomotor
tone, such that they may also be expected to be potentially more sensitive to
(L. Patients with COLD may or may not be potentially more sensitive to CL,
depending on their clinical and functional state. Although currently available
evidence indicates that individuals with preexisting disease respond to CL
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 CU can be adequately determined. Furthermore, it should be
noted that ethical constraints have precluded the testing in controlled studies
of individuals with severe pre-existing disease. It is also prudent to consider
carefully whether small functional changes in individuals with COLD, asthma,
or allergy represent equivalent or more severe physiological significance
compared to the normal subject.
13.7.3 Potentially At-Risk Groups
As the preceding discussion and discussion in Sections 13.3 and 13.4
indicate, only small samples of the population, either of healthy individuals
or those with pre-existing disease, have been tested. Definitive data on the
relative susceptibilities to ozone of various kinds of individual subjects are
therefore lacking, both in epidemiological and controlled-exposure studies.
Notwithstanding the uncertainties that exist in the data, it is possible tu
identify the groups that might be at particular risk from exposure to ozone.
In the legislative history of Section 109 of the Clean Air Act (U.S.
Senate, 1970), the definition of a "sensitive population" excludes "individuals
who are otherwise dependent on a controlled internal environment" 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
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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.:p
Concern should be given to the "contribution of age, ethnic, social, occupa-
tional, smoking, and other factors to susceptibility to air pollution agents."
Consonant with the provisions of the Clean Air Act and with its legisla-
tive history, the first group that appears to be at particular risk from
exposure to ozone is that group of the general population characterized as
having preexisting respiratory disease. Available data on actual differences
in sensitivity between these and healthy members of the general population
indicate that under the exposure regimes used to date, individuals with pre-
existing respiratory disease may not be more sensitive to ozone than normal
individuals. Nevertheless, several important considerations place these
individuals among groups at potential risk from exposure to ozone. First, it
must be noted that concern with triggering untoward reactions has necessitated
the use of low concentrations and low exercise levels in most studies on
subjects with pre-existing disease. Therefore, few or no data on responses at
higher concentrations and higher exercise levels are available for comparison
with responses in normal subjects. Second, subjects in controlled studies may
not have been adequately characterized in all instances regarding disease
state. Thus, definitive data on responses in individuals with preexisting
disease are not available. Third, the effects that ozone may have on groups
with pre-existing disease may not be measured by traditional tests of lung
function and identification of any effects may require the use of different
tests or may have to await new technological developments. Finally, it must
be emphasized that in individuals with already compromised pulmonary function,
the decrements in function produced by exposure to ozone, while similar to or
even the same as those experienced by normal subjects, represent a further
decline in volumes and flows that are already diminished. 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.
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The second group apparently at special risk from exposure to ozone consists
of individuals ("responders"), not yet characterized medically except by their
response to ozone, who experience greater decrements in lung function from
exposure to ozone than the average response of the groups studied. It is not
known if "responders" are a specific population subgroup or simply represent
the upper 5 to 20 percent of the ozone response distribution. As yet no means
of 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 the references therein) 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.
Data presented in Chapter 11 and in this chapter underscore the importance
of exercise in the potentiation of effects from exposure to ozone. Thus, the
third group potentially at risk from exposure to ozone is composed of those
individuals, healthy or otherwise, whose activities out of doors, whether
vocational or avocational, result in increases in minute ventilation. As
stated in section 13.7.2, "the most prominent modifier of response to Cu in
the general population is minute ventilation, which increases proportionately
with increases in exercise workload." Although many individuals with pre-
existing 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.
As pointed out in this chapter, other biological and nonbiological factors
are suspected of influencing responses to ozone. Data remain inconclusive at
the present, however, regarding the importance of age, gender, and other
factors in influencing response to ozone. Thus, at the present time, no other
groups are thought to be at particular risk from exposure to ozone in ambient
air through biological predisposition or activity patterns than those identified
in this section.
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
019C13/A 13-73 11/18/85
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for the social, economic, and housing characteristics of every residence. In
determining residence, the census counts each person as an inhabitant of the
place where eating and sleeping usually take place rather than a person's
legal or voting residence. Each residence is, in turn, grouped according to
the official standard metropolitan statistical areas (SMSA's) and standard
consolidated statistical areas (SCSA's) as defined by the Office of Management
and Budget. Briefly, SMSA's represent a large population nucleus together
with adjacent communities which have a high degree of social and economic
integration; SCSA's are large metropolitan complexes consisting of groups of
closely related adjacent SMSA's. Table 13-6 gives the geographical distribu-
tion 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 metropo-
litan (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 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
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
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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,
mi 1 1 ions
226.5
49.1
58.9
75.4
43.2
169.4
68.0
101.5
57.1
167.1
59.5
Population,
percent
100.0
21.7
26.0
33.3
19.0
74.8
30.0
44.8
25.2
73.7
26.3
aU.S. Bureau of the Census (1982).
Represented by 318 standard metropolitan statistical areas (SMSA's).
Comprises all persons living in cities, villages, boroughs, and towns of
2500 or more inhabitants but excluding those persons living in the rural
portions of extended cities.
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
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.
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TABLE 13-7. TOTAL POPULATION OF THE UNITED STATES
BY AGE, SEX, AND RACE, 1980
Age, sex, race
Population,
mi 11 ions
Population,
percent
Total
226.5
100.0
Under 5 years
5-17 years
18-44 years
45-64 years
65 years and over
Male
Female
White^
BlackP
Other
16.3
47.1
93.3
44.4
25.5
110.0
116.5
194.8
26.6
5.1
7.2
20.8
41.2
19.6
11.3
48.6
51.4
86.0
11.7
2.3
U.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.
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TABLE 13-8. PREVALENCE OF CHRONIC RESPIRATORY CONDITIONS BY SEX AND AGE FOR 1979°
Number of persons, in thousands
Condition
Chronic bronchitis
Emphysema
Asthma
Hay fever and
other upper
respiratory
al lergies
Totalc
7474
2137
6402
15,620
Male
3289
1364
3113
7027
Female
4175
770
3293
8584
<17
years old
2458
12d
2225
3151
17-44
years old
2412
127d
2203
8278
45-64
years old
1547
1008
1482
3012
>65
years old
1060
990
488
1181
% of U.S.
population
3.5
1.0
3.0
7.2
U.S. Department of Health and Human Services, 1981.
Classified by type, according to the Ninth Revision of the International Classific of Diseases (World Health
Organization, 1977).
"Reported as actual number in thousands; remaining subsets have been calculated from percentages and are rounded off.
Does not meet standards of reliability or precision set by the National Center for Health Statistics (more than 30%
relative standard error).
2With or without hay fever.
Without asthma.
f
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13.8 SUMMARY AND CONCLUSIONS
13.8.1 Health Effects in the General Human Population
Controlled human studies of at-rest exposures to 03 lasting 2 to 4 hr
have demonstrated decrements in forced expiratory volume and flow occurring at
and above 0.5 ppm of 0, (Chapter 11). Airway resistance was not significantly
changed at these 0~ concentrations. Breathing 0~ at rest at concentrations
< 0.5 ppm did not significantly impair pulmonary function although the occur-
rence 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 (V.-), 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 V^ not only increase the overall volume of inhaled pollutant, but
the increased tidal volume may lead to a higher concentration of ozone in the
lung regions most sensitive to ozone. These processes are further enhanced at
high work loads (Vp > 35 L/min), since the mode of breathing changes at that
Vp from nasal to oronasal.
Even in well-controlled experiments on an apparently homogeneous group of
healthy subjects, physiological responses to the same work and pollutant loads
will vary widely among individuals. Despite large interindividual variability,
the magnitude 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 (Chapter 11 and references therein), significant pulmo-
nary function impairment (decrement) occurs when exercise is combined with
exposure to ozone:
1. Light exercise (Vp < 23 L/min) - Effects at > 0.37 ppm Cu;
2. Moderate exercise (V = 24 to 43 L/min) - Effects at ;> 0.30 ppm 0,;
3. Heavy exercise (V£ = 44 to 63 L/min) - Effects at > 0.24 ppm 03; and
4. Very heavy exercise (vV >_ 64 L/rnin) - Effects at > 0.18 ppm 0,, with
suggestions of decrements at 0.12 ppm 0-^.
For the majority of the controlled studies, 15-min intermittent exercise
alternated with 15-min rest was employed for the duration of the exposure.
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The maximum response to 0., exposure can be observed within 5 to 10 min follow-
ing 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 func-
tional recovery, other regulatory systems may still exhibit abnormal responses
when stimulated; e.g., airway hyperreactivity might persist for days.
Continuous exercise equivalent in duration to the sum of intermittent
exercise periods at comparable ozone concentrations (0.2 to 0.4 ppm) and
minute ventilation (60 to 80 L/min) seems to elicit greater changes in pulmonary
function but the differences between intermittent and continuous exercise are
not clearly established. More experimental data are needed to make any quanti-
tative evaluation of the differences in effects induced by these two modes of
exercise.
A close association has been observed between the occurrence of respiratory
symptoms and changes in pulmonary function in adults acutely exposed in environ-
mental chambers to 0, (Chapter 11) or to ambient air containing 0., as the
predominant pollutant (Chapter 12). This association holds for both the
time-course and magnitude of effects. Studies on children and adolescents
exposed to 03 or ambient air containing 03 under similar conditions have found
no significant increases in symptoms despite significant changes in pulmonary
function (Avol et al., 1985a,b; McDonnell et al., 1985b,c). Epidemiological
studies of exposure to ambient photochemical pollution are of limited use for
quantifying exposure-response relationships for 0., because they have not
adequately controlled for other pollutants, meteorological variables, and
non-environmental factors in the data analysis. Eye irritation, for example,
one of the most common complaints associated with photochemical pollution, is
not characteristic of clinical exposures to 0.,, even at concentrations several
times higher than any likely to be encountered in ambient air. There is
limited qualitative evidence to suggest that at low concentrations of 0.,,
other respiratory and nonrespiratory symptoms, as well, are more likely to
occur in populations exposed to ambient air pollution than in subjects exposed
in chamber studies (Chapter 12).
Discomfort caused by irritative symptoms may be responsible for the
impairment of athletic performance reported in high school students during
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PRELIMINARY DRAFT
cross-country track meets in Los Angeles (Chapter 12). Only a few controlled-
exposure studies, however, have been designed to examine the effects of 0, on
exercise performance (Chapter 11). In one study, light intermittent exercise
(VV = 20-25 L/min) at a high 0., concentration (0.75 ppm) reduced postexposure
maximal exercise capacity by limiting maximal oxygen consumption; submaximal
oxygen consumption changes were not significant. The extent of ventilatory
and respiratory metabolic changes observed during or following the exposure
appears to have been related to the magnitude of pulmonary function impairment.
Whether such changes are consequent to respiratory discomfort (i.e., symptomatic
effects) or are the result of changes in lung mechanics or both is still
unclear and needs to be elucidated.
Environmental conditions such as heat and relative humidity may alter
subjective symptoms and physiological impairment associated with 0, exposure.
Modification of the effects of CL by these factors may be attributed to in-
creased ventilation associated with elevated body temperature but there may
also be an independent effect of elevated body temperature on pulmonary function
(VC).
Numerous additional factors have the potential for altering responsiveness
to ozone. For example, children and older individuals may be more responsive
than young adults. Other factors such as gender differences (at any age),
personal habits such as smoking, nutritional deficiencies, or differences in
immunologic status may predispose individuals to susceptibility to ozone. In
addition, social, cultural, or economic factors may be involved. Those actually
known to alter sensitivity, however, are few, largely because they have not
been examined adequately to determine definitively their effects on sensitivity
to On. The following briefly summarizes what is actually known from the data
regarding the importance of these factors (see Section 13.3.3 for details):
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 0.,, sufficient numbers of studies have not been performed to provide
any sound conclusions for effects of 03 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- -,
might be affected more than that of men under similar exercise and exposure
conditions, but the possible differences have not been tested systematically.
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Further research is needed to determine whether there are systematic differ-
ences in response that are related to sex.
3. Smoking Status. Differences between smokers and nonsmokers have
been studied often, but the smoking histories are not documented well. There
is some evidence, however, to suggest that smokers may be less sensitive to CL
•J
than nonsmokers.
4. Nutritional Status. Antioxidant properties of vitamin E in preventing
ozone-initiated peroxidation ui vitro are well demonstrated and their protective
effects _i_n vivo are clearly demonstrated in rats and mice. No evidence indi-
cates, however, that man would benefit from increased vitamin E intake relative
to ambient ozone exposures.
5. Red Blood Cell Enzyme Deficiencies. There have been too few studies
performed to document reliably that individuals with a hereditary deficiency
of glucose-6-phosphate dehydrogenase may be at-risk to significant hematolog-
ical effects from 0, exposure. Even if 0, or a reactive product of O.-tissue
interaction were to penetrate the red blood cell after _ui vivo exposure, it is
unlikely that any depletion of glutathione or other reducing compounds would
be of functional significance for the affected individual.
Successive daily brief exposures of healthy human subjects to CL (<0.7 ppm
for approximately 2 hr) induce a typical temporal pattern of response (Chap-
ter 11, Section 11.3). Maximum functional changes that occur after the first
or second exposure day become progressively attenuated on each of the subsequent
days. By the fourth day of exposure, the average effects are not different
from those observed following control (air) exposure. Individuals need between
3 and 7 days 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 CL concentration. It is not known how variations in the length or
frequency of exposure will modify the time course of this altered responsive-
ness. In addition, concentrations of CL that have no detectable effect appear
not to invoke changes in response to subsequent exposures at higher 0, concen-
trations. 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 the severity of symptoms is generally
related to the magnitude of the functional response, partial attenuation of
symptoms appears to persist longer, for up to 4 weeks.
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Whether populations exposed to photochemical air pollution develop at
least partial attenuation is unknown. No epidemiological studies have been
designed to test this hypothesis and additional information is required from
controlled laboratory studies before any sound conclusions can be made.
Ozone toxicity, in both humans and laboratory animals, may be mitigated
through altered responses at the cellular and/or subcellular level. At present,
the mechanisms underlying altered responses are unclear and the effectiveness
of such mitigating factors in protecting the long-term health of the indivi-
dual against ozone is still uncertain. A growing body of experimental evidence
suggests the involvement of vagal sensory receptors in modulating the acute
responsiveness to ozone. It is highly probable that most of the decrements in
lung volume reported to result from exposures of greatest relevance to standard-
setting (<0.3 ppm OT) are due to inhibition of maximal inspiration rather than
changes in airway diameter. None of the experimental evidence, however, is
definitive and additional research is needed to elucidate the precise mecha-
nism(s) associated with ozone exposure.
13.8.2 Health Effects in Individuals with Pre-Existing Disease
Currently available evidence indicates that individuals with preexisting
disease respond to 0, exposure to a similar degree as normal subjects. Patients
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 CL can be
adequately determined. None of these factors has been sufficiently studied in
relation to CL exposures to give definitive answers.
13.8.3 Extrapolation of Effects Observed in Animals to Human Populations
Animal experiments on a variety of species have demonstrated increased
susceptibility to bacterial respiratory infections following 0.. exposure.
Thus, it could be hypothesized that humans exposed to 0_ could experience
decrements in their host defenses against infection. At the present time,
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PRELIMINARY DRAFT
however, these effects have not been described in humans exposed to CL, 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
CL, including cardiovascular, reproductive, and teratological effects, along
•J
with changes in endocrine and metabolic function. The implications of these
findings for human health are difficult to judge at the present time. In
addition, central nervous system effects, alterations in red blood cell mor-
phology and enzymatic activity, as well as cytogenetic effects on circulating
lymphocytes, have been observed in laboratory animals following exposure to
0.,. While similar effects have been described in circulating cells from human
subjects exposed to high concentrations of 0.,, the results were either incon-
sistent or of questionable physiological significance (Section 13.3.8). It is
not known, therefore, if extrapulmonary responses would be likely to occur in
humans when exposure schedules are used that are representative of exposures
that the population at large might actually experience.
Despite wide variations in study techniques and experimental designs,
acute and subchronic exposures of animals to levels of ozone < 0.5 ppm produce
similar types of responses in all species examined. A characteristic ozone
lesion occurs at the junction of the conducting airways and the gas-exchange
regions of the lung after acute 0., exposure. Dosimetry model simulations
predict that the maximal tissue dose of 0., occurs in this region of the lung.
Continuation of the inflammatory process during longer CL exposures is espe-
cially important since it appears to be correlated with increased airway
resistance, increased lung collagen content, and remodeling of the centriacinar
airways, suggesting the development of distal airway narrowing. No convincing
evidence of emphysema in animals chronically exposed to 0, has yet been pub-
lished, but centriacinar inflammation has been shown to occur.
Since substantial animal data exist for 0,-induced changes in lung struc-
ture and function, biochemistry, and host defenses, it is conceivable that man
may experience more types of effects than have been established in human
clinical studies. It is important to note, however, that this is a qualitative
probability; it does not permit assessment of the ozone concen-trations at
which man might experience similar effects.
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13.8.4 Health Effects of Other Photochemical Oxidants and Pollutant Mixtures
Controlled human studies have not consistently demonstrated any modifica-
tion of respiratory effects for combined exposures of CL with S0?, NCL, CO, or
rLSO, and other particulate aerosols. Ozone alone is considered to be respon-
sible for the observed effects of those combinations or of multiple mixtures
of these pollutants. Combined exposure studies in laboratory animals have
produced varied results, depending upon the pollutant combination evaluated,
the exposure design, and the measured variables (Section 13.6.3). Thus, no
definitive conclusions can be drawn from animal studies of pollutant interac-
tions. There have been far too few controlled toxicological studies with
other oxidants, such as peroxyacetyl nitrate or hydrogen peroxide, to permit a
sound scientific evaluation of their contribution to the toxic action of
photochemical oxidant mixtures. There is still some concern, however, that
combinations of oxidant pollutants with other pollutants may contribute to the
symptom aggravation and decreased lung function described in 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.
13.8.5 Identification of Potentially At-Risk Groups
Despite uncertainties that may exist in the data, it is possible to
identify the groups that may be at particular risk from exposure to ozone,
based on known health effects, activity patterns, personal habits, and actual
or potential exposures to ozone.
The first group that appears to be at particular risk from exposure to
ozone is that subgroup of the general population characterized as having
preexisting respiratory disease. Available data on actual differences in
sensitivity between these and healthy members of the general population indi-
cate that, under the exposure regime used to date, individuals with preexisting
disease may not be more sensitive to ozone than healthy individuals. Neverthe-
less, two considerations place these individuals among groups at potential
risk from exposure to ozone. First, it must be noted that concern with trig-
gering untoward reactions has necessitated the use of low concentrations and
low exercise levels in most studies on subjects with mild preexisting disease.
019C13/A 13-84 11/18/85
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Therefore, few or no data on responses at higher concentrations and higher
exercise levels are available for comparison with responses in healthy subjects.
Thus, definitive data on responses in individuals with preexisting disease are
not available. Second, however, it must be emphasized that in individuals
with already compromised pulmonary function, the decrements in function produced
by exposure to ozone, while similar to or even the same as those experienced
by normal subjects, represent a further decline in volumes and flows that are
already diminished. 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.
The second group at apparent special risk from exposure to ozone consists
of individuals ("responders"), not yet characterized medically except by their
response to ozone, who experience greater decrements in lung function from
exposure to ozone than the average response of the groups studied. It is not
known if "responders" are a specific population subgroup or simply represent
the upper 5 to 20 percent of te ozone response distribution. 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 group
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 indivi-
duals with preexisting respiratory 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
groups may be considered to be potentially at. risk, depending upon other
determinants of total ozone dose, 0, concentration, and exposure duration.
Other biological and nonbiological factors have the potential for influenc-
ing responses to ozone. Data remain inconclusive at the present, however,
regarding the importance of age, gender, and other factors in influencing
response to ozone. Thus, at the present time, no other groups are thought to
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PRELIMINARY DRAFT
be biologically predisposed to increased sensitivity to ozone. It must be
emphasized, however, that the final identification of those effects that are
considered "adverse" and the final identification of "at-risk" groups are both
the domain of the Administrator.
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APPENDIX A: GLOSSARY OF PULMONARY TERMS AND SYMBOLS*
Acetylcholine (ACh): A naturally occurring substance in the body having
important parasympathetic effects; often used as a bronchoconstrictor.
Aerosol: Solid particles or liquid droplets that are dispersed or suspended
in a gas, ranging in size from 10 to 10 micrometers (urn).
Air spaces: All alveolar ducts, alveolar sacs, and alveoli. To be contrasted
with AIRWAYS.
Airway conductance (Gaw): Reciprocal of airway resistance. Gaw = (I/Raw).
Airway resistance (Raw): The (frictional) resistance to airflow afforded by
the airways between the airway opening at the mouth and the alveoli.
Airways: All passageways of the respiratory tract from mouth or nares down to
and including respiratory bronchioles. To be contrasted with AIR SPACES.
Allergen: A material that, as a result of coming into contact with appropriate
tissues of an animal body, induces a state of allergy or hypersensitivity;
generally associated with idiosyncratic hypersensitivities.
Alveolar-arterial oxygen pressure difference [P(A-a)0?]: The difference in
partial pressure of 0? in the alveolar gas spaces and that in the systemic
arterial blood, measured in torr.
Alveolar-capillary membrane: A fine membrane (0.2 to 0.4 |jm) 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 (PACO«): Partial pressure of carbon dioxide
in the air contained in the lung alveoli.
Alveolar oxygen partial pressure (P/vOp^' Partial pressure of oxygen in the
air contained in the alveoli or tne lungs.
Alveolar septum (pi. septa): A thin tissue partition between two adjacent
pulmonary alveoli, consisting of a close-meshed capillary network and
interstitium covered on both surfaces by alveolar epithelial cells.
*References: Bartels, H. ; Dejours, P.; Kellogg, R. H. ; Mead, J. (1973) Glossary
on respiration and gas exchange. J. Appl. Physiol. 34: 549-558.
American College of Chest Physicians - American Thoracic Society
(1975) Pulmonary terms and symbols: a report of the ACCP-ATS
Joint Committee on pulmonary nomenclature. Chest 67: 583-593.
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Alveolitis: (interstitial pneumonia): Inflammation of the lung distal to the
terminal non-respiratory bronchiole. Unless otherwise indicated, it is
assumed that the condition is diffuse. Arbitrarily, the term is not used
to refer to exudate in air spaces resulting from bacterial infection of
the lung.
Alveolus: Hexagonal or spherical air cells of the lungs. The majority of
alveoli arise from the alveolar ducts which are lined with the alveoli.
An alveolus is an ultimate respiratory unit where the gas exchange takes
place.
Anatomical dead space (V~ .): Volume of the conducting airways down to the
level where, during a^froreathing, 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 (PaO,,): Partial pressure of dissolved
oxygen in arterial blood.
Asthma: A disease characterized by an increased responsiveness of the airways
to various stimuli and manifested by slowing of forced expiration which
changes in severity either spontaneously or as a result of therapy. The
term asthma may be modified by words or phrases indicating its etiology,
factors provoking attacks, or its duration.
Atelectasis: State of collapse of air spaces with elimination of the gas
phase.
ATPS condition (ATPS): Ambient temperature and pressure, saturated with water
vapor. These are the conditions existing in a water spirometer.
Atropine: A poisonous white crystalline alkaloid, C-,7H?,NO.,, from belladonna
and related plants, used to relieve spasms of smoorn muscles. It is an
anticholinergic agent.
Breathing pattern: A general term designating the characteristics of the
ventilatory activity, e.g., tidal volume, frequency of breathing, and
shape of the volume time curve.
Breuer-Hering reflexes (Hering-Breuer reflexes): Ventilatory reflexes originat-
ing in the lungs. The reflex arcs are formed by the pulmonary mechanore-
ceptors, the vagal afferent fibers, the respiratory centers, the 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.
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Bronchiole: One of the finer subdivisions of the airways, less than 1 mm in
diameter, and having no cartilage in its wall.
Bronchiolitis: Inflammation of the bronchioles which may be acute or chronic.
If the etiology is known, it should be stated. If permanent occlusion of
the lumens is present, the term bronchiolitis obliterans may be used.
Bronchitis: A non-neoplastic disorder of structure or function of the bronchi
resulting from infectious or noninfectious irritation. The terra bronchitis
should be modified by appropriate words or phrases to indicate its etiol-
ogy, its chronicity, the presence of associated airways dysfunction, or
type of anatomic change. The term chronic bronchitis, when unqualified,
refers to a condition associated with prolonged exposure to nonspecific
bronchial irritants and accompanied by mucous hypersecretion and certain
structural alterations in the bronchi. Anatomic changes may include
hypertrophy of the mucous-secreting apparatus and epithelial metaplasia,
as well as more classic evidences of inflammation. In epidemiologic
studies, the presence of cough or sputum production on most days for at
least three months of the year has sometimes been accepted as a criterion
for the diagnosis.
Bronchoconstrictor: An agent that causes a reduction in the caliber (diame-
ter) of airways.
Bronchodilator: An agent that causes an increase in the caliber (diameter) of
airways.
Bronchus: One of the subdivisions of the trachea serving to convey air to and
from the lungs. The trachea divides into right and left main bronchi
which in turn form lobar, segmental, and subsegmental bronchi.
BTPS conditions (BTPS): Body temperature, barometric pressure, and saturated
with water vapor. These are the conditions existing in the gas phase of
the lungs. For man the normal temperature is taken as 37°C, the pressure
as the barometric pressure, and the partial pressure of water vapor as 47
torr.
Carbachol: A parasympathetic stimulant (carbamoylcholine chloride, CgH-jrClN-O,,)
that produces constriction of the bronchial smooth muscles.
Carbon dioxide production (VCO?): Rate of carbon dioxide production by organ-
isms, tissues, or cells. Common units: ml C0« (STPDykg-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 O.
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Chronic obstructive lung disease (COLD): This term refers to diseases of
uncertain etiology characterized by persistent slowing of airflow during
forced expiration. It is recommended that a more specific term, such as
chronic obstructive bronchitis or chronic obstructive emphysema, be used
whenever possible. Synonymous with chronic obstructive pulmonary disease
(COPD).
Closing capacity (CC): Closing volume plus residual volume, often expressed
as a ratio of TLC, i.e. (CC/TLC%).
Closing volume (CV): The volume exhaled after the expired gas concentration
is inflected from an alveolar plateau during a controlled breathing
maneuver. Since the value obtained is dependent on the specific test
technique, the method used must be designated in the text, and when
necessary, specified by a qualifying symbol. Closing volume is often
expressed as a ratio of the VC, i.e. (CV/VC%).
Collateral resistance (R ,,): Resistance to flow through indirect pathways.
See COLLATERAL VENTrOfTION 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 complia
given by the slope of a static volume-pressure curve at a point,
liance is
or the
linear approximation of a nearly straight portion of such a curve, ex-
pressed in liters/cm FLO or ml/cm H^O. Since the static volume-pressure
characteristics of lungs are nonlirrear (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.CCL, D.CO): Amount of gas (0,,
CO, C0?) commonly expressed as mr gas CSTPD) diffusing between alveolar
gas ana pulmonary capillary blood per torr mean gas pressure difference
per min, i.e., ml 0-/(min-torr). Synonymous with transfer factor and
diffusion factor.
Dynamic compliance (C, ): The ratio of the tidal volume to the change in
intrapleural pressure between the points of zero flow at the extremes of
tidal volume in liters/cm HJ) or ml/cm hLO. Since at the points of zero
airflow at the extremes of T,idal 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.
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Elastance (E): The reciprocal of COMPLIANCE; expressed in cm H,,0/liter or cm
H20/ml. ' L
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.
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:
= instantaneous forced expiratory flow after 75%
of the FVC has been exhaled.
FEF9nn 1?nn = mean forced expiratory flow between 200 ml
^uu-i^uu and 1200 m] Qf the pvc (formerly Ca11ed the
maximum expiratory flow rate (MEFR).
FEF?r 7ra; = mean forced expiratory flow during the middle
" D half of the FVC [formerly called the maximum
mid-expiratory flow rate (MMFR)].
FEF = the maximal forced expiratory flow achieved during
max an FVC.
Forced expiratory volume (FEV): Denotes the volume of gas which is exhaled in
a given time interval during the execution of a forced vital capacity.
Conventionally, the times used are 0.5, 0.75, or 1 sec, symbolized FEV., ,.,
FEVn 7t., FEV, n. These values are often expressed as a percent of the
forCed3vitalCapacity, e.g. (FEVj Q/VC) X 100.
Forced inspiratory vital capacity (FIVC): The maximal volume of air inspired
with a maximally forced effort from a position of maximal expiration.
Forced vital capacity (FVC): Vital capacity performed with a maximally forced
expiratory effort.
Functional residual capacity (FRC): The sum of RV and ERV (the volume of air
remaining in the lungs at the end-expiratory position). The method of
measurement should be indicated as with RV.
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PRELIMINARY DRAFT
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 hemp 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 amlno 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 07/100 ml arterial blood; in mixed venous blood
at rest it is 13-18 ml 02/l6o 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 Pn? is low in the environment, whether because of
decreased barometric pressure or decreased fractional concentration of
Op, the condition is termed environmental hypoxia. Hypoxia when referring
to the blood is termed hypoxemia. Tissues are said to be hypoxic when
their P~» is low, even if there is no arterial hypoxemia, as in "stagnant
hypoxia 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.
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PRELIMINARY DRAFT
Maximal aerobic capacity (max VOp): 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 (MW).
Maximum expiratory flow (V x): Forced expiratory flow, related to the
total lung capacity or Ins 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 7t.y = instantaneous forced expiratory flow when the
max /D*
V , n = instantaneous forced expiratory flow when the
m 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
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 (MW): 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 volume (V,) and breathing frequency (fn). See VENTILA-
TION. ' B
Minute volume: Synonymous with minute ventilation.
Mucociliary transport: The process by which mucus is transported, by ciliary
action, from the lungs.
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).
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PRELIMINARY DRAFT
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 NCL is the most
important toxicologically.
Nitrogen washout (AN?, dN~): The curve obtained by plotting the fractional
concentration of N, in expired alveolar gas vs. time, for a subject
switched from breathing ambient air to an inspired mixture of pure 0?. A
progressive decrease of N., concentration ensues which may be analyzed
into two or more exponential components. Normally, after 4 min of pure
Oy 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. Common unit?: ml 02 (STPD)/(kg-min) or ml 0- (STPD)/(kg-hr).
For whole organisms the oxygen consumption is commonly expressed per unit
surface area or_ some power of the body weight. For tissue samples or
isolated cells Qn? = pi 0?/hr per mg dry weight.
Oxygen saturation (SOp): The amount of oxygen combined with hemoglobin,
expressed as a percentage of the oxygen capacity of that hemoglobin. In
arterial blood, SaO?.
Oxygen uptake (VO-): 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 (Vn): Calculated volume which accounts for the
difference between the pressures of CO? ip 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.
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PRELIMINARY DRAFT
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, permanent enlargement of the air spaces
distal to the terminal nonrespiratory bronchiole, accompanied by destructive
changes of the alveolar walls and without obvious fibrosis. The term
emphysema may be modified by words or phrases to indicate its etiology,
its anatomic subtype, or any associated airways dysfunction.
Residual volume (RV): That volume of air remaining in the lungs after maximal
exhalation. The method of measurement should be indicated in the text
or, when necessary, by appropriate qualifying symbols.
Resistance flow (R): The ratio of the flow-resistive components of pressure
to simultaneous flow, in cm H?0/lit.er per sec. Flow-resistive components
of pressure are obtained by subtracting any elastic or inertial 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.
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PRELIMINARY DRAFT
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 (fp): The number of breathing cycles per unit of time.
Synonymous with breathing frequency (fp)-
Respiratory quotient (RQ, R): Quotient of the volume of CO,, produced divided
by the volume of 0? 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 CO,, output and Oy
uptake by the tissues. With this definition, respiratory quotient and
respiratory exchange ratio are identical in the steady state, a condition
which implies constancy of the 0^ and CO- 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, RESPIRA10RY CYCLE.
Spirometer: An apparatus similar to a spirograph but without recording facil-
ity.
Static lung compliance (C, .): Lung compliance measured at zero flow (breath-
holding) over linear portion of the volume-pressure curve above FRC. See
COMPLIANCE.
Static transpulmonary pressure (P .): Transpulmonary pressure measured at a
specified lung volume; e.g., ^ .TLC 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.
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PRELIMINARY DRAFT
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, should be used.
Tissue resistance (R..): Frictional resistance of the pulmonary and thoracic
tissues. tl
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 = Raw + Rtr
Trachea: Commonly known as the windpipe; a cartilaginous air tube extending
from the larynx (voice box) into the thorax (chest) where it divides into
left and right branches.
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PRELIMINARY DRAFT
Transpulmonary pressure (P,): Pressure difference between airway opening
(mouth, nares, or cannula opening) and the visceral pleural surface, in
cm H?0. 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. ,
VV - 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 to.tal 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 (Vr,): 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./Q): Ratio of the alveolar ventilation to the
blood perfusion volume flow through the pulmonary parenchyma. This ratio
is a fundamental determinant of the 0,., and C0? pressure of the alveolar
gas and of the end-capillary blood. Throughout the lungs the local
ventilation/perfusion ratios vary, and consequently the local alveolar
gas and end-capillary blood compositions also vary.
Vital capacity (VC): The maximum volume of air exhaled from the point of
maximum inspiration.
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