EPA
            United States
            Environmental Protection
            Agency
             Environmental Criteria and
             Assessment Office
             Research Triangle Park NC 27711
600884020A5
   July 1984
   External Review Draft C^ /"
             Research and Development
Air Quality
Criteria for
Ozone  and Other
Photochemical
Oxidants
    Review
    Draft
    (Do Not
    Cite or Quote)
             Volume V of V
                          NOTICE

             This document is a preliminary draft. It has not been formally
             released by EPA and should not at this stage be construed to
             represent Agency policy. It is being circulated for comment on its
             technical accuracy and policy implications.

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                         NOTICE

Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.
  US.  Envrronmental Protection Agencrf '

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                                   ABSTRACT
     Scientific information is presented and evaluated relative to the health
and welfare effects associated with exposure to ozone and other photochemical
oxidants.  Although it is not intended as a complete and detailed literature
review, the document covers pertinent literature through 1983 and early 1984.

     Data on health and welfare effects are emphasized, but additional infor-
mation is provided for understanding the nature of the oxidant pollution pro-
blem and for evaluating the reliability of effects data as well as their
relevance to potential exposures to ozone and other oxidants at concentrations
occurring in ambient air.  Separate chapters are presented on the following
exposure-related topics:  nature, source, measurement, and concentrations of
precursors to ozone and other photochemical oxidants; the formation of ozone
and other photochemical oxidants and their transport once formed; the proper-
ties, chemistry, and measurement of ozone and other photochemical oxidants;
and the concentrations of ozone and other photochemical oxidants that are
typically found in ambient air.

     The specific areas addressed by chapters on health and welfare effects
are the toxicological appraisal of effects of ozone and other oxidants; effects
observed in controlled human exposures; effects observed in field and epidemio-
logical studies; effects on vegetation seen in field and controlled exposures;
effects on natural and agroecosystems; and effects on nonbiological materials
observed in field and chamber studies.
                                      iii
0190LG/B                                                              May 1984

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                              CONTENTS


                                                                      Page

VOLUME I
  Chapter 1.   Summary and Conclusions 	      1-1

VOLUME II
  Chapter 2.   Introduction 	      2-1
  Chapter 3.   Precursors to Ozone and Other Photochemical
               Oxidants 	      3-1
  Chapter 4.   Chemical and Physical  Processes in the Formation
               and Occurrence of Ozone and Other Photochemical
               Oxidants 	      4-1
  Chapter 5.   Properties, Chemistry, and Measurement of Ozone
               and Other Photochemical Oxidants 	      5-1
  Chapter 6.   Concentrations of Ozone and Other Photochemical
               Oxidants in Ambient Air	      6-2

VOLUME III
  Chapter 7.   Effects of Ozone and Other Photochemical  Oxidants
               on Vegetation 	      7-1
  Chapter 8.   Effects of Ozone and Other Photochemical  Oxidants
               on Natural and Agroecosystems 	      8-1
  Chapter 9.   Effects of Ozone and Other Photochemical  Oxidants
               on Nonbiological Materials 	      9-1

VOLUME IV
  Chapter 10.  Toxicological Effects of Ozone and Other
               Photochemical Oxidants 	     10-1

VOLUME V
  Chapter 11.  Controlled Human Studies of the Effects of Ozone
               and Other Photochemical Oxidants 	     11-1
  Chapter 12.  Field and Epidemiological Studies of the  Effects
               of Ozone and Other Photochemical Oxidants 	     12-1
  Chapter 13.  Evaluation of Integrated Health Effects Data for
               Ozone and Other Photochemical Oxidants 	     13-1
0190LG/B
                                       IV
May 1984

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                               TABLE OF CONTENTS
LIST OF TABLES 	   viii
LIST OF FIGURES 	   ix
LIST OF ABBREVIATIONS 	   xi
AUTHORS, CONTRIBUTORS, AND REVIEWERS 	   xvi i

11.  CONTROLLED HUMAN STUDIES OF THE EFFECTS OF OZONE AND
     OTHER PHOTOCHEMICAL OXIDANTS 	   11-1
     11.1  INTRODUCTION 	   11-1
     11.2  ACUTE PULMONARY EFFECTS OF OZONE 	   11-6
           11.2.1  At-Rest Exposures	   11-6
           11.2.2  Exposures with Exercise 	   11-10
           11.2.3  Intersubject Variability and Reproducebility of
                   Responses 	   11-18
           11.2.4  Prediction of Acute Pulmonary Effects 	   11-21
           11.2.5  Bronchial Reactivity 	   11-25
           11.2.6  Mechanisms of Acute Pulmonary Effects 	   11-27
           11.2.7  Pre-existing Di sease 	   11-29
           11.2.8  Other Factors Affecting Pulmonary Responses to
                   Ozone 	   11-34
                   11.2.8.1  Cigarette Smoking	   11-34
                   11.2.8.2  Age and Sex Di fferences 	   11-36
                   11.2.8.3  Environmental Conditions 	   11-38
     11.3  PULMONARY EFFECTS FOLLOWING REPEATED EXPOSURE TO OZONE 	   11-39
     11.4  EFFECTS OF OZONE ON VIGILANCE AND EXERCISE PERFORMANCE 	   11-52
     11.5  INTERACTIONS BETWEEN OZONE AND OTHER POLLUTANTS 	   11-57
           11.5.1  Ozone Plus Sulfates or Sulfuric Acid 	   11-57
           11.5.2  Ozone and Carbon Monoxide	   11-65
           11.5.3  Ozone and Nitrogen Dioxide 	   11-66
           11.5.4  Ozone and Other Mixed Pol 1utants 	   11-67
     11.6  EXTRAPULMONARY EFFECTS OF OZONE 	   11-68
     11.7  PEROXYACETYL NITRATE 	   11-75
     11.8  SUMMARY 	   11-78
     11.9  REFERENCES 	   11-86

12.  FIELD AND EPIDEMIOLOGICAL STUDIES OF THE EFFECTS OF OZONE
     AND OTHER PHOTOCHEMICAL OXIDANTS 	   12-1
     12.1  INTRODUCTION 	   12-1
     12.2  FIELD STUDIES OF EFFECTS OF ACUTE EXPOSURE 	   12-2
           12.2.1  Symptoms and Pulmonary Function in General Field
                   Conditions 	   12-2
           12.2.2  Symptoms and Pulmonary Function under High-
                   Altitude Conditions 	   12-10
     12.3  EPIDEMIOLOGICAL STUDIES OF EFFECTS OF ACUTE EXPOSURE 	   12-13
           12.3.1  Acute Exposure Morbidity Effects 	   12-13
                   12.3.1.1  Respiratory and Other Symptoms of
                             Irritation 	   12-13
                   12.3.1.2  Altered Performance 	   12-15
                   12.3.1.3  Acute Effects on Pulmonary Function 	   12-17
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                         TABLE OF CONTENTS (continued)
                   12.3.1.4  Aggravation of Existing Respiratory
                             Di seases 	   12-21
                   12.3.1.5  Incidence of Acute Respiratory Illness 	   12-28
                   12.3.1.6  Physician, Emergency Room, and Hospital
                             Visits 	   12-28
                   12.3.1.7  Occupational Studies 	   12-32
           12.3.2  Trends in Mortality 	   12-32
     12.4  EPIDEMIOLOGICAL STUDIES OF EFFECTS OF CHRONIC EXPOSURE 	   12-35
           12.4.1  Pulmonary Function and Chronic Lung Disease 	   12-35
           12.4.2  Chromosomal Effects 	   12-37
     12.5  SUMMARY AND CONCLUSIONS 	   12-39
     12.6  REFERENCES 	   12-45

13.   EVALUATION OF INTEGRATED HEALTH EFFECTS DATA FOR OZONE AND
     OTHER PHOTOCHEMICAL OXIDANTS 	   13-1
     13.1  INTRODUCTION 	   13-1
     13.2  EXPOSURE ASPECTS 	   13-3
           13.2.1  Exposures to Ozone 	   13-3
           13.2.2  Potential Exposures to Other Photochemical
                   Oxidants 	   13-9
                   13.2.2.1  Concentrations 	   13-9
                   13.2.2.2  Patterns 	   13-11
           13.2.3  Potential Combined Exposures and Relationship of
                   Ozone and Other Photochemical Oxidants 	   13-12
     13.3  HEALTH EFFECTS IN THE GENERAL HUMAN POPULATION 	   13-14
           13.3.1  Clinical Symptoms 	   13-14
           13.3.2  Pulmonary Function at Rest and with Exercise and
                   Other Stresses 	   13-16
                   13.3.2.1  At-Rest Exposures 	   13-16
                   13.3.2.2  Exposures with Exercise 	   13-17
                   13.3.2.3  Environmental Stresses 	   13-33
           13.3.3  Other Factors Affecting Pulmonary Response to
                   Ozone 	   13-34
                   13.3.3.1  Age 	   13-34
                   13. 3. 3. 2  Sex 	   13-35
                   13.3.3.3  Smoking Status	   13-36
                   13.3.3.4  Nutritional Status	   13-36
                   13.3.3.5  Red Blood Cell Enzyme Deficiencies 	   13-38
           13.3.4  Effects of Repeated Exposure to Ozone 	   13-39
                   13.3.4.1  Introduction	   13-39
                   13.3.4.2  Development of Altered Responsiveness to
                             Ozone 	   13-39
                   13.3.4.3  Mechanisms of Altered Responsiveness to
                             Ozone 	   13-40
                   13.3.4.4  Conclusions Relative to Attenuation with
                             Repeated Exposures 	   13-43
           13.3.5  Relationship Between Acute and Chronic Ozone
                   Effects 	   13-44

                                      vi

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                         TABLE OF CONTENTS (continued)
           13.3.6  Resistance to Infection 	    13-47
           13.3.7  Extrapulmonary Effects of Ozone 	    13-49
     13.4  HEALTH EFFECTS IN POTENTIALLY SUSCEPTIBLE INDIVIDUALS 	    13-51
           13.4.1  Patients with Chronic Obstructive Lung Disease
                   (COLD) 	    13-51
           13.4.2  Asthmatics 	    13-52
           13.4.3  Subjects with Allergy, Atopy, and Hyperreactive
                   Airways 	    13-54
     13.5  EXTRAPOLATION OF EFFECTS OBSERVED IN ANIMALS TO HUMAN
           POPULATIONS 	    13-55
           13.5.1  Species Comparisons 	    13-55
           13.5.2  Dosimetry Modeling 	    13-61
     13.6  HEALTH EFFECTS OF OTHER PHOTOCHEMICAL OXIDANTS AND
           POLLUTANT MIXTURES 	    13-62
           13.6.1  Effects of Peroxyacetyl Nitrate 	    13-63
           13.6.2  Effects of Hydrogen Peroxide	    13-64
           13.6.3  Interactions with Other Pollutants 	    13-64
     13.7  IDENTIFICATION OF POTENTIALLY AT-RISK POPULATIONS OR
           SUBPOPULATIONS 	    13-66
           13.7.1  Introduction 	    13-66
           13.7.2  Potentially At-Risk Individuals 	    13-67
           13.7.3  Potentially At-Risk Subpopulations 	    13-70
           13.7.4  Demographic Distribution of the General Popula-
                   tion 	    13-72
           13.7.5  Demographic Distribution of Individuals with
                   Chronic Respiratory Conditions 	    13-73
     13.8  SUMMARY AND CONCLUSIONS 	    13-76
     13.9  REFERENCES	    13-84

     APPENDIX A 	    A-l
                                      VI 1

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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 	     11-7
11-3   Estimated values of oxygen consumption and minute
       ventilation associated with levels of exercise 	     11-12
11-4   Ozone exposure in subjects with pulmonary disease 	     11-30
11~5   Changes in lung function after repeated daily exposure
       to ambient ozone 	     11-41
11-6   Effects of ozone on exercise performance 	     11-55
11-7   Interactions between ozone and other pollutants 	     11-58
11-8   Human extrapulmonary effects of ozone exposure 	     11-69
11-9   Acute human exposure to peroxyacetyl nitrate 	     11-76
11-10  Summary table:  controlled human exposure to ozone 	     11-79

12-1   Subject characteristics and experimental conditions of
       the mobile laboratory studies	     12-4
12-2   Pollutant levels (mean ± S.D.) monitored inside a mobile
       laboratory during ambient air exposures 	     12-4
12-3   The relationship between average standardized deviations
       of peak flow and outdoor concentrations of ozone and
       total suspended particulate matter 	     12-20
12-4   The relationship between average standardized deviations
       of peak flow in asthmatics and the interaction of ozone
       and temperature	     12-27
12-5   Studies of acute respiratory illness 	     12-29
12-6   Studies of acute effects from occupational exposure 	     12-33
12-7   Additional studies of chronic morbidity 	     12-38
12-8   Summary table:  acute effects of ozone and other
       photochemical oxidants in population studies 	     12-41

13-1   Probability that specified concentrations of ozone will
       persist for stated consecutive days or longer 	    13-7
13-2   Relationship of ozone and peroxyacetyl nitrate at urban
       and suburban sites in the United States in reports
       pub! ished 1978 or 1 ater 	    13-14
13-3   Effects of intermittent exercise and ozone concentration
       on 1-sec forced expiratory volume 	    13-26
13-4   Comparison of the acute effects of ozone on breathing
       patterns in animals and man 	    13-58
13-5   Comparison of the acute effects of ozone on airway reactivity
       i n animal s and man 	    13-59
13-6   Geographical distribution of the resident population of
       the United States, 1980 	    13-73
13-7   Total population of the United States by age, sex, and
       race, 1980 	    13-74
13-8   Prevalence of chronic respiratory conditions by sex and
       age for 1979  	    13-75
                                     vm
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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 ?c_7c
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                          LIST OF FIGURES (continued)


Figure                                                                     Rage

12-1   Mean symptom score changes with exposure for all subjects,
       normal and allergic subjects, and asthmatic subgroup of
       subjects 	      12-7
12-2   Relationship of average daily percent adjusted (i.e.,
       without fever, chill, or temperature) symptoms to photo-
       chemical oxidant level, May 1961 - May 1964 (868 days) 	      12-16

13-1   Collective distributions of the three highest 1-hr ozone
       concentrations for 3 years (1979, 1980, and 1981) at valid
       sites (906 station - years) 	      13-5
13-2   The effects of ozone concentration on 1-sec forced
       expiratory volume during 2-hr exposures with light
       intermittent exercise.   Quadratic fit of group mean data,
       weighted by sample size, was used to plot a concentration-
       response curve with 95 percent confidence limits 	      13-20
13-3   The effects of ozone concentration on 1-sec forced
       expiratory volume during 2-hr exposures with moderate
       intermittent exercise.   Quadratic fit of group mean data,
       weighted by sample size, was used to plot a concentration-
       response curve with 95 percent confidence limits 	      13-21
13-4   The effects of ozone concentration on 1-sec forced
       expiratory volume during 2~hr exposures with heavy
       intermittent exercise.   Quadratic fit of group mean data,
       weighted by sample size, was used to plot a concentration-
       response curve with 95 percent confidence limits 	      13-22
13-5   The effects of ozone concentration on 1-sec forced
       expiratory volume during 2-hr exposures with very heavy
       intermittent exercise.   Quadratic fit of group mean data,
       weighted by sample size, was used to plot a concentration-
       response curve with 95 percent confidence limits 	      13-23
13-6   Group mean decrements in 1-sec forced expiratory volume
       during 2-hr ozone exposures with different levels of
       intermittent exercise:   light (Vp < 25 L/min); moderate
       (VE = 26-43 L/min); heavy (VV = 44-63 L/min); and very
       heavy (V_ > 64 L/min).   Concentration-response curves
       are taken from Figures 13-2 through 13-5 	      13-24
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                             LIST OF ABBREVIATIONS
ACh
AM
ANOVA
AOD
ATPS

BTPS

CC
Cdyn
CE
CHEM
CHESS
CL
CLst
CNS
CO
COHb
COLD
COPD
co2
CV
D,
D
 LCO
E
ECG,
EEC
EPA
ERV
FEFn

FEF
  EKG
max
Acetylcholine
Alveolar macrophage
Analysis of variance
Airway obstructive disease
ATPS condition (ambient temperature and pressure, saturated
with water vapor)
BTPS conditions (body temperature, barometric pressure,
and saturated with water vapor)
Closing capacity
Dynamic lung compliance
Continuous exercise
Gas phase chemiluminescence
Community Health Environmental Surveillance System
Lung compliance
Static lung compliance
Central nervous system
Carbon monoxide
Carboxyhemogiobi n
Chronic obstructive lung disease
Chronic obstructive pulmonary disease
Carbon dioxide
Closing volume
Diffusing capacity of the lungs
Carbon monoxide diffusion capacity of the lungs
Elastance
Electrocardiogram
Electroencephalogram
U.S. Environmental Protection Agency
Expiratory reserve volume
The maximal forced expiratory flow achieved
during an FVC.
Forced expiratory flow
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                       LIST OF ABBREVIATIONS (continued)
FEF200-1200            Mean forced expiratory flow between 200 ml and 1200 ml of
                       the FVC [formerly called the maximum expiratory flow rate
                       (MEFR)].
                       Mean forced expiratory flow during the middle half of the
                       FVC [formerly called the maximum mid-expiratory flow rate
                       (MMFR)].
                       Instantaneous forced expiratory flow after 75% of the FVC
                       has been exhaled.
FEV                    Forced expiratory volume
FEV,                   Forced expiratory volume in 1 sec
FEV./FVC               A ratio of timed forced expiratory volume (FEV.) to
                       forced vital capacity (FVC)
FIVC                   Forced inspiratory vital capacity
fR                     Respiratory frequency
FRC                    Functional residual capacity
FVC                    Forced vital capacity
G                      Conductance
G-6-PD                 Glucose-6-phosphate dehydrogenase
Gaw                    Airway conductance
GS-CHEM                Gas-solid chemiluminescence
GSH                    Glutathione
Hb                     Hemoglobin
Hct                    Hematocrit
HO-                    Hydroxy radical
H20                    Water
1C                     Inspiratory capacity
IE                     Intermittent exercise
IRV                    Inspiratory reserve volume
IVC                    Inspiratory vital capacity
LDH                    Lactate deyhydrogenase
LDrQ                   Lethal dose (50 percent)
LM                     Light microscopy
MAST                   Kl-coulometric (Mast meter)
                                      XII
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                       LIST OF ABBREVIATIONS (continued)
max VE
max V02
MBC
MEFR
MEFV
MetHb
MMAD
MMFR or MMEF
MVV
NBKI
V
°3
P(A-a)0
PABA
PAco2
PaC02
PAN
PA°2
Pa02
PBZN
PEF
PEFV
PG
rl_
PMN
Pst
PUFA
R
Raw

019DH/G
Maximum ventilation
Maximal aerobic capacity
Maximum breathing capacity
Maximum expiratory flow rate
Maximum expiratory flow-volume curve
Methemoglobin
Mass median aerodynamic diameter
Maximum mid-expiratory flow rate
Maximum voluntary ventilation
Neutral buffered potassium iodide
Ammonium sulfate
Nitrogen dioxide
Nitrogen washout
Oxygen
Oxygen radical
Ozone
Alveolar-arterial oxygen pressure difference
para-aminobenzoic acid
Alveolar partial pressure of carbon dioxide
Arterial partial pressure of carbon dioxide
Peroxyacetyl nitrate
Alveolar partial pressure of oxygen
Arterial partial pressure of oxygen
Peroxybenzoyl nitrate
Peak expiratory flow
Partial expiratory flow-volume curve
Prostaglandin
Arterial pH
Transpulmonary pressure
Polymorphonuclear leukocyte
Static transpulmonary pressure
Polyunsaturated fatty acid
Resistance to flow
Airway resistance
              xiii
                                                                       6/29/84

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                        LIST  OF  ABBREVIATIONS  (continued)
 RBC                     Red  blood  cell
 RCO]-|                   Collateral  resistance
 rh                      Relative humidity
 R[_                      Total pulmonary  resistance
 RQ,  R                   Respiratory quotient
 Rt                      Total respiratory  resistance
 RJ..J                     Tissue  resistance
 RV                      Residual volume
 Sa02                    Arterial oxygen  saturation
 SBNT                    Single-breath nitrogen test
 SCE                     Sister  chromatid exchange
 Se                      Selenium
 SEM                     Scanning electron  microscopy
 SGaw                    Specific airway conductance
 SH                      Sulfhydryls
 SOD                     Superoxide  dismutase
 SO^                     Sulfur  dioxide
 S04                     Sulfate
 SPF                     Specific pathogen-free
 SRaw                    Specific airway resistance
 STPD                    STPD conditions (standard temperature and
                        pressure, dry)
 TEM                     Transmission electron microscopy
 TGV                     Thoracic gas volume
 THC                     Total hydrocarbons
 TLC                     Total lung  capacity
 TV                      Tidal volume
 UV                      Ultraviolet photometry
 V^                      Alveolar ventilation
 •  •
V^/Q                    Ventilation/perfusion ratio
 VC                      Vital capacity
VCO£                    Carbon dioxide production
VQ                      Physiological  dead space

                                      xi v
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                       LIST OF ABBREVIATIONS  (continued)
V                      Dead- space ventilation
 D
       .                Anatomical dead  space
Vr:                     Minute ventilation; expired volume per minute
V,                     Inspired volume per minute
V.                     Lung volume
V                      Maximum expiratory flow
 fflclX
VOp                    Oxygen uptake
*     *
V0>  Q0                Oxygen consumption
                                      xv
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                           MEASUREMENT ABBREVIATIONS
9
hr/day
kg
kgm/mi n
L/min
L/s
ppm
nig/ kg
  / 3
mg/m
min
ml
mm
pro
MM
sec
gram
hours per day
kilogram
ki1ogram-meter/mi n
liters/min
liters/sec
parts per million
milligrams per kilogram
milligrams per cubic meter
minute
fliilliliter
millimeter
micrograms per cubic meter
micrometers
micromole
second
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                                      xvi
                                                 6/29/84

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                    AUTHORS, CONTRIBUTORS, AND REVIEWERS
Chapter 11:  Controlled Human Studies of the Effects of Ozone
             and Other Photochemical Oxidants

Principal Authors

Dr. Donald H. Horstman
Health Effects Research Laboratory
MD-58
U.S. Environmental Protection Agency
Research Triangle Park, NC  27711

Dr. Steven M. Horvath
Institute of Environmental Stress
University of California
Santa Barbara, CA  93106

Mr. James A. Raub
Environmental Criteria and
  Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC  27711


Authors also reviewed individual sections of the chapter.  The following addi-
tional persons reviewed chapter 11 at the request of the U.S. Environmental
Protection Agency.  The evaluations and conclusions contained herein, however,
are not necessarily those of the reviewers.

Dr. Karim Ahmed
Natural Resources Defense Council
122 East 42nd Street
New York, NY  10168

Dr. David V. Bates
Department of Medicine
St. Paul's Hospital
University of British Columbia
Vancouver, British Columbia
Canada V6Z1Y6

Dr. Philip A. Bromberg
Department of Medicine
School of Medicine
University of North Carolina
Chapel Hill, NC  27514

Dr. George L. Carlo
Dow Chemical, U.S.A.
1803 Building,  U.S.  Medical
Midland, MI  48640

                                     xv ii
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Dr.  Lawrence J.  Folinsbee
Institute of Environmental Stress
University of California
Santa Barbara, CA  93106

Dr.  Robert Frank
Department of Environmental
  Health Sciences
Johns Hopkins School of Hygiene
  and Public Health
615 N. Wolfe Street
Baltimore, MD  21205

Dr.  Judith A. Graham
Health Effects Research Laboratory
MD-82
U.S. Environmental Protection Agency
Research Triangle Park, NC  27711

Dr.  Jack D. Hackney
Rancho Los Amigos Hospital
7601 East Imperial Highway
Downey, CA  90242

Dr.  Milan J. Hazucha
School of Medicine
Center for Environmental Health
  and Medical Sciences
University of North Carolina
Chapel Hill, NC  27514

Dr.  Thomas J. Kulle
Department of Medicine
School of Medicine
University of Maryland
Baltimore, MD  21201

Dr.  Michael D. Lebowitz
Department of Internal Medicine
College of Medicine
University of Arizona
Tucson, AZ  85724

Dr.  Susan M. Loscutoff
16768 154th Ave., S.E.
Renton, WA  98055

Dr.  William F. McDonnell
Health Effects Research Laboratory
MD-58
U.S.  Environmental  Protection Agency
Research Triangle Park, NC  27711
                                     xvi i i
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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

Principal Author

Dr. Michael D.  Lebowitz
Department of Internal Medicine
College of Medicine
University of Arizona
Tucson, AZ  85724

Contributing Authors

Dr. Benjamin G.  Ferris
School of Public Health
Harvard University
Boston, MA  02115

Dr. Lester D.  Grant
Environmental  Criteria and
Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC  27711

Mr. James R. Kawecki
TRC Environmental Consultants, Inc.
701 W. Broad Street
Falls Church,  VA  22046
                                      xix
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Authors also reviewed individual sections of the chapter.  The following addi-
tional persons reviewed chapter 12 at the request of the U.S. Environmental
Protection Agency.   The evaluations and conclusions contained herein, however,
are not necessarily those of the reviewers.


Dr. Karim Ahmed
Natural Resources Defense Council
122 East 42nd Street
New York, NY  10168

Dr. David V. Bates
Department of Medicine
St. Paul's Hospital
University of British Columbia
Vancouver, British Columbia
Canada  V6Z1Y6

Dr. Patricia A. Buffler
School of Public Health
University of Texas
P.O. Box 21086
Houston, TX  77025

Dr. George L. Carlo
Dow Chemical, U.S.A.
1803 Building, U.S. Medical
Midland, MI  48640

Dr. Robert S. Chapman
Health Effects Research Laboratory
MD-58
U.S. Environmental Protection Agency
Research Triangle  Park, NC  27711

Dr. Robert Frank
Department of Environmental
   Health Sciences
Johns Hopkins School of Hygiene
   and Public Health
615 N. Wolfe Street
Baltimore, MD  21205

Dr. Judith A. Graham
Health Effects Research Laboratory
MD-82
U.S. Environmental Protection Agency
Research Triangle  Park, NC  27711

Dr. Jack D.  Hackney
Rancho Los Amigos  Hospital
7601  East  Imperial Highway
Downey, CA   90242
                                       XX
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 Dr. Victor Hasselblad
 Health  Effects  Research  Laboratory
 MO-55
 U.S. Environmental  Protection Agency
 Research Triangle Park,  NC  27711

 Dr. Milan J. Hazucha
 School  of Medicine
 Center  for Environmental Health
  and Medical Sciences
 University of North Carolina
 Chapel  Hill, NC  27514

 Dr. Dennis J. Kotchmar
 Environmental Criteria and
  Assessment Office
 MD-52
 U.S. Environmental  Protection Agency
 Research Triangle Park,  NC  27711

 Dr. Thomas J. Kulle
 Department of Medicine
 University of Maryland
 Baltimore, MD  21201

 Dr. Lewis H. Kuller
 Department of Epidemiology
 Graduate School of  Public Health
 University of Pittsburgh
 Pittsburgh, PA  15261

 Dr. Harold A. Menkes
 Department of Environmental
  Health Sciences
 Johns Hopkins School of  Hygiene
  and Public Health
 615 N.  Wolfe Street
 Baltimore, MD  21205

 Mr. James A. Raub
 Environmental Criteria and
  Assessment Office
 MD-52
 U.S.  Environmental Protection Agency
 Research Triangle Park,  NC  27711

 Dr.  Jonathan M.  Samet
 Department of Medicine
 University of New Mexico Hospital
Albuquerque, NM  87131
                                      xxi
019DH/G                                                                6/29/84

-------
Dr.  Jan A.  J.  Stolwijk
Department of Epidemiology and
  Public Health
School of Medicine
Yale University
New Haven,  CT  06510

Ms.  Beverly E. Tilton
Environmental  Criteria and
  Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC  27711

Dr.  Harry M. Walker
Monsanto Fibers and Intermediates
  Company
P.O. Box 711
Alvin, TX  77511
Chapter 13:   Evaluation of Integrated Health Effects Data
             for Ozone and Other Photochemical Oxidants

Contributing Authors

Dr. Robert Frank
Department of Environmental
  Health Sciences
Johns Hopkins School of Hygiene
  and Public Health
615 N. Wolfe Street
Baltimore, MD  21205

Dr. Donald E. Gardner
Northrop Services, Inc.
Environmental Sciences
P.O. Box 12313
Research Triangle Park, NC  27709

Dr. Judith A. Graham
Health Effects Research Laboratory
MD-82
U.S. Environmental Protection Agency
Research Triangle Park, NC  27711

Dr. Milan J. Hazucha
School of Medicine
Center for Environmental Health
  and Medical Sciences
University of North Carolina
Chapel Hill, NC  27514
                                     xxn
019DH/G                                                                6/29/84

-------
Dr. Donald H. Horstman
Health Effects Research Laboratory
MD-58
U.S. Environmental Protection Agency
Research Triangle Park, NC  27711

Mr. Michael D. Lebowitz
Department of Internal Medicine
College of Medicine
University of Arizona
Tucson, AZ  85724

Dr. Daniel B. Menzel
Laboratory of Environmental Toxicology
  and Pharmacology
Duke University Medical Center
P.O. Box 3813
Durham, NC  27710

Dr. Frederick J.  Miller
Health Effects Research Laboratory
MD-82
U.S. Environmental Protection Agency
Research Triangle Park, NC  27711

Mr. James A. Raub
Environmental Criteria and
  Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC  27711

Ms. Beverly E. Til ton
Environmental Criteria and
  Assessment Office
MD-52
U.S. Environmental Protection Agency
Research Triangle Park, NC  27711

Dr. Walter S. Tyler
Department of Anatomy
School of Veterinary Medicine
University of California,
Davis, CA  95616
                                     XXTM
019DH/G                                                                6/29/84

-------
Authors also reviewed individual sections of the chapter.  The following addi-
tional persons reviewed parts of chapter 13 at the request of the U.S. Environ-
mental Protection Agency.  The evaluations and conclusions contained herein,
however, are not necessarily those of the reviewers.


Dr.  Steven M. Horvath
Institute of Environmental Stress
University of California
Santa Barbara, CA  93106

Dr.  Thomas J. Kulle
Department of Medicine
School of Medicine
University of Maryland
Baltimore, MD  21201
                                     xxiv
019DH/G                                                                 6/29/84

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                11.   CONTROLLED HUMAN STUDIES OF THE EFFECTS OF
                       OZONE AND OTHER PHOTOCHEMICAL OXIDANTS

11.1  INTRODUCTION
     Four major summaries on the effects of controlled human exposure to ozone
(Oo) have been published (National Research  Council, 1977; U.S. Environmental
Protection Agency, 1978; World Health Organization, 1978; and Hughes, 1979).
In addition, two other reports (National Air Pollution Control Administration,
1970; F.R. April 30,  1971)  have reviewed earlier studies.
     In 1977 the National Research Council report on ozone and other photochem-
ical oxidants  stated  a  need  for comprehensive human experimental studies that
were carefully  controlled  and  documented to ensure reproducibility.  This
statement was understandable, considering that the major portion of the report's
section on  controlled human  studies  was devoted to reviews  of test  methods,
protocol  designs, review of  a  scant  amount of published data,  and  recommenda-
tions for future  studies.   The available data  on controlled studies through
1975 were limited to some 20 publications.  Nonetheless, this data base repre-
sented a  substantial  increase  above  the information available prior to 1970,
and it became evident that exposure to 0- at low ambient concentrations resul-
ted in  some degree of pulmonary dysfunction.  Additional  research  was  conduc-
ted in  the  intervening  years,  and by  1978  data were available from studies
conducted on over 200 individuals (Table 11-1).   By this time the first reports
were available  indicating  that under  the same  exposure conditions,  greater
functional  deficits were measured during  exercise than  at rest.  In  addition,
five studies  in  which several  pollutants (nitrogen dioxide, sulfur  dioxide,
and carbon  monoxide plus oxidants) were present during  exposure became avail-
able for  review.  Two reports  on repeated daily exposure  to  03 ("adaptation")
had  appeared,  as well  as  one experimental  study in  which asthmatics were
evaluated.   This  research  was  just  the beginning of interest  in  03 as an
ambient pollutant affecting  pulmonary functions of  exposed man.  Although  the
data base was still  smaller than desirable, a general  conception of this
particular air pollutant's influence was beginning to form.
     The  early  reports  summarized  in Table  11-1 were described in detail  in
the  previous 0., criteria  document   (U.S.   Environmental  Protection  Agency,
1978).   In  this  chapter,  emphasis has  been  placed on the more recent  litera-
ture; however,  some  of the older studies  have  been reviewed again.    Tables

019PO/A                              11-1                                5/2/84

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TABLE 11-1.   HUMAN EXPERIMENTAL EXPOSURE  TO OZONE  UP  TO  1978
Ozone
concentration
jjg/m3
196


196
784
1176
1960






294
— 588
i
NJ
392
980






451



490
725
980


ppm
0


0
0
0
1






0
0


0
0






0



0
0
0


10


1
4
6
0






15
30


2
5






23



25
37
50


. Exposure
Measurement ' duration and
method activity
CHEM, 2 hr
NBKI IE (2xR)
@ 15-min intervals
I 1 hr
R








UV, 1 hr (mouth-
NBKI piece) R (11)
& CE (29, 43,
66)
I 3 hr/day
6 days/week
x 12 weeks





CHEM, 2 hr
NBKI IE (2xR)
@ 15-min intervals

CHEM, 2-4 hr
NBKI R & IE (2xR)
@ 15-min intervals


No. and sex
Observed effect(s) of subjects Reference
P(A-a)02 and R increased. 12 male von Niedinq et al . , 1977
dw

Airway resistance: mean increases of 3.3% 4 male Goldsmith and Nadel , 1969
(0.1 ppm), 3.5% (0.4 ppm), 5.8% (0.6 ppm),
and 19.3% (1.0 ppm) at 0 hr after exposure;
mean increases of 12.5% (0.4 ppm), 5% (0.6
and 1.0 ppm) at 1 hr after exposure; one
subject had history of asthma and experi-
enced hemoptysis 2 days after 1 ppm. No
symptoms at 0.1 ppm; odor detected at 0.4
and 0.6 ppm; throat irritation and cough
at 1.0 ppm.
RV, FEVj.Q, MMFR, and VT decreased and fg 6 male DeLucia and Adams, 1977
increased at 0.30 ppm during IE (66); small
but nonsignificant changes at 0.15 ppm.
Congestion, wheezing, and headache reported.
Slight (nonsignificant) decrease in VC and 6 male Bennett, 1962
significant decrease in FEVj.Q at 0.5 ppm
toward end of 12 weeks; returned to normal
within 6 weeks after exposure; 0.66 (0.2 ppm),
0.80 (0.5 ppm) upper respiratory infections/
person in 12 weeks compared to 0.95 for the
controls. No irritating symptoms, but
could detect ozone by smell at 0.5 ppm.
No changes in spirometry, closing volume, and 20 male (asthma) Linn et al., 1978
N2 washout; small blood biochemical changes; 2 female (asthma)
increased frequency of symptoms reported.
Medication maintained during exposure.
No effect in normal reactors Changes 16 normal and Hackney et al., 1975a,b,c
(2-12%) observed in spirometry, lung reactive subjects
mechanics, and small airway function
in non-reactors (IE) and liyperreactors
(R) at 0.5 ppm

-------
TABLE 11-1.   HUMAN EXPERIMENTAL EXPOSURE TO OZONE UP TO 1978   (continued)
Ozone
concentration
ug/m3 ppm
725 0.37
725 0.37
725 0.37
1470 0.75
725 0.37
980 0.50
1470 0.75
725 0.37
980 0. 50
1470 0.75
784 0.4
784 0.4
980 0.5
Exposure
Measurement 'C duration and
method activity
CHEM,
NBKI
CHEM,
NBKI
MAST,
NBKI
MAST,
NBKI
MAST,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
2 hr
IE (2xR)
@ 15-min intervals
2 hr
IE (2xR)
@ 15-min intervals
2 hr
IE (2xR)
@ 15-min intervals
2 hr
R (11) & IE (29)
@ 15-min intervals
2 hr
R (11) & IE (29)
@ 15-min intervals
1-4 hr
IE (4xR) for two
15-min periods
2.25 hr
IE (2xR)
@ 15-min intervals
4 days
2.5 hr/day
IE (2xR)
@ 15-min intervals
Observed effect(s)6
No changes in spirometry or small airway
function in the combined group; sensitive
subjects had decreased FEV^o (4.7%).
No changes in group mean pulmonary function;
individual subjective symptoms and spiro-
metric decrements were more severe
in Toronto than L.A. subjects. Blood
enzyme activity increased in both
groups, but RBC fragility increased
in Toronto subjects only.
At 0.37 ppm, less than 20% decrements in
spirometry. Smokers less responsive than
nonsmokers. At 0.75 ppm, severe decrements
in spirometric variables (20%-55%). Smokers
more responsive, with RV and CC increased.
0.75 ppm: at rest, less than 21% decrements
in spirometry, while during IE nearly 33%
decrements in spirometry and dN2. Relatively
smaller effects at lower concentrations.
Reasonably good correlation between dose
(cone, x min. vent.) and changes in spiro-
metric variables.
fn increasea and V, decreased with exercise;
V02 not affected by exposure. Variables
correlated to total dose of ozone.
FVC and MMEF decreased and R increased at
2 hr and 4 hr; FEVj.0) V50, and V25 decreased
at 4 hr only.
FVC, FEV,.0, and MMF decreased in new arrivals,
which were more responsive than L A. residents.
Inconsistent changes in blood biochemistry.
Very small changes in pulmonary function; tem-
poral pattern of these changes is suggestive of
"adaptation. "
No. and sex
of subjects
4 normal (L. A. )
4 sensitive (L. A. )
2 male (Toronto)
2 female (Toronto)
3 male (L.A. )
1 female (L.A. )
12 male
20 male
8 female (divided into
6 exposure groups)
20 male
8 female (divided into
6 exposure groups)
22 male
6 female (L.A )
7 female (new arrival)
2 male (new arrival )
6 male (atopic)
Reference
Bell et al. , 1977
Hackney et al. , 1977b
Bates and Hazucha, 1973
Hazucha et al. , 1973
Hazucha, 1973
Silverman et al . , 1976
Folinsbee et al. , 1975
Knelson et al. , 1976
Hackney et al , 1976
Hackney et al. , 1977a

-------
TABLE 11-1.   HUMAN EXPERIMENTAL EXPOSURE TO OZONE UP TO 1978   (continued)
Ozone
concentration
ug/mj ppm
980 0. 5
980 0. 5
1176 0.6
1176 0.6
1176 0.6
1568 0.8
1470 0. 75
1470 0. 75
Measurement >c
method
CHEM,
NBKI
MAST,
NBKI
CHEM,
NBKI
CHEM,
NBKI
MAST
MAST,
NBKI
MAST,
NBKI
Exposure
duration and
activity
2 hr
R (9) & IE (37)
for 30 min
6 hr
IE (44) for two
15-min periods
2 hr (noseclips)
R
2 hr
IE for two
15-rain periods
2 hr
R(9)
2 hr
IE
@ 15-min intervals
2 hr
R & IE (2XR)
@ 15-rain intervals
Observed effect(s)e
Changes in pulmonary function (FVC, FEV^u,
FEF^a,^) were greatest immediately following
exercise. Heat stress potentiated the re-
sponse while relative humidity had insignifi-
cant effects.
FVC, FEVj.u, and SG decreased and R, in-
creased. Nonsmokerl were more susceptible.
Inconsistent changes in lung mechanics and
small airway function.
Bronchoreactivity to histamine increased
following exposure; persisted for up to
3 weeks; blocked by atropine.
Significant decrements in spirometric
variables (19%-35%). Cough and pain on
deep inspiration most frequently reported;
no symptoms persisted beyond 48 hr.
DLrn: mean decrease of 25% (11/11 subjects).
VCru mean decrease of 10% (10/10 subjects).
FEV0./5 x 40: mean decrease of 10%. FEF
25-75: mean decrease of 15%, which was not
significant. Mixing efficiency: no change
(2/2 subjects). Airway resistance: slight
increase, but within normal limits. Dynamic
compliance: no change (2/2 subjects).
Substernal soreness and trachea! irritation
6 to 12 hr after exposure.
HR , Vr, VT, VO^ , and maximum workload
all^Secreased. At maximum workload only,
fg decreased (45%) and V-j- increased (29%).
FEF3U and PrjTLC decreased, R, increased;
returned to control levels within 24 hr.
IE attenuated changes in R, , C. , maxP,
and spirometry. Cough and substernal sore-
ness reported.
No. and sex
of subjects
14 male
(divided into 2
exposure groups)
19 male
1 female
(equally divided by
smoking history)
3 male
5 female
20 male
10 male
1 female
13 male
13 male:
10(R) & 3(IE)
Reference
Folinsbee et al. , 1977b
Kerr et al. , 1975
Golden et al., 1978
Ketcham et al., 1977
Young et al . , 1964
Folinsbee et al. , 1977a
Bates et al. , 1972

-------
                                              TABLE  11-1.   HUMAN  EXPERIMENTAL  EXPOSURE TO  OZONE UP  TO  1978a   (continued)
Ozone
concentration
ug/m3 ppm
1764 0.9
2940 1.5
3920 2.0
Up to Up to
7840 4. 0
i
U1
9800 5-10
19600

b Exposure
Measurement ' duration and
method activity Observed effect(s)6
MAST> 5 mi'n SG decreased during and 5 min following
NBKI CE exposure. Recovery complete within 30 min
post-exposure.
1 2 hr VC: decreased 13%; returned to normal in
R 22 hr. FEV3.0: decreased 16.8% after 22 hr.
Maximum breathing capacity decreased very
slightly. CNS depression, lack of coordina-
tion, chest pain, tiredness for 2 weeks.
MAST 10-30 min VC: mean decrease of 16.5% (4/8 subjects
R showed decrease > 10%). FEV^o: mean
decrease of 20% (5/8 subjects showed
decrease > 10%. FEF2S_75: mean decrease
of 10.5% (5/6 subjects showed a decrease).
MBC: decrease of 12% (5/8 subjects showed
decrease). DL-,.: decrease of 20 to 50% in
7/11 subjects; increase of 10 to 50% in 4/11
subjects; only 5/11 subjects tolerated
1 to 3 ppm for full 30 min. Wide varia-
tions in OLpQ- Headache, shortness of
breath, lasting more than 1 hr.
I Not available Drowsiness and headache reported.
ality Criteria for Ozone and Other Photochemical Oxidants, Research Trianqle Park. NC: U.S.
No. and sex
of subjects Reference
4 male Kagawa and Toyama, 1975
1 male Griswold et al., 1957
11 subjects Hallett, 1965
3 male Jordan and Carlson, 1913
Environmental Protection Agency,
 Measurement methods:  MAST = Kl-coulometric (Mast meter); I = iodometric; CHEM = gas-phase chemiluminescence; UV = ultraviolet photometry.

 Calibration methods:  NBKI = neutral buffered potassium iodide.


 Activity level:  R = rest; CE = continuous exercise; IE = intermittent exercise; minute ventilation (V,.) given in L/min or in multiples of resting
 ventilation.                                                                                          E' a                         K             M
p

 See Glossary for the definition of symbols.

-------
have been provided to give the reader an overview of the studies discussed in
the text and provide some additional information about measurement techniques
and exposure protocols.   Unless otherwise stated,  the 0~  concentrations presented
in the text  and  tables  are the levels cited in the original manuscript.  No
attempt has  been  made  to convert the concentrations  to  a common standard,
although suggestions for conversion along with a discussion of 0- measurement
can be found in Chapter 5.
11.2  ACUTE PULMONARY EFFECTS OF OZONE
11.2.1  At-Rest Exposures
     Results from  studies  reported  prior to 1978 (Table 11-1) indicate that
impairment  of  pulmonary function and  pulmonary  symptoms  occur when normal
subjects are exposed  for 2 hr at rest to 1176-1568 ug/m  (0.6-0.8 ppm) of 03
(Young  et  al.,  1964),  to 1479 ug/m3  (0.75  ppm)  of  0  (Bates et al.  ,  1972;
                                         3
Silverman  et al. ,  1976),  and to 980 ug/m  (0.5 ppm) of 03 (Folinsbee et al. ,
1977b).  In  addition  to  decrements  in  the usual  indicators of pulmonary func-
tion,  Young  et  al.  (1964)  also found  decreases  in  diffusion capacity  of  the
lung (DLCO).
     Results from studies of at-rest exposures published since 1978  (Table 11-2)
have  generally  confirmed these  earlier findings.   Folinsbee et al.  (1978)
observed decrements  in  forced vital capacity (FVC), forced expiratory volume
in 1 s  (FEV-. n), and other spirometric variables when 10 normal subjects rested
            1. u                     3
for  2  hr while  exposed to 980 ug/m  (0.5 ppm) of 03; airway resistance (Raw)
was  not affected.  No changes in pulmonary function resulted from exposures to
588  or 196 ug/m3 (0.3 or 0.1 ppm) of 03-  Horvath et al.  (1979)  reported  that
decreases  in FVC and  FEV, n  resulted from 2-hr at-rest exposures of  15 subjects
                                          3
(8 males,  7 females)  to 980 and 1470  ug/m   (0.50  and 0.75 ppm) of  03; the
decreases  at 0.75 ppm were greater than those at 0.50 ppm of 0~.  No  changes
                                               3
in pulmonary function were observed at 490 ug/m  (0.25 ppm) of 03_
      Kagawa and Tsuru  (1979a)  observed small  decreases in  specific airway
conductance (SG  )  when three subjects  rested for  2 hr while  exposed  to  588
             ^   clW
and  980 ug/m  (0.3 and 0.5 ppm) of  03-  In  contrast to other studies,  this is
 the  only  report  of  changes  in  airway  resistance  resulting  from  at  rest  exposures
 to03.
      Konig  et  al.  (1980)  exposed  14 healthy  nonsmokers  (13 men,  1  woman)  for  2
 hr at rest  to  0,  196,  627,  and 1960 ug/m3  (0.0,  0.10, 0.32,  and 1.0  ppm)  of 03-
 019PO/A                             11-6                                 5/2/84

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TABLE 11-2.   STUDIES ON ACUTE PULMONARY EFFECTS OF OZONE SINCE 1978
Ozone
concentration
ug/mj
196


196
588
980




196
627
1960

235
353
470
588
784


294
588

392



392


ppm
0.1


0.1
0.3
0.5




0.1
0.32
1.0

0.12
0.18
0.24
0.30
0.40


0.15
0.3

0.2



0.2



Measurement '
method
CHEM,
NBKI

CHEM,
NBKI





MAST,
NBKI


CHEM,
UV





CHEM,
NBKI

UV,
NBKI


UV,
NBKI

. Exposure
duration and
activity
2 hr
IE (2xR)
@ 15-min intervals
2 hr
R (10), IE (31,
50, 67)
@ 15-min intervals



2 hr
R


2.5 hr
IE (65)
@ 15-min intervals




2 hr
IE
@ 15-min intervals
2 hr
IE (2xR)
@ 15-min intervals

2 hr
IE (2xR)
@ 15-min intervals

j
Observed effect(s)
No effect on Pa02 or R taking into account
intra-individual variation

Changes in pulmonary function found at 0.5 ppm
during R and 0.3 and 0.5 ppm with IE. The
magnitude of spirometric changes was gener-
ally related to ozone concentration and
minute ventilation, but concentration showed
stronger association. Effective dose-
functional response curves developed.
No changes in SR following exposure; SR
increased with Acfi challenge at ^0.32 ppmf
SR increased in 2/3 COLD patients at 0.1 ppm.
aw
Small decreases in FVC, FEV^o, and
FEF25_75<£ at 0.12 and 0.18 ppm with larger
decreases at £0.24 ppm; f and SR in-
creased and V, decreased at £0.2$wppm;
regression curves produced; coughing
reported at all concentrations, pain and
shortness of breath at iO.24 ppm.
SG and FVC decreased at 0.15 and 0.30
ppm 03. Increased AN2 at 0.15 ppm 03.
Questionable statistics.
No meaningful changes in PA02 , Pa02, and
P(A-a)02. Inconsistent changes in spirometric,
plethysmographic, and ventilatory distribution
variables.
Variable changes in FEV].0. Possible
calibration error for spirometry.


No. and sex
of subjects Reference
11 male von Nieding et al. , 1979


40 male Folinsbee et al . , 1978
(divided into 4
exposure groups)




13 male Kdnig et al . , 1980
1 female
(3 COLD)
(1 asthma)
135 male McDonnell et al . , 1983
(divided into six
exposure groups)




15 male Kagawa, 1983a


13 male Linn et al . , 1979
5 female


9 reactive subjects; Linn et al., 1980
4 (normal)
5 (asthma)

-------
TABLE 11-2.   STUDIES OF ACUTE PULMONARY EFFECTS OF OZONE SINCE 1978  (continued)
Ozone
concentration
ug/m3
392
588
784
392
686



392
823
980

i ^^_^__™
oo 392
784


412




490
980
1470







ppm
0.2
0.3
0.4
0.20
0.35



0.2
0.42
0.50


0.2
0.4


0.21




0.25
0.50
0.75







. Exposure
Measurement ' duration and
method activity
UV, 30-80 min
UV (mouthpiece)
CE (34.9, 61.8)
UV, 1 hr (mouthpiece)
UV IE (77.5) @ vari-
able competitive
intervals
CE (77.5)
UV, 2 hr
UV IE (30 for
male, 18 for
female subjects)
@ 15-min intervals
UV, 2 hr
NBKI IE (2xR)
@ 15-min intervals

UV, 1 hr
UV CE (81)



CHEM, 2 hr
NBKI R (8)










Observed effect(s)
Progressive impairment of lung function with
increasing effective dose; questionable sig-
nificance during CE (61.8).
FVC, FEVi.0, and FEF25_75 decreased, subjective
symptoms increased with 03 concentration; f»
increased and V-, decreased during CE; no effect
on V02, HR, Vc, or V.. No exposure mode effect.
t n
Pre-exposure to 0.2 ppm did not alter response
to higher concentrations; FEV^o decreased
in sensitive subjects (n = 9) at 0.2 ppm;
no significant sex differences.

SR increased with histamine challenge
in * subjects at 0.4 ppm. "Adaptation" shown
with repeated exposures.

Decreases in FVC (6.9%), FEVj.o (14.8%),
FEF25_75% (18%), 1C (11%), and MVV (17%).
Symptoms reported: laryngeal and tracheal
irritation, soreness, and chest tightness
on inspiration.
Spirometry: FVC, FEVj.0, and MMFR decreased
immediately following 0.75 ppm; FVC and FEV,.0
decreased immediately following 0.5 ppm. Meta-
bolism: respiratory exchange ratio and venti-
latory equivalent increased (0.75 ppm); oxygen
uptake decreased at all 03 concentrations. In-
creased Vp during exposure facilitates decrement
in lung function but does not facilitate return
to normal following exposure. No effect on max
V02 following exposure.

No. and sex
of subjects Reference
8 male Adams et al., 1981


10 male Adams and Schelegle,
(distance runners) 1983



8 male Gliner et al., 1983
13 female



12 male Dimeo et al., 1981
7 female
(divided into three
exposure groups)
6 male Folinsbee et al . , 1984
1 female
(distance cyclists)


8 male Horvath et al. , 1979
7 female









-------
                                        TABLE 11-2.   STUDIES  OF  ACUTE  PULMONARY EFFECTS OF  OZONE  SINCE 1978  (continued)
Ozone
concentration
ug/ma ppm
588 0.3
980 0.5
588 0.3
7 784 0.4
£>
1176 0.6
Measurement3 '
method
CHEM,
NBKI
MAST,
BAKI
CHEM,
NBKI
UV,
NBKI
Exposure
duration and
activity
2 hr
R
1 hr (mouthpiece)
CE (34.7 for
female and 51
for male subjects)
3 hr
IE (4-5xR)
for 15 min
2 hr (noseclip)
IE (2xR)
@ 15-min intervals
Observed effect(s)d
SG decreased at 0.3 and 0.5 ppm.
Tefioency toward increased bronchial
reactivity to ACh challenge. Smoking
effects were similar to those of ozone.
FVC, FEVj.o and flfzs.tsv decreased; fg
increased and V,. decreased with exercise;
nonsmokers and females may be more sensi-
tive; increase in subjective complaints
noted.
FVC and FEVj.o decreased and bronchial re-
activity to methacholine increased following
exposure. Adaptation shown with repeated
exposure.
SR increased in nonatopic subjects (n = 7)
witrl histamine and methacholine and in atopic
subjects (n = 9) with histamine following
exposure, returning to control values by the
following day; response prevented by pre-
treatment with atropine aerosol.
No. and sex
of subjects
6 male
(equally divided
by smoking history)
12 male
12 female
(equally divided
by smoking history)
13 male
11 female
(divided into 2
phases)
11 male
5 female (divided
by history of atopy)
Reference
Kagawa and Tsuru, 1979a
DeLucia et- al. , 1983
Kulle et al. , 1982b
Kulle, 1983
Holtzman et al . , 1979
Measurement method:   MAST = Kl-coulometric (Mast meter);  CHEM =  gas  phase  chemiluminescence;  UV =  ultraviolet  photometry.
Calibration method:   NBKI = neutral  buffered potassium iodide; BAKI  = boric  acid potassium iodide;  UV = ultraviolet photometry.
Activity level:   R = rest; CE = continuous exercise;  IE = intermittent exercise; minute  ventilation (Vc) given in L/min or as a  multiple of resting
ventilation.                                                                                           fc
See Glossary for the definition of symbols.

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Specific airway  conductance was measured and samples of arterialized ear  lobe
capillary blood  were  taken  for determinations  of oxygen tension (P0?)  before
and after the exposures.  No changes in P07 or  SG   were observed.   Subjective
                                                                           O
symptoms (substernal  burning)  were  reported by two individuals at 196 ug/m
(0.1 ppm),  by three at 627 ug/m3 (0.32 ppm), and by eight at 1960  ug/m3 (1.0 ppm)
of 03.

11.2.2  Exposures With Exercise
     The majority of  controlled  human studies  since 1978 have been concerned
with the effects of combined rest and exercise  exposures to various concentra-
tions of 03  for  variable periods of time (Table 11-2).  Exercise during these
exposures has been  at different intensities and at different times during the
exposures.   The  level of  minute  ventilation (V^),  which varies with exercise
intensity,  is  a primary determinant  of the magnitude  of pulmonary effects
resulting from  exposure to a  given level  of 07.  Therefore,  results  from
                                               O
studies using different regimens  of exercise,  even with exposure  to the same
0- concentration, may be difficult to compare.   Most studies used alternating
15-min periods  of  rest  and exercise.   Pulmonary function  and/or  subjective
symptoms were usually measured pre-  and post-exposure.   In a few studies,  such
measurements  were also made during the rest periods after each exercise period.
Exposures in these  studies  were  usually performed only on one day, and were
therefore likely to induce smaller functional decrements than would have  been
observed if  subjects  had  been  exposed on two  sequential  days,  as noted  in
Section 11.3  entitled "Pulmonary Effects Following  Repeated Exposures."
     Other factors  that may influence the  results obtained by different inves-
tigators and account  for some  of the  inconsistencies observed among the find-
ings from various studies  are  discussed in  this chapter.   Such factors  include
experimental  design (more  specifically:  number of subjects, exposure time,
recurrent exposures, length of and sequencing of exercise periods,  and  time of
measurements),  and  specific measurement techniques  used to determine 03 concen-
tration (see  Chapter 5)  and to characterize pulmonary responses.   The variabil-
ity of intrinsic responsiveness of individual  subjects  to 0,, effects of 0_ on
subjects with pulmonary disease,  and other  factors  affecting the responsiveness
of subjects to 03,  such as smoking history,  sex, and environmental  conditions,
are discussed in this section.   Studies on  the  interaction between 0., and other
pollutants  are presented in Section  11.5.

019PO/A                             11-10                                5/2/84

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     As  previously  stated,  increased V,. accompanying  exercise  is  one  of the
most important contributors to pulmonary decrements during CL exposure.  While
the  more recent reports  include  actual  measurements  of VV obtained during
exposure, earlier publications often included only a description of the exercise
regimen.  Table 11-3 may  aid the  reader in estimating  the VF associated with a
given exercise regimen.
     The  values  for CL consumption and  VV  in  Table  11-3 are approximate  esti-
mates for average physically fit  males exercising on a  bicycle ergometer at 50
to 60  rpm (if rpms are higher or lower, values may be  different).   Note that
individual variability is great  and that the level of  physical fitness, age,
level of  training,  and other physiological factors may modify  the estimated
values.  The only precise method  of obtaining these data is to actually measure
     •
the Vp  and  0« consumption.  If exercise is conducted on a treadmill, adequate
relative standards  for Op consumption and Vr can not be estimated.   Thus, with
such activity, there is an absolute need to measure these variables.
     Bates et al.  (1972)  and  Bates and Hazucha  (1973), as  described in the
previous 03  criteria  document (U.S. Environmental Protection Agency,  1978),
were the first to consider the role of increased ventilation due to exercising
in an 0~  environment.   These observations emphasized  an  important aspect of
ambient exposure; namely, that individuals who are engaged in some type of ac-
tivity  during ambient  exposure  to polluted air  experience greater pulmonary
function decrement  than resting individuals.
     Hazucha et al.  (1973)  reported data obtained on 12 subjects exposed for
2 hr to  either 725  (n=6)  or 1470  (n=6)  ng/m3  (0.37 or  0.75 ppm) of CL.   These
subjects performed  light exercise  (VV reported to be double resting ventilation)
alternately  every  15  minutes.   Three subjects also had total  lung capacity
(TLC),  residual  volume (RV),  and  closing capacity  (CC) measured  before and
                                3
after 2-hr exposure to 1470 ug/m   (0.75 ppm)  of  0,..  Significant decreases in
lung function derived  from  the  measurements of  forced expiratory  spirometry
were observed at  both  0.37  ppm  (P <0.05) and 0.75 ppm (P <0.001)  of 0  • the
decrease was greater at the higher level of 0~.   After exposures,  all subjects
complained to varying  degrees of  substernal  soreness,  chest  tightness,  and
cough.   While  the  number of  subjects  was small and the  results  therefore
inconclusive, RV  and  CC increased and  TLC was  unchanged after exposure to
0.75 ppm of 0-
019PO/A                             11-11                               5/2/84

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                        TABLE 11-3.  ESTIMATED VALUES OF OXYGEN CONSUMPTION AND MINUTE VENTILATION ASSOCIATED WITH  LEVELS  OF  EXERCISE0
FV>
Level of work
Light
Light
Light
Moderate
Moderate
Moderate
Heavy
Heavy
Very heavy
Very heavy
Severe
Watts
25
50
75
100
125
150
175
200
225
250
300
Kgm/minb
150
300
450
600
750
900
1050
1200
1350
1500
1800
02 consumption
(L/min)
0.65
0.96
1.25
1.54
1.83
2.12
2.47
2.83
3.19
3.55
4.27
Minute
ventilation
(L/min)
13
19
25
30
35
40
55
63
72
85
100+
Representative
activities
Level walking at 2 mph; washing clothes
Level walking at 3 mph; bowling; scrubbing floors
Dancing; pushing wheelbarrow with 15- kg load;
simple construction; stacking firewood
Easy cycling; pushing wheelbarrow with 75-kg load;
using sledgehammer
Climbing stairs; playing tennis; digging with spade
Cycling at. 13 mph; walking on snow; digging trenches
Cross-country skiing; rock climbing; stair climbing
with load; playing squash and handball; chopping
with axe
Level running at 10 mph; competitive cycling
Competitive long distance running; cross-country
skiing
       a,
        See text for discussion.
        Kgm/rain = work performed each minute to move a mass of 1 kg through a vertical distance of 1 m against  the  force  of  gravity.
       ^Adapted from Astrand and Rodahl (1977).

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     Kerr et al.  (1975) reported small, but significant, decreases in FVC, FEV3
RI , and SG   when 20 subjects were exposed to 980 ug/m  (0.5 ppm) of 0, for 6 hr
  L        oW                                                          O
with two 15-min periods of medium exercise (100 W).  The symptoms of dry cough
and chest discomfort were also experienced after exposure.   No changes in TLC,
RV, Cst, dN2, or DLCO were observed.
     Von Nieding et  al.  (1977) exposed normal  subjects  to  196 ug/m   (0.1  ppm)
Og for  2 hr with  light intermittent exercise  and  found no changes  in either
forced  expiratory  functions or  symptoms.   However, they  found  significant
increases  (~ 7 mm Hg) in both alveolar-arterial  P02 difference and airway
resistance  (~ 0.5 cm H20/L/s).
     Folinsbee et  al.  (1977b) demonstrated  that the  heightened pulmonary
effect  of  0, associated  with intermittent exercise  during exposure  occurred
principally,  if  not entirely, during  the  exercise period.  In  this study,
involving  subjects who had  exercised for a single  30-min period  during a  2-hr
        2
980-ug/m   (0.50-ppm) 0,  exposure, the  maximum  impairment of forced  expiratory
spirometry  appeared  immediately  (2 to  4 min)  after exercise  (Figure 11-1).
Despite continued  exposure to 0^,  but at rest, pulmonary function either
improved or showed no further impairment.   No change in RV or R,  was observed,
                                                               clw
while TLC was reduced.
     Folinsbee et  al.  (1978) reported  results from 40 subjects in  studies
designed to  evaluate the effects of various concentrations of 0, at several
different  levels of  activity from rest through heavy exercise.  Half of  the
subjects had previously  resided  in  an area having high 0, concentrations; 14
reported symptoms  associated with  irritation  or  breathing difficulty on
high-pollution days.   Five subjects  who had not resided in such areas reported
similar symptoms  upon visiting a high-oxidant-pollution region.   Nine subjects
had a history of allergy, 11 were former smokers,  and one  had had asthma  as a
child.   Ten subjects in each of four groups were exposed four times, in random
order,   to  filtered air or 196, 588, or  980 ug/m3 (0, 0.10,  0.30, or  0.50  ppm)
of 0,.  One group  rested throughout the exposure.   The other three groups
exercised  at  four  intervals throughout the  exposure;  each 15-min exercise
period was  followed by a 15-min  rest period.   Each  subject in the three exer-
cise groups walked on  a  treadmill at  a level  of  activity to  produce minute
ventilations of approximately 30, 50,  or 70 L/min,  respectively.   The integra-
ted minute  ventilatory volumes for the  total 2 hr  of exposure were 10, 20.35,
29.8,  and  38.65  L,  respectively.  No  pulmonary  changes were  observed with
019PO/A                             11-13                               5/2/84

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                         GROUP A
              GROUP B
              6.5
           (0
           CD
          ~  6.0
          O
          fc
              5.5
          (A
          0.
              5.0
              4.5
          25  4.0
          ffi
           u
           o
          -55  5.0
          UJ
          "-  4.0
              3.5 —
              5.5
                     I     I
                    30   60    90   120     "0   30   60
                         EXERCISE                  EXERCISE
                                  EXPOSURE, minutes
                         90   120
                 Figure 11-1. Change in forced vital capacity (FVC), forc-
                 ed expiratory volume in 1-sec (FEV 1.0), and maximal
                 mid-expiratory flow (FEF25-75%) during exposure to
                 filtered air (o) or ozone (A) (0.5 ppm) for 2 hr. Exercise
                 at 45% maximal aerobic capacity (max VO2) was per-
                 formed for 30 min by Group A after 60 min of ozone
                 exposure and by Group B after 30  min of ozone ex-
                 posure.
                 Source: Folinsbee et al. (1977b).
019PO/A
11-14
5/2/84

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                                     3
exposure to  filtered  air or 196 ug/m  (0.10 ppm) of 0~.  At rest (10 L/min),
                                                    3
pulmonary function changes were confined to 980 ug/m  (0.50 ppm) 0,. exposures.
                                                                           3
Some changes were  apparent at the lowest work  load  (30 L/min)  and 588 (jg/m
                                                           3
(0.30 ppm) of  0-.,  and  effects were more marked  at 980 ug/m  (0.50 ppm) of 0,.
At the  two  highest work loads (49 and 67 L/min), pulmonary  function changes
                                  3
occurred at  both  588  and 980 ug/m  (0.30 and 0.50 ppm), with the changes at
        3
980 ug/m   (0.50 ppm)   of  0,, usually  significantly  greater than  those  at
        3
588 ug/m  (0.30 ppm) of 0~.  During exercise, respiratory frequency was greater
and tidal volume  lower with 0- exposure than with sham exposure.  The change
in respiratory pattern was progressive and was most striking at the two heavi-
est work  loads and at the  highest 0- concentrations.   Reductions in TLC and
inspiratory  capacity  (1C),  but  not RV or functional  residual capacity (FRC),
were also noted.
     In a study similar to that of von Nieding et al.  (1977),   Linn et al.
(1979)  exposed normal  subjects to  392 ug/m   (0.2 ppm) of 0_.  The 12 subjects
had blood and  alveolar gas samples taken shortly  after 1  and 2 hr of their
2.5 hr of exposure.  These subjects also exercised at twice resting ventilation
for 15 min of  every half hour.  Blood samples were taken both from an arterial-
ized ear  lobe  and  a brachial artery.   Alveolar P0? exhibited no changes with
time or exposure.   Brachial  artery P0? showed  highly significant variations
with time,  decreasing between  the 0  and 1-hr  samples  and being partially
reversed at 2  hr.   The alveolar-arterial  oxygen pressure difference [P(A-a)0?]
was increased  at 1 hr and reversed at 2 hr.   This pattern was seen on both the
no-O,, and 0,, exposure  days.   Ear lobe sample data showed some differences but
were not  related  to Q- exposure.   In six subjects (bringing the total  number
of subjects  exposed to 18) on whom both  ear lobe and arterial  samples were
obtained,  the  authors reported a  significant  change in arterial  P0?.   An
explanation  for the differences in response  of  the P(A-a)0?  obtained by these
two groups of  investigators was not readily apparent.
     Adams et  al.  (1981) required  eight subjects (22 to 46 years of age) to
exercise continuously  (i.e.,  no rest periods) while  orally inhaling 0.0, 392,
588,  and 784 ug/m3  (0.0,  0.2, 0.3, and 0.4  ppm) of  0^.  The duration of the
exercise periods varied  from 30 to 80 min,  and the  two exercise loads were
sufficient to  induce minute ventilations  of 34.9 and 61.8 L/min, respectively.
Pulmonary functions were measured before  and within 15 min  after exercise.   At
both minute  ventilations,  decrements  in forced  expiratory  spirometry were ob-
                                         3
served for exposures  to  588 and 784 ug/m  (0.30 and 0.40 ppm) of 0-  with the
019PO/A                             11-15                               5/2/84

-------
magnitude of decrement greater at the higher minute ventilation.  The magnitude
of  decrement  also  increased  with increasing  exposure  time.   No pulmonary
                                                            O
effects were observed for exposures to clean air or 392 ug/m  (0.2 ppm) of 03.
The  authors suggested  that the detectable level for 03 functional effects in
healthy subjects during sustained exercise at a moderately heavy work load (V£
of ~62 L/min) occurred between 03 concentrations of 392 and 588 ug/m3 (0.2 and
0.3 ppm).  The responses to continuous exercise were similar to those observed
in studies using intermittent but equivalent exercise.
     Kagawa (1983a)  presented data  on 15 subjects exercising  intermittently
                                                                           f\
(15 min  exercise,  15 min  rest) during a  2-hr  exposure  to 294  or 588 ug/m
(0.15 or 0.30 ppm) of Q^.   These subjects reported the typical symptoms at the
higher 03 concentrations.   Paired t-tests were used to compare responses  to
filtered air  and 0~.   SGauj decreased 6.4 percent  (P <0.05)  following the
        •^          *3      ClW
294-ug/m   (0.15-ppm) exposure  and  16.7  percent  (P <0.01)  following  the
588-ug/m  (0.30-ppm) exposure.   In  the latter environment, only FVC showed a
significant (P <0.05)  decrement;  FEV1 was  unaffected.   These  subjects had
resided in a low-oxiriant-pollutant environment.
     McDonnell et al.  (1983)  provided further information related to high
levels of ventilation  during  exercise in 135 subjects exposed  to  03.   They
divided  their  subjects  into six groups,   each  group  exposed to a different
concentration of 03; viz.  0.0 (n=20), 0.12 (n=22),  0.18 (n=20), 0.24 (n=21),
0.30 (n=21), and  0.40  (n=29)  ppm, equivalent to 0.0, 235, 353, 470, 588,  and
        3
784 ug/m  of 03-   The subjects were  exposed for 2.5  hr,  with exposure consist-
ing of alternating 15-min periods of rest and exercise (VE/BSA of = 35 L/m  or
VE = 64 to 68 L/min) during the first 2 hr.   With continued 03 exposure,  forced
expiratory spirometry and pulmonary  symptoms were measured between 5 and 10 min
after the final  exercise,  while  plethysmography was performed between 25 and
30 min after  the  final  exercise.   The pulmonary  symptom,  cough,  showed the
                                                                             3
greatest sensitivity to 03 (it occurred at the lowest concentration, 235 ug/m
or 0.12 ppm of 0.,).  Small  changes  in forced expiratory spirometric measures
                                                                               3
(FVC, FEV-p  maximal  mid-expiratory flow [FEFpS-75%^ were  suggested at 235 ug/m
(0.12 ppm)  of 0-  and were definitely present at 353 ug/m  (0.18 ppm) of 0,.
                                                3
Greater changes were found at  and above 470 ug/m  (0.24  ppm) of 03.   Significant
decreases in tidal  volume  (Vy)  and  increases  in  respiratory  frequency  (fR)
during exercise (similar changes  had been reported by other investigators) and
specific airway resistance  (SR  ), pain on deep inspiration, and shortness of
                              3W

019PO/A                             11-16                               5/2/84

-------
breath  occurred at 03 levels  of  >470  ug/m  (0.24 ppm).   The sigmoid-shaped
dose-response  curves  indicated a relatively large decrease in FVC, FEV,, and
                                    3
FEF25_75c/  between 353 and  470 ug/m   (0.18 and  0.24  ppm)  0~.   However, in
contrast to  the results  of other investigations,  a  plateau in response was
                                         3
observed at  the higher levels (>470 ug/m  ; 0.24  ppm)  of 0_.   In  contrast to
                                                               3
the spirometric tests, SR   increased  significantly at 470 ug/m  (0.24 ppm) of
                         oW
0~  and  continually increased  with increasing 0-  levels,  in  agreement  with the
results of other  investigators.  These two different patterns in response plus
the observation that  individual changes in SR   and FVC were poorly correlated
                                             clW
prompted these investigators  to  suggest that  more than a  single  mechanism
might have to  be  implicated to define  the effects of 0- on pulmonary functions.
Findings from  this study are  particularly relevant  in that a large subject
population was studied and  pulmonary effects were present at  an 0,.  concentra-
               3
tion  (235  ug/m ;  0.12 ppm)  lower  than  that for which  they had previously been
observed.
     More  recent  studies on well-trained subjects have become available.  Six
well-trained men  and  one well-trained  woman (all  of  the subjects  except one
male being a competitive distance cyclist) exercised continuously on a bicycle
                                                            3
ergometer  for  1 hr while breathing  filtered air  or 412 ug/m  (0.21  ppm) of 0.,
                                                                            O
(Folinsbee et  al.  ,  1984).   They worked at  75 percent  maximal  aerobic  capacity
(max  Vgp)  with mean  minute ventilations  of 89  L/min.   Pulmonary function
measurements were made pre-  and  post-exposure.   Decreases  occurred  in FVC
(6.9 percent), FEV-j^ Q  (14.8 percent),  ^^2b-7b% (18 Percent) • IC (11 percent),
and maximum  voluntary ventilation (MVV) (17 percent).  The  magnitude  of these
changes were of  the  same  order  as  those  observed in subjects performing
moderate intermittent  exercise for  2 hr in a 686-ug/m  (0.35-ppm) 0-  environ-
                                                                    O
ment.   Symptoms included laryngeal  and/or  trachea! irritation and  soreness as
well as chest tightness upon taking a deep breath.
     Adams  and  Schelegle (1983)  exposed  10 well-trained distance  runners to
                       3
0.0, 392,   and  686 ug/m  (0.0, 0.20, and 0.35  ppm) of 03  while the runners
exercised  on a bicycle ergometer at work loads  simulating either a 1-hr steady-
state training bout or a 30-min warmup  followed immediately by a 30-min competi-
tive bout.    These exercise  levels were of  sufficient magnitude (68  percent of
their max  VQ2)  to increase  mean VE  to 80  L/min.   In  the last 30  min  of the
competitive  exercise  bout,  minute ventilations were  approximately 105 L/min.
Subjective  symptoms,  including shortness  of  breath,  cough, and raspy throat
019PO/A                             11-17                               5/2/84

-------
increased as a function of 0_ concentration for both continuous  and competitive
levels.   The  high ventilation volumes (80  L/min) resulted in marked pulmonary
function impairment and altered ventilatory patterns (increased  fR and decreased
                                           3
VT) when exercise was performed in 392 ug/m  (0.20  ppm) of Og.   Two-way analysis
of variance  (ANOVA) procedures performed on the pulmonary function data indi-
cated significant decrements (P <0.0002) for FVC, FEV.^ and FEF25-75%-  These
investigators  noted  that percent  decrement  in FEV, g was similar  to that
observed by  Folinsbee  et  al. (1978) when the two studies were compared on the
basis of effective  dose.   The  concept of effective dose will  be treated in a
later section.

11.2.3  Intersubject Variability and Reproducibility of Responses
     In the  majority  of the above studies, assessment of the significance of
results was typically based on the mean ± variance  of changes in lung function
resulting  from  exposure to  0-  as  compared  to exposure  to  clean  air.   Although
consideration  of mean  changes  is  useful  for making statistical  inferences
about homogeneous populations,  it  may not  be adequate  to  describe  the differ-
ences in  responsiveness to 0^ among individuals.   While the significant mean
changes observed demonstrate that the differences  in response between 03 and
clean air  exposures  were not due  to  chance, the variance of responses was
quite large  in most studies.  Characterization of reports of individual res-
ponses to  0-  is  pertinent since it permits the assessment of the proportion of
           O
the population  that may actually be affected during exposure to 03-
     Results  from  a small number  of  studies (Horvath et al., 1981; Gliner et
al., 1983; McDonnell  et al. , 1983) that  have  reported individual responses
indicate that a considerable amount of  intersubject variability does  exist in
the  magnitude of response to 03.   Figure  11-2 illustrates the variability of
responses  in FEV,  n and SR   obtained  from  subjects exposed  to different 0-
   r             1.0       aw                                               °
concentrations.
     Decreases  in FEV,  Q  ranging  from 2 to 48  percent  (mean = 18 percent) were
reported  by Horvath et al.  (1981)  for  24  subjects  exposed for  2 hours to 823
ug/m3  (0.42 ppm) of 0- while performing moderate intermittent exercise.   When
                      J
these  same subjects were exposed  to  clean air under the  same conditions, the
response of  FEV,  _  ranged from  an  8-percent  increase to an 11-percent decrease
(mean =  0  percent).
 019PO/A                             11-18                                5/2/84

-------
NUMBER OF SUBJECTS
O Ul O OUIO OUIO OUIO OUIO OUIO
1 1 1 1 1 1 1 1 1 1
0.40 ppm
~,rl fflnF

1 1 1 1 1 1 1
0.30 ppm
i H H rn i r

i i i 1 1 i i i
0.24 ppm
TfLrTTJ
i 1 1 In M i !-•

ii i i i i i i i
r~j 0.18 ppm
i "hi n i i i

i i i i i i i i i
0.12 ppm
>-r "T-i i i i i

i i I i i i i i i i
0.00 ppm
1 -1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1
0.40 ppm
-r-Tl H M 1-r-i

1 1 1 I 1 1 1 1 1 1
0.30 ppm
-HThrn n i

1 1 1 1 1 1 1 1 1 1
0.24 ppm
"rlhfL , , ,"

II 1 1 1 1 1 1 1
0.18 ppm
TuTn ,,,,"

i i i i i I i i i i
0.12 ppm
1 I r-i-r-i I I I

I 1 I 1 1 I I 1 M
0.00 ppm
1 1 M 1 1 I 1 1 1
019PO/A
  -10  0  10  20  30 40     -20  0  20 40 60  80

AFEV-|.o(DECREASE), percent  ASRaw(INCREASE), percent

   Figure 11-2. Frequency distributions of
   response (percent change from baseline)
   in specific airway resistance (SRaw) and
   forced expiratory volume in 1-sec (FEVi.o)
   for individuals exposed to six levels of
   ozone. One individual with 260% increase
   in SRaw exposed to 0.4 ppm of ozone is
   not graphed.
   Source:  McDonnell et al. (1983).

                  11-19
5/2/84

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     Gliner et al .  (1983)  exposed  subjects (13 females, 8 males) performing
                                                              o
intermittent light  exercise for 2 hr to clean air and 392 (jg/m  (0.20 ppm) of
0.,.   Changes  in  FEV-, Q  resulting  from clean-air exposure  ranged between
+7.8 percent and -7.5 percent  (mean =  0 percent), while the range of changes
in FEV-. n was  +6.0  to  -16.6 percent (mean = -4 percent) with exposure to 392
    T 1. U
ug/m  (0.20 ppm)  of 03.
     For subjects performing 2 hr of intermittent heavy exercise while exposed
to 0.,,  McDonnell  et al .  (1983) observed changes in  FEV, n ranging from -3 to
-43 percent (mean = -16  percent) at 784 ug/m   (0.40 ppm), -4 to -38 percent
                                3
(mean = -17 percent) at 588 ug/m  (0.30 ppm),  -2 to  -41 percent (mean = -15 per-
cent) at 470 |jg/m3  (0.24 ppm), -2 to -22 percent (mean = -7 percent) at 353
    3                                                                3
ug/m  (0.18 ppm), +7 to  -17 percent (mean = -4 percent)  at 235 ug/m  (0.12
ppm), and +3 to  -7  percent  (mean = -2 percent)  in clean air.  Large  intersub-
ject variability was also reported for changes  in SR  ,  during these  exposures
                                                    aw
(Figure 11-2).
     The factors  that  contribute to the observed variability  of  individual
responses have  not  been  identified.   One factor to be considered  is  real
intersubject differences  in the  stable intrinsic level of responsiveness  to
0-.   The degree  to  which a  subject's response to a given 0- concentration  can
be reproduced is  an indication of how precisely the  measured response estimates
that subject's  intrinsic responsiveness.    In  a 1983 study, Gliner  et al .
                                                                            3
exposed subjects performing intermittent  light  exercise for 2 hr to  392 ug/m
(0.20 ppm) of  0~ on three consecutive days, followed the next day by an expo-
                               o
sure to either 823  or  980 ug/m  (0.42 or 0.50  ppm) of  0Q.  Each subject had
                                                                            3
also been exposed prior  to  or  was exposed after the study to 823 or  980 ug/m
(0.42 or 0.50  ppm)  03.    For individual responses of FEv^ Q, a moderate corre-
lation  (r =  0.58)  between changes  resulting from the  first exposure to 392
ug/m3 (0.20 ppm)  of 03 and the first  exposure  to  823 or 980 ug/m3 (0.42 or
0.50 ppm) of OT  was observed.   When responses  in FEV-,  Q  from the first and
second exposures  to 0.42 or 0.50 ppm 0- were compared, the correlation between
the two exposures was quite high (r = 0.92).  Although  these comparisons were
confounded by  possible  effects of prior  03 exposure,  they  do suggest that
individual  changes  in FEV.,  Q resulting from 03  exposure are reasonably repro-
ducible.  Moreover,  a  given individual's  response to a single 03 exposure is
probably a reliable estimate of that individual's intrinsic responsiveness to
019PO/A                             11-20                               5/2/84

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11.2.4  Prediction of Acute Pulmonary Effects
     Nomograms  for  predicting changes  in  lung function resulting from  the
performance  of  light intermittent  exercise while  exposed  to  different CL
                                                                          O
concentrations  were  included  in  one of  the  earliest reports  of the effects of
0~  on  normal subjects (Bates and  Hazucha,  1973).   Then in  1976, Silverman
et al.  reported that pulmonary function decrements  were  related  as linear and
second-order polynomial  functions  of the effective  dose  of  0~, defined  as the
product of  concentration,  exposure duration, and V.-.  Equations were derived
from lung  function  measurements  at 1 and 2 hr of exposure to 725,  980, and
         3
1470 ug/m   (0.37, 0.50,  and 0.75 ppm) of 0_ under conditions of  both  rest and
intermittent exercise sufficient to increase Vr by  a factor  of 2.5.   Although
the  fit of  their data to linear  and second-order  curves  was  good, the authors
also commented  that  for  a  given  effective dose, exposure to  a high concentra-
tion of 0,  for  a short  period of  time  induced greater functional decrements
than a longer exposure to a lower concentration.  This phenomenon implies that
0- concentration  is  a more important contributor  to response than is  exposure
duration.    Moreover,  they  also  observed extensive  individual variability in
pulmonary  function  changes,   suggesting  that use of  effective dose  is  not
satisfactory for predicting individual responses to 03 exposure.
     Since  the  inception  of  the concept of an effective  dose,  additional
studies have used,  and  in some cases refined,  it for prediction of pulmonary
responses to 0_ exposure.  Extension of the effective-dose  concept was  accom-
plished in  the  studies  of Folinsbee et  al.   (1978)  on subjects  at rest  and
performing  intermittent  exercise during 2-hr exposures  to  0, 196,  588, and
980 ug/m  (0.0,  0.10, 0.30, and  0.50 ppm) of 03-  The exercise loads  required
VE of  some  three,  five,  and  seven  times greater  than resting ventilations.
Again,  the  effective dose  was calculated as the product  of 0, concentration x
Vp (L/min) during exposure (includes both exercise and rest minute ventilation)
x duration  of exposure.   Polynomial regression analyses were performed first
                               •
on mean data at each level of Vp,  and  second  on  all  subject groups together
after computing  the  effective dose.  Figure 11-3 (an example of the calcula-
tions made)  presents the linear  and polynomial regression  lines for  percent
change  in pulmonary  functions (FVC  and  FEV-.  0) as a function of  0~ concentra-
tion during the 2-hr exposure.  Figure 11-4 presents the polynomial  regression
lines for percentage change in FEV, 0 as a  function of "effective dose"  of 0,..
Data from other investigators are  also  presented.   Predictions  of pulmonary
function changes  in  FEV, based on  effective doses up to  1.5  ml 03 agreed with
019PO/A                             11-21                               5/2/84

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                        o
                        u
O
oc
2
O
O
                       O
                       CC
                       LL
                       LL
                       O
                       2
                       <
                       *?•
                       O
                       O
                       >
                        c
                        «>
                        U
a
_J
O
                       O
                       o
                       o
                       a,
                       LL
                       U
                       CJ
                       Z
                       O
                       cs

                       >"
                       LU
                       LL.
                           -30
                           25
                           -20
                           -15
MiNUTE VENTILATION
      A 10 l/min
      S 30 l/min
      C 50 i/min
      D 70 i/min
                                  0.10  0.20   0.30  0/,0  0,50  0.80
                                         OZONE, spr.i
                           .25
 !     I      f     i
MiiMUTE VENTILATION
      S 30 i/min
                             0    0.10  0.20   0.30  0.40  0.50   0.60

                                          OZONE, ppm

                             Figure 11-3. Linear and polynomiai
                             regression iines for percentage
                             change In pulmonary function  [forced
                             vital capacity (FVC) and 1-sec forced
                             expiratory volume tF^V^.j)/] as  a func-
                             tion of ozone concentration during a
                             2-hr exposure with intermittent exer-
                             cise. Letters indicate groups in which
                             exercise levels were adjusted to
                             achieve a given minute ventiiation: A
                             (rest), B (30 l/min), C ISO i/min),  and  D
                             {70 S/min). Nonsignificant Jlnes were
                             omitted.
                             Source: Foiinsbee et ai. 11978).
019PO/A
                 11-22
                                               5/2/84

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    8
    o
    GC

    O
    o
    5
    o
    £
    LU
    0
    <
    o
        -20
        -15
-10
              I   TTT
                 T    I
   I   I
                         +    +S50
                        J50DI
                     J37DI
           A1.B1.C1.D1
                      D2
             A2  B2A3'C2 I  A4  B3
             I    I  II  I  I   I
                                 B4
                                _L
          03
           I
      C4
       I
      D4
       I
         0.0
               0.5
1.0
1.5
2.0
2.5
                           EFFECTIVE DOSE OF OZONE, milliliters
          Figure 11-4. Polynomial regression line of percentage change in 1-sec
          forced expiratory volume (FEV-j Q) as a function of "effective dose" of
          ozone calculated  as the product  of  ozone concentration (ppm),
          minute ventilation (l/min), and exposure time (min). A, B, C, D, and
          subgroups (•)<= Folinsbee et al.,  1978; other studies ( + ) are H =
          Hazucha et al., 1973; S = Silverman et al., 1976; F = Folinsbee et al.,
          1977a; J = Hackney et al., 1975c; L = Folinsbee et al., 1977b; for which
          accompanying numbers indicate ozone concentrations in pphm. Dl
          after J37 and J50 refers to the first of two exposure days. SR75 refers
          to resting exposure at 0.75 ppm from reference S.
          Source: Adapted from Folinsbee et al. (1978).
019PO/A
                            11-23
                                     5/2/84

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data collected  by other  investigators.  Prediction equations using the effec-
tive dose for all measured pulmonary functions were constructed.   All equations
were significant at  the  0.01  level.  These investigators also used a multiple
regression approach  to  refine further the prediction of changes in pulmonary
function resulting from 0- exposure.  Duration of exposure was not analyzed as
a contributing  factor since all exposures were of equal time.  Their analyses
indicate that essentially  all of the variance of pulmonary  responses could be
explained by  0_ concentration  and Vp.   For example,  these two predictors
accounted for approximately 80  percent  (multiple r = 0.89)  of the variance in
FEV-. n.  Moreover, 0-  concentration accounted for more of  variance  than  did
   J. * U               J
Vp, and  for  a given  effective  dose, exposure to a high concentration with a
low VV  induced  greater  functional  decrements than exposure  to a  lower concen-
tration with elevated VV.  Equations (with appropriately weighted 03 concentra-
tion and Vp)  for predicting the magnitude of pulmonary decrements were also
provided.
     Adams et al. (1981) further extended the effective-dose concept in studies
using  a  multiple regression approach  and arrived at essentially  the  same  con-
clusions reached by  Folinsbee et al.  (1978),  namely that most of the variance
for pulmonary function  variables  could be accounted for by 0., concentration,
followed by VF,  and then by exposure time.   Adams et al. emphasized  the predomi-
nant importance  of 0^  concentration and suggested that the detectable  level
for 0.,  functional  effects in healthy subjects during sustained  exercise  at a
moderately heavy work  load (Vc ~ 62 L) occurred between 0., concentrations of
                 3
392 and  588  jjg/m  (0.2  and 0.3 ppm).   The  responses  to continuous  exercise
were similar  to those  observed in  studies using  intermittent but equivalent
exercise.  They also noted, as  had  others, that the effective-dose concept was
not satisfactory for predicting individual responses.
     Colucci  (1983)  assembled data available  from  the  literature and analyzed
them with  the purpose of  constructing  dose/effects  profiles for predicting
pulmonary responses  to 0-  based on  results combined from many different labora-
                         O
tories.   Basically,  he  examined changes in  R   and  FEV,  „ as  functions  of
                                              dW         -L • \J
exposure rate (0- concentration x Vp) and total exposure dose (exposure rate x
duration of exposure), which  is equivalent to effective dose.  The correlation
for changes  in  R   was  slightly better than that for changes in FEV1 Q.  The
author  states  that  he  elected  to  use linear equations to fit the data rather
 019PO/A                              11-24                                5/2/84

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than polynomials because  he  found  little difference  in the degree of correla-
tion between the two methods.  This statement somewhat contradicts his observa-
                                                             •
tion of an  attenuation  in the rate of  increase  of SR   as  Vc increased to
                                                      aw     t
higher levels; there was no attenuation of the decrease in FEV,  g as a function
of increasing Vp.   This observation suggested to Colucci  that different mecha-
nisms may be  involved in  the  effects on R    and  FEV,  n.  Whether  expressed as
                                         d w        J- • \J
functions of  exposure  rate or total exposure dose, the patterns of pulmonary
responses were  approximately  equivalent.   This is not surprising since both
Folinsbee et al. (1978) and Adams et al. (1981) had previously shown that most
of the variance in pulmonary response depended primarily on 0^ concentration
and Vp.  The  overall  finding, that increases  in  R   and decreases  in  FEV^^ Q
are reasonably correlated with increases in effective dose of 0.,, only confirms
the  results reported by  previous  investigators.   As proposed by Folinsbee
et al. (1978)  and  Adams et al.  (1981),  a better  fit  of the data  may have been
obtained had Colucci used multiple regression and  equations  that appropriately
weighted the  relative contributions  of each  of  the exposure  variables to
pulmonary decrements.

11.2.5  Bronchial  Reactivity
     In addition to overt changes  in pulmonary function,  several  studies have
reported increased nonspecific  airway  sensitivity resulting  from 0^ exposure.
Airway responsiveness  to  the  drugs acetylcholine  (ACh),  methacholine, or
histamine is most  often used to define nonspecific airway sensitivity.
     Eight  healthy  nonsmoking men  served as subjects  (Golden et al., 1978) for
evaluation  of  bronchial  reactivity due to histamine  after a 2-hr exposure to
         •3
1176 ug/m   (0.6 ppm) of 0~.  The resting subjects  breathed orally (a nose-clip
was worn).   These  investigators  concluded  that 0~ exposure at  this  concentra-
tion  and dose produced an enhanced response  to  histamine, which returned  to
normal within  1 to  3 weeks after exposure.
     Kagawa and Tsuru  (1979a) studied both smokers  and nonsmokers  exposed to
0.0,  588, and 980  ug/m3 (0.0, 0.3, and  0.5  ppm) 03-  Their  three nonsmoking
subjects were  exposed  for 2 hr followed by  measurements  of bronchial reac-
tivity to   ACh.  They  found that  these  subjects demonstrated an increased
reactivity  to  ACh.  However, because of the  small number of subjects  and the
large  variability  of responses, the results  may not represent a significant
effect.
019PO/A                              11-25                                5/2/84

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     The bronchial  reactivity  of atopic and nonatopic subjects was evaluated
by Holtzman  et al.  (1979).   They studied  16 healthy  nonsmoking  subjects  and
found that  nine could be classified as "atopic" based on medical history and
allergen skin  testing.  All subjects had normal pulmonary functions determined
in preliminary screening  tests and were asymptomatic.   Both  atopic and non-
atopic  subjects  performed intermittent exercise while wearing nosedips  and
                                                   o
exposed by mouthpiece to  filtered air and 1176 ug/m  (0.6 ppm) of 0~.   Bronchial
reactivity was determined 1 hr after exposure to  each condition  (when post-
exposure SR    had returned to normal) by measuring the increase in SR   produced
           aw                                    3                   aw
by inhalation  of histamine  or methacholine aerosols.  In both atopic and non-
atopic  subjects,  the bronchial  response  to histamine and methacholine was
enhanced after 0.,  exposure  when compared to exposure  in filtered air.   The
increase in SR   resulted predominantly from an increase in airway resistance,
               dw
with only  small  changes  in  trapped  gas  volume.  Symptoms of bronchial irrita-
tion were  increased; however,  these changes were transient,  and were  not
detectable by  the  next  day.   This  result  contrasts  with  previous results
observed by  these  investigators  (Golden et al., 1978),  which  indicated that
enhanced bronchial  responsiveness persisted for  a more  prolonged period.
Premedication  with  atropine sulfate aerosol prevented the  increase  in  SR
                                                                          aw
histamine inhalation.  Atopic subjects appeared to respond to a greater degree
than nonatopic subjects,  although the  pattern  of change  and the  induction  and
time course  of increased  bronchial  reactivity after  exposure  to  CL were  un-
related to the presence of atopy.
     Kb'nig et  al.  (1980)  exposed 14 healthy nonsmokers (13 men,  1 woman) for
2 hr to 0,  196,  627, and 1960 |jg/m3  (0.0,  0.10,  0.32,  and 1.00 ppm)  of 0,.
Bronchial  reactivity  to  ACh was determined after  exposure.   Significant  in-
creases in  bronchial reactivity  were observed with  the ACh challenge at
        3                         3
627 ug/m  (0.32 ppm) and  1960 ug/m  (1.0 ppm) of 0-.
     Bronchial  reactivity of  normal  adult subjects was assessed by measuring
the increase in SR   produced by inhalation of histamine aerosol  (Dimeo et al.,
1981).   Seven  subjects,   intermittently exercising (15 min  exercise,  15 min
                                                                               3
rest) at a load sufficient to double their resting VE, were exposed to 392 ug/m
(0.2 ppm)  of 0,. over a 2-hr period.   Two air exposures preceded the 0_ exposure,
which was  followed  by another  air exposure.  Another  group  (five  individuals)
were only  repeatedly tested pre- and post-air exposure for their response to
histamine.   In these two  groups, the bronchial  responsiveness to histamine was
019PO/A                             11-26                               5/2/84

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not  different  in the air  exposures.   The  bronchomotor response to  inhaled
                                                        3
histamine aerosol was not altered following the 392-ug/m  (0.2-ppm) 0_ exposure.
However, a  third group  (seven  individuals) was also exposed to  air for 2 days
                3
and  to  784  ug/m  (0.4 ppm) of 0~ on  the  following day.  The mean bronchial
responsiveness  to  inhaled  histamine was increased following exposure to 784
    3
ug/m   (0.4  ppm) of 0,.   Baseline  SR   (i.e., before  histamine)  after  the
                     o               aW
0.4-ppm exposure remained unchanged.
     As part of a study of repeated  exposures to  0.. (discussed in detail  in
Section 11.3),  Kulle  et al.  (1982b) exposed  two separate groups of  subjects
(13  males,  11  females)  for 3 hr to filtered air and then 1 week later to 784
    3
ug/m  (0.4 ppm) of 0,.   One hour before the end of exposure,  15 min of exercise
at 100 W was performed approximating a Vp of four to five times resting values.
Bronchial reactivity to  methacholine was assessed  after each exposure and  was
significantly enhanced  (P  <0.01) in both subject groups following exposure to
0,, as compared  to filtered-air exposure.

11.2.6  Mechanisms of Acute Pulmonary Effects
     The primary  acute  respiratory  responses  to 0~ exposure are decrements in
                                                 O
variables derived  from  measures  of forced expiratory spirometry (volumes and
flows)  and  respiratory  symptoms  (notably, cough and substernal  pain  upon deep
inspiration).    Altered  ventilatory  control  during exercise (increased fD and
                                                                        K
decreased VT with V,. remaining unchanged) and small increases in airway resis-
tance have also been observed.
     Decrements  in  FVC  observed  at relatively high (1470-ug/m  ; 0.75-ppm)  03
concentrations  have  been associated with  increases  in RV (Hazucha  et al. ,
1973; Silverman et  al.,  1976).   Since increased RV occurs only at higher  0~
concentrations,  it  has been postulated by  Hazucha et  al.  (1973)  that this
increase results  from  gas  trapping and premature  airway closure caused by a
direct effect of 0, on small airway smooth muscle or by interstitial  pulmonary
edema.
                                      3
     At 0_  concentrations  of 980 ug/m   (0.50  ppm)  and  less, decrements in  FVC
are  related to  decreases  in TLC without changes in RV.  Decreased TLC results
from reductions in maximal expiratory position as indicated by the observation
that  inspiratory capacity also  declines  (Hackney et al.,  1975c;  Folinsbee
et al. , 1977b;  Folinsbee  et al. ,  1978).   Moreover, a decrease in  inspiratory
effort,  rather  than a decrease in  lung  compliance,  most likely causes the
019PO/A                             11-27                               5/2/84

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reduced inspiratory capacity  resulting  from 03 exposure (Bates and Hazucha,
1973; Silverman et al.,  1976;  Folinsbee et al.,  1978).   Ozone is thought to
"sensitize" or stimulate irritant (rapidly adapting)  and possibly other airway
receptors (Folinsbee et al., 1978; Golden et al.,  1978;  Holtzman  et al., 1979;
McDonnell  et al.,  1983).   This  results  in vagally mediated  inhibition of
maximal inspiration,  either involuntarily .or due to discomfort (Bates et al.,
1972;  Silverman et  al.,  1976; Folinsbee et al.,  1978;  Adams  et  al.,  1981).
Stimulation of irritant  receptors is  also believed to be responsible for the
occurrence of respiratory symptoms (Folinsbee et  al.,  1977b;  McDonnell et al.,
1983)  and  for alterations  in  ventilatory  control  (Folinsbee et al. , 1975;
Adams et al., 1981;  McDonnell  et al.,  1983).
     Unless measured at absolute lung volumes,  decrements in  forced expiratory
flows  (e.g., FEV  ~,  FEFpc.ycy)  are  difficult to interpret.   Surely,  most of
the decline in flow is related to reduced maximal  expiratory  position, while a
smaller portion results from airway narrowing (Folinsbee et al.,  1978; McDonnell
et al., 1983).   Airway narrowing, as  indicated by increased airway resistance,
probably  results  from either  smooth-muscle contraction,  mucosal edema, or
secretion  of mucus.   These  can be initiated by vagally  mediated  reflexes from
irritant receptor stimulation, by the interaction of an endogenous or exogenous
substance with the  vagal  efferent pathway, or by the direct  action of 03 (or
an 0.,-induced, locally released substance) on smooth muscle or mucosa (Folinsbee
et al., 1978;  Holtzman et al.,  1979;  McDonnell et al., 1983).   While it is
possible  that  stimulation  of  airway  receptors is the  mechanism common to
changes in airway resistance as well  as in volumes and flows, McDonnell et al.
(1983)  have  postulated the  existence of more than  one mechanism  of action  for
Ov  They  base this postulation  on their observed  lack  of  correlation between
 O
individual changes  in FVC and SR  and  on  differences in dose-response  curves
                                 d.W
for these two variables.
     Two hypotheses have been proposed that are consistent with the observations
of  increased airway  reactivity  to histamine and methacholine following 03
exposure (Holtzman et  al.,  1979).  The first suggests that 03 increases airway
epithelial permeability,  resulting in greater access  of histamine and methacholine
to bronchial smooth muscle  and vagal  sensory receptors.  The  second hypothesis
suggests  that  0-  or a byproduct  of CL  causes an  increase  in  the  number or  the
binding affinity of acetylcholine  receptors on bronchial smooth muscle.
019PO/A                             11-28                                5/2/84

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11.2.7  Pre-existing Disease
     According to  the  National  Health  Interview Survey  for 1979  (U.S. Depart-
ment of Health  and Human Services, 1981), there were an estimated 7,474,000
chronic bronchitics, 6,402,000  asthmatics, and 2,137,000 emphysematics  in the
United States.   Although  there  is some overlap of  about  1,000,000  in these
three categories,  it can be reasonably estimated that over 15,000,000 individ-
uals experienced chronic respiratory  conditions.   That the  effects of air
pollutants  on  this large segment  of our  population have  not received  more
attention by clinical  investigators  is surprising.   In clinical studies that
have been  published,  individuals  with asthma or chronic  obstructive lung
disease (COLD) do  not appear to be more sensitive to the effects of 0, exposure
than are  normal  subjects.   Table 11-4 presents  a  summary of  data  from 0.,
exposure in humans with pulmonary disease.
     Linn et al.  (1978) assessed pulmonary and biochemical  responses  of  22
asthmatics  (minimal  asthma to  moderately  severe  chronic  airway obstruction
                                                                              3
with limited disability) to 2-hr exposures to clean air, sham CL, and 392 \jg/m
(0.20 ppm)  0-  with  secondary  stressors  of heat  (31°C, 35 percent  rh)  and
intermittent light exercise (VV = 2 x resting Vp).  Subjects  continued the use
of appropriate medication  throughout  the study.   Evaluation  of responses was
not made in relation to the severity of the disorder present in these patients.
After  baseline  (zero 0_) studies  were  completed,  subjects  were exposed to
filtered air, a  sham (i.e., some  0^ was  initially  present  in the exposure
                                 o J
chamber),  and a  392- to 490-pg/m  (0.20-  to  0.25-ppm)  03 condition  (a  3-day
control study was  conducted over 3 days [0 ppm 0.,] on 14 of these individuals).
During each 2-hr exposure  condition,  subjects exercised for the first 15 min
of each 30-min  period.   The exercise load was designed to double ventilatory
volumes, but because of the relative physical condition of the  subjects there
was a  wide  variation in absolute VV so that inhaled 03 volume varied widely.
Standard pulmonary function tests were performed pre- and post-exposure.   No
significant changes  were  noted  except for a small change in  TLC, which could
have been explained  by typical  daily variations  in this function.   A slight
increase in symptoms was also noted during 0- exposures, but this increase was
not statistically  different from sham or control conditions.   A spectrum of
biochemical  parameters was measured in blood obtained only post-exposure.   The
significant biochemical changes reported were small, and probably only represent
the normally found individual  and group variability seen in these parameters

019PO/A                             11-29                               5/2/84

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                                                   TABLE 11-4.  OZONE EXPOSURE IN SUBJECTS WITH PULMONARY DISEASE
Ozone ,
concentration Measurement
ug/m3 ppiii method
h-1
1 — i
1
CO
o
196 0.1
627 0.32
1960 1.0
235 0.12
353 0.18
490 0.25
392 0. 2
392 0.2
588 0.3
490 0. 25
784 0.4
MAST,
NBKI
UV,
NBKI
UV,
NBKI
CHEM,
NBKI
CHEM,
NBKI
CHEM,
NBKI
UV/CHEM,
UV
Exposure
duration and
activity
2 hr
R
1 hr
IE (variable)
& 15-min intervals
1 hr
IE (variable)
@ 15-min intervals
2 hr
IE (2xR)
@ 15-min intervals
2 hr
IE (28) for
7.5 min each
half hour
2 hr
R
3 hr/day
6 days
IE(4-5xR)
for 15 min
Observed effect(s)
No effect on SR and Pa02 ; increased bronchial
reactivity to ACn at 0.32 and 1.0 ppm in healthy
subjects. SR increased following ACh
challenge in f/3 COLD subjects at 0.1 ppm.
No significant changes in forced expiratory
performance or symptoms. Decreased Sa02
during exercise was observed.
No significant changes in forced expiratory
performance or symptoms. Group mean Sa02 was
not altered by 03 exposure.
No significant changes in pulmonary function.
Small changes in blood biochemistry. Increase
in symptom frequency reported.
No significant changes in pulmonary function or
symptoms. SaOz decreased during exposure to
0.2 ppm.
No significant effect on pulmonary function.
V50 decreased in approximately 1/3 of the
subjects demonstrating selective sensitivity
to 03.
FVC and FEV3 decreased on the first of five
consecutive exposure days and with re-exposure.
No. and
description
of subjects Refe'rence
3 COLD Konig et al. , 1980
1 asthma
14 healthy
25 COLD Linn et al. , 1982a
Hackney et al. , 1983
28 COLD Linn et al. , 1983
22 asthma Linn et al., 1978
13 COLD Solic et al., 1982
Kehrl et al. , 1983
17 asthma Silverman, 1979
20 smokers with Kulle et al., 1984
chronic bronchitis
Measurement method:  MAST = Kl-Coulometric (Mast meter);  CHEM = gas-phase chemiluminescence;  UV = ultraviolet photometry.
Calibration method:  NBKI = neutral buffered potassium iodide; UV = ultraviolet  photometry.
Activity level:  R = rest; IE = intermittent exercise; minute ventilation (V^) given in L/min.
See Glossary for the definition of symbols.

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despite the  investigators' suggestion that asthmatics may react biochemically
at lower 0, concentrations than nondiseased individuals.
     Clinically documented  asthmatics  (16 years  duration of  asthma)  were
                                           3
exposed either to  filtered  air or 490 jjg/m   (0.25 ppm) of 03  for 2 hr while
quietly resting (Silverman,  1979).  Pulmonary functions were measured in these
17 asthmatics before and after exposure.   Additional  measurements of expiratory
flow-volume  and ventilation  were  made  at half-hour intervals during the 2-hr
exposures.   The objective of the study was to study asthmatics irrespective of
the severity  of their  disease under the best degree of control that could be
achieved,  i.e., in  their  normal conditions of  life.  Paired t-tests showed no
significant  changes  in  lung-function  measures related to 0~.  However, some
individual  asthmatics  did respond  to  03 exposure with a decrease  in  lung
function and an  exacerbation  of  symptoms.   One group of six  subjects  had
demonstrable  decreases  in function, but information concerning  the  stage
and/or development  of their  asthma was inadequately addressed.  Such informa-
tion would have been extremely valuable in providing opportunities to study
this more susceptible portion of the asthmatic population further.
     Data from clinical  studies  have  not indicated that asthmatics are more
sensitive to  0~ than are normal   subjects.  However, the relative paucity of
studies and  some  of the experimental  design  considerations (subject popula-
tion,  control of medication,  exposure VE, appropriateness of pulmonary function
measurements) in the two  studies  that have been  published  suggest  that the
responsiveness of asthmatics  to  0^,  relative to  normal  subjects, may  be an
unresolved issue.   (This issue  is  treated in more detail  in  Chapter 13).
     Linn et al.  (1982a)  studied  25 individuals  (46 to  70  years old) with
COLD;   12 percent  were  nonsmokers and the  remainder  were moderate to heavy
smokers, with 11  individuals not  smoking at this time.   All  had chronic res-
piratory symptoms with  subnormal  forced  expiratory flow rates.  Each subject
                                               3
underwent a  control  filtered  air  and a 235-pg/m   (0.12-ppm) 0_ exposure (ran-
domized) for 1 hr.   These subjects first exercised for 15 min,  then  rested for
15 min, then  exercised  for  15 min,  and  finally rested for 15  min.  Exercise
loads  were designed to  elevate VF to 20  L/min  (the physiological cost of this
exercise to  each  of the wide variety of subjects was not identified).  Pre-
and post-exposure  measurements of  various  pulmonary functions  as  well  as
arterial oxygen saturation (SaO?) (Hewlett-Packard ear oximeter) were made.
Only one pulmonary function test showed a significant difference related to 03

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(no tabulated  data were presented).  From pre-exposure values at rest  (normal
saturations) to mid-exposure  values  during  exercise, mean SaCL increased by
0.65 ± 2.28 percent with purified  air,  but  decreased by 0.65 ± 2.86 percent
with 0-.   This difference was significant.   However, the decrement attributable
to 03 was  near the limit of  resolution  of  the oximeter and was detected by
computer signal averaging;  thus,  its physiological  and clinical significance
is uncertain.  Moreover, since many  of the COLD subjects were smokers,  inter-
preting changes in SaO,,  without  knowing carboxyhemoglobin saturation (%COHb)
is difficult.  Preliminary reports of these  same data have also been published
(Hackney et al.,  1983).
     Solic et al.   (1982) conducted a similar study  of 13 COLD  patients with
the same age  range (40 to 70  years)  and  with an approximately similar  history
as those used by Linn et al. (1982a).  Their protocol consisted of two exposure
days,  one  to  filtered  air (sham OO  and  one to 392  |jg/m  (0.2 ppm)  of  0, in a
randomized fashion.   Subjects maintained their usual  patterns  of activity,
drug use,  etc., except for  an imposition of no smoking for 1 hr prior to the
baseline studies.   During  the 2-hr  exposures, the subjects  exercised for
7.5 min every  half-hour at  a  load  sufficient to increase Vp to  20 to 30 L/min
and an oxygen uptake of *» I L/min.   SaOp was measured during the last exercise
period.   Pulmonary function measurements were made  before and after exposure,
with FVC maneuvers also obtained at  1 hr of exposure.  There was no statisti-
cally significant  difference  between the effects of  air  exposure  versus  0_
exposure in  any of the spirometric measurement values or symptoms.   The only
significant alteration resulting  from  0,, exposure  was found  in SaO«,  where
decrements were reported in 11 of  13 subjects.  Arterial saturation was 95.3
percent on filtered-air days and 94.8 percent on 0^ days.  Again, knowledge of
%COHb is necessary to  interpret these small  changes in SaO^ correctly.
     Kehrl  et  al.  (1983) presented  further information  on  individuals with
COLD.   They  restudied  eight subjects from the group that Solic et  al.  (1982)
                        3
had exposed  to  392 ug/m  (0.2 ppm)  of 0-.  However,  in this experiment the
                                   3
subjects were  exposed to 588 |jg/m  (0.3 ppm)  of 03-  Kehrl  et al. used a
protocol similar  to  that used by  Solic  et  al.   Data presented consisted of
                                     3
measurements made during the 392-ug/m  (0.2-ppm) exposure, as well  as  new data
                            3
obtained during the 588-ug/m  (0.3-ppm)  exposures.  The second exposure occurred
6  to  9 months  later.   No  statistically significant Og-induced changes in
respiratory mechanics  or symptoms were found in the COLD patients at either 0-

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concentration.   These  observations are  consistent  with those  obtained on
normal individuals who exercised  intermittently at similar  levels of ventila-
tion.   Patients with COLD are exercise-limited, and studies that would  induce
higher ventilation  are apparently  not  feasible.   Therefore,  it  cannot be
determined whether  the failure  to detect respiratory  decrements  could have
been demonstrated if these  individuals had been exercising  more vigorously  at
        3
588 |jg/m   (0.3 ppm) of 0,,  inducing changes similar  to those  observed in
normals at the same concentration.
     Linn et al. (1983) presented data on 28 COLD patients  exposed for 1 hr to
                     3
0, 353, and  490 |jg/m  (0.0, 0.18, and 0.25 ppm) of 0_.  These subjects exer-
cised for the  first and third 15-min periods and  rested in the second and
fourth periods.  The exercise performed  varied  in intensity as did the  corre-
sponding VE.   Forced expiratory  function and  symptoms measured before and
after exposure  were  not influenced by the exposures, confirming other  reports
that these individuals  do  not respond to 0- exposures even at levels of 0_
exceeding first-stage  alert  levels.   In  contrast to other  reports of a small
decrement in SaO?,  arterial  oxygen saturation  (ear oximeter)  was  not changed
during the second exercise period and post-exposure.   Medication and severity
of disease may explain the divergent results previously obtained.   Differences
may also be  related to the level  of exercise and the  resulting ventilation.
As a consequence, these patients may have inhaled comparatively small doses of
°3-
     In all  these  studies  on COLD patients,  a  wide diversity  of symptoms and
ventilatory deficits was present.   The common findings by Linn and Solic as to
small  changes  in Sa02  may be of  some significance,  although  they were not
confirmed in subsequent  studies at higher 03 concentrations.   The  exercise
performed in these  studies  was  of very  low  intensity, and  results  from 0^
                                                                          J
exposures where  COLD patients  exercised at higher  intensities  may be of
interest.   However,  the possibility that increased exercise intensity will  be
a  relevant factor  is unlikely;  COLD patients in general cannot sustain much
higher work outputs than used in these studies  because of their limited maximal
ventilation and possible cardiovascular  insufficiency.
     Kb'nig et al. (1980) performed studies  on  18 individuals, three of whom
suffered from  COLD  and one  of whom had  extrinsic allergic  asthma (bronchial
symptom free).  The  bronchial reactivity test used ACh as the test substance.
Specific airway resistance was measured  in the patients after a 2-hr exposure

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           3
to 196 ug/m  (0.1 ppm) of 0_ as well  as on a sham-exposure day.   In two of the
three patients with COLD, increases in SR   of 37 and 39 percent were recorded
                                         dw
after the 03 exposure.   The asthmatic patient was not affected by exposure to
this level  of  0.,.   Whether the results presented represent the  response to a
bronchial reactivity  test  immediately  post-exposure  or to the 0., exposure is
unclear.   In  addition,  the small  number of  COLD  subjects studied makes an
adequate evaluation difficult.
     Kulle et al .  (1984)  exposed  20  chronic bronchitic smokers  for  3 hr to
                          3
filtered  air  and 804 ug/m   (0.41  ppm)  of 0-.  Fifteen minutes  of bicycle
exercise at 100 W  was performed during the  second hour of exposure.   Forced
vital capacity and  FEV~  decreased significantly with exposure to 0~ compared
to clean-air exposure;  the decreases were small  in magnitude (< 3 percent),
and respiratory symptoms were mild.

11.2.8  Other Factors Affecting Pulmonary Responses to Ozone
11.2.8.1  Cigarette Smoking.   Smokers  have been studied as a population  group
having potentially  altered  sensitivity to oxidant exposures.   Hazucha et al.
(1973) and  Bates and Hazucha  (1973)  reported the responses of  12  subjects
divided  by  smoking  history (six smokers and six nonsmokers) who were exposed
to 725 and  1470  ug/m3 (0.37 and 0.75 ppm) 03-  These young (23.6 ±0.7 years
old) individuals alternated  15 min of exercise at twice  resting ventilation
and  15 min  of  rest during the 2 hr of the test.  Pulmonary- function measure-
ments were made after each exercise period.  The characteristic odor of 03 was
initially detectable by all subjects, but they were unaware of it after one-half
hour.  Symptoms  of  typical  oxidant exposures were reported by all  subjects  at
the termination of exposure.  Decrements in  FVC and FEFrc  were greater for
nonsmokers after  either  0.,  exposure, whereas  smokers  exhibited  greater  decre-
                                                            3
ments in  FEV,  „ and  50%  V    .   Smokers  exposed  to  1470  ug/m  (0.75  ppm)  of  0_
             i. u          max                                                -j
had a greater decrease in FEF^Try than did nonsmokers.  The ^25-757 cnan9es
were much  larger  than the changes in FEV, ,,, regardless of 0., concentration,
exposure duration, and smoking habit.  Smoking history  (not given specifically)
appeared to have different effects on the various pulmonary functions measured.
     Kerr  et al.  (1975)  exposed  their  subjects  (10  smokers  and  10  nonsmokers)
to 980 ug/m  (0.5 ppm) of 0, for 6 hr, during which time the subjects exercised
twice for  15 min each (Vp = 44 L).  For the remainder of the exposure time the
subjects were resting.   Follow-up measurements were made 2 and 24 hr later.  A

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control day  on  which subjects breathed filtered air preceded the 0--exposure
day.  The  24-hr post-exposure study was conducted in filtered air.   Variance
analyses were used  to interpret the data.  In nonsmokers, significant decre-
ments in ventilatory function were  observed following 0,  exposure, being most
prominent  for FVC and FEV.,.   Similar  significant decrements were  observed  for
                          O
FEV, and maximum mid-expiratory flow.  No decrements were  observed  in mean
spirometry values in smokers as a  group;  in  fact,  all  tests disclosed some
degree of  improvement,  with significance at the 5 percent  level  for MEF.  A
significant  reduction  in  SG   was observed, for the most part  in nonsmokers
                            aw
experiencing subjective  symptoms.   (All nonsmokers experienced  one  or more
symptoms,  while  only 4 of 10  smokers  had  symptoms.   These  four smokers had
been smoking for relatively short periods of time.)
     Six subjects (three nonsmokers and three smokers of 20 cigarettes/day for
2 to 3 years)  were  studied by Kagawa and Tsuru (1979a).  These subjects were
exposed,  no smoking on one day and smoking on another day, in either a filtered-
                                            0
air environment or  one containing  588  ug/m   (0.3  ppm)  of O^.  Two periods
(10 min in duration)  during  the  2-hr  exposure were devoted  to smoking  a ciga-
rette.   Smokers took one puff each minute (a total  of 20 puffs) and nonsmokers
took one  puff   every  2 min  (a total of 10 puffs).   Both  groups  reported  a
slight degree of dizziness  and nausea  after smoking.   Measurements  of SG_V1
                                                                          clw
were obtained before and at the end of the first and second hours of exposure.
Bronchial  reactivity to an ACh challenge was determined pre- and post-exposure.
The data presented  in this  report  are  minimal  and sketchy, and statistical
analyses  are inadequate.   One of the six subjects (a smoker) was a nonresponder
to OT.   The  remaining five  responded in variable  fashions, and direction  of
change  could not be  evaluated.
     Kagawa  (1983a)  presented data  on 5 smokers and 10 nonsmokers apparently
exposed to 294  jjg/m   (0.15  ppm)  of 0^  for 2 hr to his  standard intermittent
rest-exercise regime.  SG    was  measured three times:  at  1  and  2 hr  during
                          dW
exposure  and also at 1 hr post-exposure.  Significant  decreases  were  found
during  exposure, i.e., 4 percent at 1 hr and 10 percent at 2 hr in nonsmokers.
No change  from  baseline  occurred in the smokers.  These  data, which suggest
significant differences in  response between smokers and nonsmokers exposed to
                                  3
the low ambient level  of  294 ug/m  (0.15 ppm) of  (L,  were  not presented in
enough  detail to permit independent evaluation of the findings.
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     DeLucia et al.   (1983) reported that smokers (six men and six women) were
                                                       0
relatively resistant to the oral  inhalation of 588  ug/m  (0.3 ppm)  of Or   Few
                                                                       O
smokers detected  the  presence  of 0,,  whereas the majority of nonsmokers (six
men and  six women)  experienced  significant  discomfort.   Pulmonary  function
tests (FVC,  FEV,  and FEVo5-757^  were  made Pre~ anc' post-exposure (within 15
min).   Overall, the  decrements in pulmonary functions  were significant and the
authors attributed them to 0,.   The relative insensitivity of smokers based on
these three measurements was indicated by the decrements of 5.9 to  12.9 percent
in nonsmokers, whereas  smokers  had 1.2 to 9.0 percent  diminutions  in these
functions.   Additional  analyses  of their pulmonary function  data  suggested
that women  nonsmokers  were  more  sensitive to 588 (jg/m  (0.3 ppm) of  0^ than
women smokers.   No apparent differences were noted  for the men.
     Thirty-two moderate  or  heavy  smoking subjects (26 men and 6 women) were
divided into four groups  and exposed  randomly to air  alone, air plus smoking
(2 cigarettes/hr), 0^  alone, and  0^  plus  smoking  (Shephard et al.  ,  1983).
                                                   3                         3
Four Oo-exposure protocols were employed:   725 ug/m  (0.37 ppm) and 1470 ug/m
(0.75 ppm) in subjects at rest; and 980 ug/m3 (0.50 ppm) and 1470 ug/m3 (0.75
ppm) with  the  subjects exercising during the last  15  min of each  half hour
(the first 15 min of each period were  at rest) for  the 2-hr exposure.  Carboxy-
hemoglobin was determined indirectly with the initial  value being 1.61 percent.
In nonsmoking days,  COHb decreased, while on smoking days COHb increased by as
much as 1.14 percent above the initial value.  The  increase in COHb was signi-
ficantly  lower on those days when  smoking was conducted in  an 0, environment.
Ozone exposure alone (no  smoking during exposure)  resulted  in the typical and
anticipated  decreases  in  pulmonary functions (FVC, FEV-, Q, 25% V    , and 50%
V   ) as  reported by others.  However, the  onset  of these  pulmonary changes
 max
was slower  and  the  response less  dramatic compared to  data obtained on non-
smokers.   The  authors  offered  two explanations to  account for the  diminished
response:    (a) the  presence of  increased  mucus  secretion by these  chronic
smokers may  have  offered  transient protection against O^'s  irritant effect  or
(b) the sensitivity  of the airway receptors may have been reduced by chronic
smoking.    The  chronic effect  of smoking induced a delay in the bronchial
irritation  response  to 03  exposure.   There  was  no significant  interaction
between cigarette smoking and responses to Do-
ll. 2. 8. 2   Age  and Sex Differences.   Although a  number of  controlled human
exposures  to 0~  have used both  male  and  female  subjects  of varying ages,  in

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most cases the  studies  have  not been designed to determine age or sex differ-
ences.   In fact,  normal  young males usually provide the subject population,
and where subjects  of  differing  age and sex are combined,  the groups studied
are often too  small in number to  test  for potential  differences reliably.
     Adams et al. (1981)  attempted to  examine the effects  of age on response
to 0, in a small number (n=8) of nonsmoking males varying in age from 22 to 46
years.   Comparison  of the mean change in pulmonary function between  the three
oldest subjects  (33 to  46 years old) and the five youngest subjects  (22 to 27
years old) revealed only small,  inconsistent differences.   Folinsbee et al.
(1975), noting the  lack of enough subjects for adequate subdivision, attempted
to make sex comparisons in a group of 20 male and 8 female  subjects exposed to
0.,.  No  significant differences  could  be shown in either  symptomology or
physiological measurements between male and female subjects.
     Horvath et al.  (1979) studied eight male and seven female subjects exposed
for 2 hr  to  0,  490, 980, and 1470 ug/m3 (0, 0.25,  0.50, and 0.75 ppm) of 03-
Forced expiratory function decreased immediately following exposure to 980 and
         3
1470 ug/m  (0.50  and 0.75 ppm), with greater changes occurring at the highest
OT concentration.  The average decrements in FEV-, Q were 3.1 and 10.8 percent,
respectively, for men,  compared  to 8.6 and 19.0 percent for women.   Although
the data  suggested  that there may be potential  sex differences in the extent
of changes in  lung  function  due to 0., exposure,  the results of an analysis of
variance for sex differences were not presented.
     Gliner  et  al.  (1983)  presented data on 8  male  and 13 female  subjects
exposed for  2  hr on five consecutive days  to 0,  392,  392, 392, and 823 or
980 ug/m3 (0,  0.20, 0.20,  0.20,  and 0.42  or  0.50  ppm)  of  03, respectively.
During exposure the subjects alternated 15 min of rest with 15 min of exercise
on a bicycle ergometer  at loads sufficient  to produce expired  ventilations of
approximately  30 L/min  for   men and 18  L/min  for women.  Forced expiratory
measurements of  FVC,  FEV^ Q, and  £^25-75% indicated tnat Pr"i°r exposure  to
392 ug/m  (0.20  ppm) of 0,  had no  effect  on  functional  decrements  occurring
                                                   3
after subsequent  exposure to either 823  or  980  ug/m  (0.42 or  0.50  ppm) of 03
on the  fourth  day (see Section 11.3).   Although differences  between men and
women were  reported for  all three measurements,  with  men  having expected
larger expired volumes and flows, there were no pollutant interactions for six
subjects, indicating that male and female subjects responded to 0^ in a similar
fashion.
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     DeLucia et al.  (1983) reported on 12 men and 12 women (equally divided by
smoking  history)  exercising  for 1 hr at 50 percent  of  their max V00 while
                  2
breathing 588 ug/m  (0.3  ppm) of 0^ through a mouthpiece.  Minute ventilation
for the  men  averaged 51 L/min and  for the women 34.7 L/min.  Women nonsmokers
who did  not inhale as much  0-  as nonsmoking men  reported  approximately a
fourfold increase in symptoms,  while smoking women had less severe symptomatic
responses than  smoking men.   Although  significant decrements in pulmonary
function were found for FVC (6.9 percent),  FEV,  ~ (7.9 percent),  and ^25-75?
(12.9 percent), there  were no  significant  differences between  the  sexes.
These  investigators also  found  increases in fn  and  decreases in VT during
exercise.  These effects  are  similar to those reported by other investigators.
     Gibbons and  Adams (1984)  recently reported the effects of exercising 10
young women for 1 hr at 66 percent of max V00 while the women breathed 0, 297,
           3
or 594 ug/m  (0,  0.15, or 0.30 ppm) of 0Q.   Significant decrements in forced
                                              3
expiratory function were  reported  at 594 ug/m  (0.30 ppm) of O^.  Comparison
of these effects with the results from male subjects previously studied by the
authors  (Adams  et al. , 1981)  indicated that the  women  appeared  to be more
responsive to 03  even  though  the men received a  greater  effective dose  than
the women.   However, large individual variations in responsiveness were present
in all subjects.
11.2.8.3  Environmental Conditions.  Very  few controlled human  studies  have
addressed the  potential  influence environmental  conditions  such as  heat or
relative humidity (rh) may have on responses to 0~.   In fact, most exposures
have been performed under standard room temperature and  humidity conditions
(20-25"C, 45-50 percent rh).   A series of studies by Hackney et al.  (1975a,b,c;
1977a) and Linn et al.  (1978) were conducted at  a higher temperature and lower
humidity (31"C, 35 percent rh)  to  simulate ambient environmental conditions
during smog  episodes in Los Angeles.  No comparisons were made to the effects
from 03  exposure  at standard environmental  conditions in other  controlled
studies.
     Folinsbee  et al.  (1977b)   studied  the  effects  of  a 2-hr exposure  to
        o
980 ug/m  (0.5 ppm) of 03 on 14 male subjects under four separate environmental
conditions:    (1)  25X  45 percent rh;  (2) 31
-------
Figure 11-1).   Decreases  in vital  capacity  and  maximum  expiratory  flow  during
0, exposure  were  most severe immediately after  exercise.   There was  a  trend
for  a  greater  reduction  when heat  stress  and  0-  exposure were combined
(WBGT=92.0gF),  but  this  effect  was only significant  for  FVC.   In  a similar
                                              3                              3
study with  eight  subjects  exposed  to  980 ug/m  (0.5 ppm)  of 0~ plus 940 |jg/m
(0.5 ppm) of nitrogen dioxide (NOO (Folinsbee et al .  , 1981) (Section 11.6.3),
the  effects  of  heat and  pollutant  exposure  on FVC were  found to be no greater
than additive.  Part of  the modification of  0,  effects by  heat stress was
attributed to increased  ventilation  since ventilatory volume and tidal  volume
increased  significantly  at  the  highest thermal  condition  studied (40yC,
50 percent rh).
     More recently, Gibbons and Adams (1984)  had 10 trained  and heat-acclimated
young women  exercise for 1 hr at  66  percent  of  their maximum  oxygen uptake
                               33                        3
while breathing either 0.0 ug/m  (0.0 ppm),  297 ug/m  (0.15  ppm), or 594 ug/m
(0.30 ppm) of OT.   These studies were conducted at two ambient  conditions,
i.e.  24y  or 35"C.   (Whether  these are only  dry bulb (db) temperatures or
represent WBGT values is unclear, since humidity was  not reported).  No signi-
                                                               3
ficant changes in any measured function were  observed at 0 ug/m  (0.00 ppm) or
        3
297 pg/m  (0.15 ppm)  of  03.   Significant reductions  in FVC, FEV,  Q,  TLC,  and
           P < 0-004) were reported as a consequence  of exercising at 594 ug/m
(0.30 ppm).  Pre-post decrements in FVC, FEV, Q, and ^25-757 in the 0.30 ppm,
24yC environment were  13.7,  16.5,  and 19.4 percent respectively, compared to
observed  decrements  of 19.9,  20.8,  and 20.8 percent,  respectively, in the
0.30-ppm O^  and  35yC condition.   Only FVC differed significantly between the
two  temperature  conditions.   Some  subjects failed to  complete  the exercise
period in  35PC and 0.30 ppm  0~,  and  one  subject could  not  finish the exercise
in 24°C and 0.30 ppm 0^.   Subjects  reported more subjective discomfort, (cough,
pain on inspiration,  throat tickle, dizziness, and nausea) as 0, concentrations
increased.  No other effects were  reported, although it was observed that 0.,
(0.30 ppm) exposure and ambient high temperature induced an interactive effect
on V. and fR.
11.3  PULMONARY EFFECTS FOLLOWING REPEATED EXPOSURE TO OZONE
     Just as pulmonary  function  decrements following a single exposure to 0,.
are well documented, several studies of the effects of repeated daily exposures

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to 0,. have  also  been completed (Table 11-5).   In general,  results from these
studies  indicate that with repeated daily exposures to CL, decrements  in pul-
monary function are  greatest on the second exposure day.  Thereafter,  on each
succeeding day decrements are less than the day before,  and on about the fifth
exposure day small  decrements or no changes are observed.   Following a sequence
of repeated  daily  exposures,  there is a gradual  time-related  return of the
susceptibility of  pulmonary  function  to CL exposure similar to that observed
prior to repeated exposures.   Repeated daily exposure to a given low concentra-
tion of 0.,  does  not affect the magnitude of decrement in pulmonary  function
resulting from exposure at higher CL concentration.
     All the  reported  studies  of repeated responses to CL have used the term
"adaptation" to describe  the attenuation of decrements in pulmonary function
that occurs.  Unfortunately,  since the initial  report of such attenuation used
adaptation,  each succeeding  author chose not to  alter the  continued use of
this selected term.  In the strict sense, adaptation implies that changes of a
genetic nature have  occurred as a result of natural selection processes, and
as such, use of adaptation in the prior context is a misnomer.
     Other  terms  (acclimation, acclimatization,  desensitization, tolerance)
have been  recommended  to replace adaptation and  perhaps  are more suitable.
However, the  correct use of any of these terms requires knowledge of  (1) the
physiological mechanisms  involved  in  the original response, (2) which mecha-
nisms are  affected and how they are affected to  alter the original   response,
and/or  (3)  whether the  alteration  of  response  is  beneficial  or detrimental  to
the  organism.  The present state of  knowledge  is such  that we do not fully
understand  the physiological  pathway(s)  whereby decrements  in  pulmonary  func-
tion  are  induced  by CL exposure,  and of course,  the  pathways involved in
attenuating  these  decrements and how they are affected with  repeated 03 exposure
are  even less understood.  Moreover, while attenuation of CL-induced pulmonary
function decrements  appears to  reflect protective mechanisms primarily directed
against the  acute  and subchronic effects of the irritant, Bromberg and Hazucha
(1982)  have also  speculated  that  this attenuation may reflect more severe
effects of  CL exposure, such  as  cell  damage  and death.   Therefore,  in  the
following  discussion of specific studies, results  will  be  presented without
use  of  a  specific term  to describe observed phenomena generally.  The use  of
response  to imply pulmonary  decrements resulting from  03 exposure and changes
in  response or  responsiveness of the  subject  to imply alterations in the
magnitude of these decrements  will  be  retained.
019PO/A                             11-40                                5/2/84

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TABLE 11-5.   CHANGES IN LUNG FUNCTION AFTER REPEATED DAILY EXPOSURE TO AMBIENT OZONE
Ozone
Concentration
ug/n3
392
392
392
686
784
784
784
784
804
823
921
980
980
ppm
0.2
0.2
0.2
0.35
0.4
0.4
0.4
0.4
0.41
0.42
0.47
0.5
0.5
Measurement8'
method
CHEH, NBKI
UV, UV
UV, UV
CHEH, NBKI
CHEH, NBKI & HAST, NBKI
CHEM, NBKI & HAST, NBKI
CHEH, NBKI & HAST, NBKI
UV, NBKI
CHEH, NBKI & UV, UV
UV, UV
UV, NBKI
CHEH, NBKI
CHEM, NBKI
Exposure duration
and activity
2 hr,
2 hr,
2 hr,
2 hr,
3 hr,
3 hr,
3 hr,
2 hr,
3 hr.
2 hr,
2 hr,
2 hr,
2.5 hr
IE(30)
IE(18 &
IEQ8 &
IE(30)
IE(4-5
IE(4-5
IE(4-5
IE(2 x
IE(4-5
IE(30)
IE(3 x
IE(30)
, IE(2

30)
30)

x R)
x R)
x R)
R)
x R)

R)

x R)
No. of
subjects
10
21
9d
10
14
13e
lle
7f
209
24
ll(7)h
8
6
Percent change in FEVt.0 on
consecutive exposure days
First
+1.4
-3.0
-8.7
-5.3
-10.2
-9.2
-8.8
ttt
-2.8
-21.1
-11.4
-8.7
-2.7
Second
+2.7
-4.5
-10.1
-5.0
-14.0
-10.8
-12.9
t
-0.9
-26.4
-22.9
-16.5
-4.9
References
Third Fourth Fifth
-1.
-1.
-3.
-2.
-4.
-5.
-4.
0
0
'-18.
-11.
-3.
-2.
6
1
2
2
7 -3.2 -2.0
3 -0.7 -1.0
1 -3.0 -1.6

-0.6 -1.1
0 -6.3 -2.3
9 -4.3
5
4 -0.7
Folinsbee et al. , 1980
Gliner et al . , 1983
Gliner et al. , 1983
Folinsbee et al. , 1980
Farrell et al . , 1979
Kulle et al. , 1982b
Kulle et al., 1982b
Dimeo et al. , 1981
Kulle et al. , 1984
Horvath et al . , 1981
Linn et al. , 1982b
Folinsbee et al. , 1980
Hackney et al. , 1977a
                                                                 given in L/min or as a multiple of resting

                                                                 0 of more than 20%.
 Measurement  methods:   HAST  =  Kl-coulometric (Hast meter); CHEM = gas-phase chemiluminescence, UV =  ultraviolet  photometry.
  Calibration  methods:   NBKI  =  neutral buffered potassium iodide; UV = UV photometry.
  Exposure  duration  and intermittent exercise (IE) intensity were variable; minute ventilation (VV)
  ventilation.
  Subjects  especially sensitive on  prior exposure to 0.42 ppm 03 as evidenced by a decrease  in FEVj
 These nine subjects are a subset of the total  group  of 21  individuals  used in  this  study.
p
 Bronchial  reactivity to a methacholine challenge was  also  studied.
 Bronchial  reactivity to a histamine challenge  (no data on  FEV^o).   SR   measured (t).   Note that on third
 day histamine response was equivalent to that  observed in  filtered air (see text).
^Subjects were smokers with chronic bronchitis.
 Seven subjects completed entire experiment.

-------
     Hackney  et  al.  (1977a) performed  the  initial  experiments that demon-
strated that  repeated  daily exposures to ()„ resulted  in augmented pulmonary
function  responses  on the  second exposure  day  and  diminution of responses
after several  additional  daily exposures.   Six subjects who in prior studies
had demonstrated responsiveness to 0_ were studied during a season of low smog
to minimize potential effects from prior 0-  exposure.   All  but one subject had
                                          •3                                     O
a history of allergies.  They were exposed for approximately 2.5 hr to 980 ug/m
(0.5 ppm) of  0-  for four consecutive days  after one sham exposure.  Ambient
conditions in  the  chamber were 31°C db  and 35 percent  rh.  During the first
2 hr, light exercise (of unknown level) was  performed for 15 min every 30 min.
The last  half hour  was used for pulmonary testing.  Small decrements occurred
in FVC and FEF75 and differed among the five test days.  Additional  statistical
evaluation showed that these differences were related to the larger decrements
in function observed on the second 0~ exposure day.   Other pulmonary functions,
i.e., total airway  resistances (R )  and  nitrogen washout (AN?), also improved
on latter exposure days,  but the differences were not statistically significant.
The pattern of change  clearly indicated that subjects  had  lesser degrees of
pulmonary dysfunction  by  the third  day of exposure, and these functions were
nearly similar on  day  4  to values found on the pre-exposure day to filtered
air.   In  this  small  subject population,  considerable variability in responses
was noted (one subject with no history of allergies  showed no pulmonary decre-
ments, while  another subject had  a  large reduction  in FVC  and FEV, and an
increase  in AN~  on  day 2 with  a return of responses to  near control levels on
day 4).
     Parrel 1   et  al.  (1979)  investigated  the pulmonary  responses of 14 healthy
nonsmoking (10 men and 4 women) subjects to  five consecutive,  daily 3-hr expo-
sures to  filtered  air  or 0~.  In the first week, subjects were studied  in a
                                                                              3
filtered-air environment, followed in a second week with exposures to 784 ug/m
(0.4 ppm) of  03.   Pulmonary function (FVC,  FEV-^ FEV3,  SGgw,  and FRC) was
determined at the end of the 3-hr exposures.  One bout of exercise (VV measured
on one subject = 44  L/min) was performed after 1.5 hr of exposure.   Statistical
evaluations used a  repeated analysis of variance for significant differences
between the control  and 0«  exposure  weeks,  using each  day of each exposure to
make the  comparisons.  The  analysis  of variance showed that FVC,  FEV,,  FEV_,
and SG    differed  significantly  between control  and 0~  exposure  weeks.   No
      oW                                               O
changes in FRC were found.   In the 0_ exposure,  SG   decreased significantly
                                     *5             dw

019PO/A                             11-42                               5/2/84

-------
only on the first 2 days; this response was similar to air exposure day values
on the  last  3  days.   The decrements were significantly greater on the second
day than on the first. Decrements in FEV, ,. and FEV~ Q were substantial on the
first  day  and increased  on the second  day of  exposure.   These decrements
diminished to  air  exposure  levels by the  third  day (FEV, „) and fourth day
(FEV, n) of  0_ exposures.   The  severity  of symptoms generally corresponded to
the magnitude  of  pulmonary  function changes.   Symptoms were maximal  on the
first 2 days, decreasing thereafter with only one subject being symptomatic on
the final  day  of  exposure to 03-   Reporting  of symptoms  was maximal on the
second 0~  day.  These investigators  noted  that  five consecutive days  of expo-
                               3
sure (10 subjects)  to 588 ug/m  (0.3 ppm) of 0_ failed to induce significant
changes in FVC  or SG  ,  implying that measurable changes are likely to occur
                     clw                                            f~j
in pulmonary function at 0- concentrations between 588 and 784 ug/m  (0.30 and
0.4 ppm) with 2 hr of exposure at these exercise levels.
     Folinsbee et al. (1980) exposed healthy adult males for 2 hr in an environ-
mental  chamber at  35°C and 45 percent rh  to  filtered  air  on day  1,  to 0- on
days 2 through 4,  and to filtered air on day 5.   Three groups of subjects were
used,  each  exposed to a different  concentration  of  0~:   group 1  (n=10),
        o                                           3
392 ug/m  (0.20 ppm) of 0~; group 2 (n=10), 686 ug/m  (0.35 ppm) of 0,; group 3
               3
(n=8),  980 ug/m   (0.50 ppm)  of  0.,.   Subjects  alternately  rested and  exercised
at a VP  of 30 L/min for 15-min  periods.   There were no significant  acute or
                                                    3
cumulative effects  of repeated  exposure to 392 (jg/m  (0.20 ppm) of Ov  With
                    3
exposure to 686 ug/m  (0.35 ppm) of 0,, decrements in forced expiratory varia-
bles appeared  on  the first 0-  exposure  day.  Similar  decrements  occurred on
the second 0_  exposure day, although there was no  significant  difference in
responses observed  on the first two  exposure  days.  On  the third  day  of expo-
sure the pulmonary function changes were of lesser magnitude than on the first
2 days.  In  group  3,  marked  decrements  in  pulmonary function occurred  (FEV, ,.
                                                           3
decreased 8.7 percent) after the first exposure to 980 ug/m  (0.50 ppm) of 0.,;
these decrements were even  greater (FEV, Q decreased 16.5 percent) after the
second 0- exposure (Figure 11-5).  While not totally abolished, an attenuation
        O
of these decrements  (FEV, Q  decreased  3.6  percent) was  observed following the
third 0- exposure.  The subjects claimed the most discomfort for the second 03
exposure.   Many noted marked reductions in symptoms on the third consecutive
                                                                          3
day of  exposure  to 0-.  Two  additional  subjects  were exposed to  980  ug/m
(0.50 ppm) of 0_ for four consecutive days.  Although effects of 03 on pulmonary

019PO/A                             11-43                               5/2/84

-------
                                      A. GROUP 2
          CO
          P-  5.0
           »  4.8
              4-6
              4.4
 "FILTERED!
    AIR
_  DAY1
OZONE
DAY 2
            1
                  1
       1
I  ' '  ' ' I
 OZONE
  DAY 3
OZONE
DAY 4
          i
       i
                                                •FILTERED!
                                                   AIR
                                                  DAY 5 _
                 £ 1 2 3 4 fc  £1234Hg1234Hg1234fc £ 1 2 3 4 fc
                 Q.       OB-       0°-        OB-       O °-        O
                         o.          a.          o.         a.          a.
                                      B. GROUP 3
          CO
          Q.

          m
          CO
          05
          UJ
  5.2


  5.0


  4.8



  4.6


?  4.4


  4.2


  4.0
                  IFILTEREDI
                    AIR
                   DAY1
             3 B i  I I  I I  I  I I I  I
             OZONE
             DAY 2
                                 i  i
           OZONE
           DAYS
           OZONE
            DAY 4
         TFILTEREDI
            AIR
           DAY 5
                         O
                         a.
                        l i i  i i I I I  i i  I I  )  i i  i  i I

                                  1  2 3 4fc  g ! 2 3  4&
                              00-       00-       C
                              a.         Q.          Q,
                 Figure 11-5. Forced expiratory volume in 1-sec (FEV*).o)
                 in two groups of subjects exposed to (A) 0.35 ppm
                 ozone, and (B) 0.50 ppm ozone, for 3 successive days.
                 Numbers on the abscissa represent successive half-hour
                 periods of exposure.
                 Source: Folinsbee et al. (1980).
019PO/A
                   11-44
                                           5/2/84

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function were  observed  on the first two  days  of exposure, few effects were
seen on  the  third day,  and no effect  was observed on the  fourth  day.  The
authors  concluded  that  there  were some short-term (2-day) cumulative effects
of exposure  to concentrations of 0- that  produced acute  functional  effects.
This response  period  was  followed by a period in which there was a marked
lessening of  the  effect of 03 on pulmonary  function  and on the subjective
feelings of discomfort associated with exposure to 0~.  The subjects for these
studies  represented a broad population mix in that some subjects had a prior
history  of respiratory  difficulties, some essentially had no past  respiratory
history, and approximately two-thirds  had prior experience with  pollutant
exposure.
     Horvath  et al. (1981)  performed studies designed not  only  to determine
                                                                         3
further  the  influence of  five  consecutive  days  of  exposure to 980 ug/m
(0.5 ppm),  but to  estimate the persistence of  the attenuation  of  pulmonary
responses.   During the 125 min of exposure, 24 male subjects alternately rested
                *
and exercised  (Vp  = 30  L/min) for 15-min periods.  Measurements of pulmonary
functions were made daily pre- and post-exposure.  A filtered-air exposure was
conducted during  the  week prior to the 0,. exposures.   Selected subjects were
then randomly  assigned to return after 6 to 7, 10 to 12, and 17 to 21 days for
a single exposure to 0-.  Ambient 0- levels in the locations where the subjects
lived  seldom exceeded 235  ug/m   (0.12 ppm).   The major  pulmonary function
measurements made and subjected to statistical analysis on these subjects were
FVC, FEV-., and FEF-j.  7cc/-   Changes with  time  in  all  three measurements were
similar  and  major emphasis was directed  toward FEV-.  changes,  since it was
believed that  this measurement would be commonly used in later epidemiological
studies.  Significant interaction effects occurred between the  two within-
subject  factors (day  of exposure and pre- and post-exposure change  in FEV,).
The interaction  resulted  primarily from  the  post-exposure FEV-.  data,  which
revealed a "U"-shaped pattern across days during 0- exposure.   A significant
decline  appeared  on day 1 (+1.7 to  -63 percent,  mean = -21 percent), and a
greater  significant decline  appeared on day 2 (-26.4 percent).   On day 3 the
decrement in  FEV,  had returned to that observed  on  day 1, but it was still
significantly  greater than  during room air exposure.   The decrements in FEV,
on days 4 and  5 had decreased significantly from day 3, but were still signifi-
cantly larger  than  those  with exposure to filtered air.  Subjective symptoms
followed a similar  pattern,  with subjects on  the  fifth day indicating that

019PO/A                             11-45                               5/2/84

-------
they had  not  perceived any 0-.  Two  subjects  showed little attenuation of
response to 03, and one subject was not affected by the 0- exposures.   Subjects
who were  more  responsive  on the first day of exposure required more frequent
daily exposure to  attenuate response  to 0.,.  Sixteen subjects were randomly
requested to return  for  an additional 03 exposure  on  days noted in Figure
11-6.   Although the  number of subjects in each repeat exposure was small,  it
was apparent that attenuation of response did not persist longer than 11 to 14
days,  with  some loss occurring within  6 to  7 days.   In general, these authors
made some interesting observations:  (1) the time required to abolish pulmonary
response  to CL was directly related to the  magnitude of the  initial response;
(2) the longer it  took for attenuation of pulmonary response to 03 to occur,
the longer  attenuation persisted;  and  (3) in some individuals, attenuation of
pulmonary response to CL may persist up to 3 weeks.   The mechanism responsible
for attenuation of response was  not elucidated, although two mechanisms were
postulated, i.e.,  diminished  irritant  receptor sensitivity  and  increased
airway mucus production.
     Linn et al.  (1982b)  also studied the persistence of  the attenuation of
pulmonary responses that occurs with repeated daily exposures to 0.,.   Initial-
ly, 11 selected subjects,  known to have previously  exhibited pulmonary  decre-
ments  in  response to 0, exposure, were exposed  for  2 hr daily for four  conse-
                        3
cutive days to 921 ug/m  (0.47 ppm) CL.  Exposure  consisted of alternating
15-min periods of moderate  exercise (Vp = 3 x resting VV)  and rest.  An expo-
sure to filtered air,  under otherwise  equivalent conditions, was conducted on
the day prior  to  the first 03 exposure.  The pattern of change in pulmonary
response  to CL was similar to that previously  reported for repeated daily
exposures.  For example, while the  initial exposure  to filtered air produced
essentially no change,  on the first 03 exposure day FEV,  decreased 11 percent,
with a further decline to  23  percent  on the second  day, returning to approxi-
mately 11 percent on the  third day.   By the fourth  day, the  mean response was
essentially equivalent to  that observed with exposure to filtered air.  While
most of the subjects demonstrated  attenuation of response  (complete data sets
on  only  seven  subjects), the  response  of one  subject, who  may  have  had a
persistent  low-grade  respiratory  infection, never  diminished.   Two others
showed relatively  little  response  to  the initial daily exposures, but showed
some severe responses  during  follow-up exposures.   This pattern was not to be
unexpected, based on other studies demonstrating similar atypical responses.

019PO/A                             11-46                               5/2/84

-------
                FILTERED
                   AIR
              PRE-EXPOSURE
DAILY 2-hr EXPOSURE
   TO 0.42 ppm O3

  12345
                              I   I   I   T
                                            H
                                 0.42 ppm O3,
                                    1 WK
                                POST EXPOSURE
a>
tl
&
q
^
UJ
<

-I- IU
o
10
-20

-30
-40

—
1
I
'%& W/A
A
- GROUP 1 -
n = 4
                FILTERED
                   AIR
              PRE-EXPOSURE
DAILY 2-hr EXPOSURE
   TO 0.42 ppm O3

  12345
                              \   I   I   I   T
                                            -I
                                 0.42 ppm O3,
                                    2 WKS
                                POST-EXPOSURE
             0)
             u
             <5
             a
             LU
+ 10

  0

 10

 -20

 -30

 -40
                     B
                  GROUP 2 H
                    n = 6
                FILTERED
                  AIR
              PRE-EXPOSURE
            DAILY 2-hr EXPOSURE
              TO 0.42 ppm O3

              12345
                     0.42 ppm O3,
                        3 WKS
                    POST-EXPOSURE
             I
             v
             a.
             p
             t-
                    Figure 11-6. Percent change (pre-post)
                    in 1-sec forced expiratory volume
                    (FEVi.Q), as the result of a 2-hr ex-
                    posure to 0.42 ppm ozone. Subjects
                    were exposed to filtered  air, to ozone
                    for five  consecutive days, and exposed
                    to ozone again: (A) 1  wk later; (B) 2
                    wks later; and (C) 3 wks later.
                    Source:  Horvath et al. (1981).
019PO/A
                    11-47
                                           5/2/84

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To evaluate persistence of attenuated response, subjects repeated 0- exposures
                                                                   O
under the  above conditions  4  days  after the  repeated  daily  exposures and
thereafter at 7-day intervals  for five successive weeks.  Four days after the
repeated daily  exposures,  decrements  in  pulmonary function in response to 0.,
exposure were  identical  to  those  observed after the first exposure  to 0-
(FEV, Q decreased 11 percent).   This magnitude of pulmonary decrement was also
observed with subsequent 0, exposures.   Subjective symptoms generally paralleled
lung-function studies, as  had  been  observed in all previous  studies.   Since
attenuation of pulmonary responses to 0-  may fail  to develop or may be reversed
quickly  in  the  absence of frequent  exposure,  these authors questioned  the
importance of attenuation of response in  the public health sense.
     Following the design of an earlier protocol (Parrel!  et a!.,  1979), Kulle
et al.  (1982b) exposed 24 subjects (13 men and 11 women) for 3 hr on five con-
secutive days beginning  on Monday to filtered  air  during week 1 and to 784
    3
ug/m  (0.4 ppm) of 0,  during week 2.  During week 3, they exposed  11  subjects
                                                  3
to  filtered  air on  the first  day and  to 784 |jg/m  (0.4 ppm) of 0-  on the
second day, while they exposed the remaining 13 subjects for 4 days to filtered
                        3
air and then to 784 ug/m  (0.4 ppm) of 0_ on the fifth day.   One hour prior to
the end  of  each exposure,  the subjects performed 15 min of exercise at 100 W
(VV =  4 to 5 times resting  VV).   Although the magnitude  of  decrement was
notably less, the patterns of change in responses of FVC and FEV,  were similar
to  those observed in previous  studies, i.e., attenuation  of response  occurred
during the 5 days of exposure.   Attenuation of response was partially reversed
4 days  after  and  not  present  7 days  after repeated daily exposures.   These
results agree with  those of Linn et al.   (1982b),  but  contrast to those of
Horvath et al.  (1981).   Since  the magnitude of decrements in pulmonary func-
tion (and also effective-exposure dose) was notably less in this study than in
that of  Horvath et al. (1981),  these authors have suggested that the  duration
of  attenuation  of pulmonary  response to  0,  may be related to  the magnitude of
decrement in response observed with the initial exposure to 03.
     Gliner et al.  (1983) performed a study to determine whether daily repeated
exposures to  a  low  concentration of 0- (392 ug/m ; 0.20 ppm) would attenuate
pulmonary function decrements  resulting from exposure to a higher 0., concentra-
                       •3                                            J
tion (823  or 980 ug/m ;  0.42  or 0.50 ppm).   Twenty-one  subjects  (8 male,
13  female) were exposed  for 2 hr on  five consecutive  days to filtered  air
                                  3
(0.0 ppm 0,)  on day 1, to  392  ug/m   (0.20 ppm) of 0, on days  2, 3,  and 4, and
                  O
to 823 or 980 ug/m  (0.42 or 0.50 ppm) of 0- on day 5.   For comparison, subjects
019PO/A                             11-48                               5/2/84

-------
who were exposed to 0.42 or 0.50 ppm of 0, were exposed to the same 0, concen-
tration under  identical conditions 12 weeks prior to or 6 to 8 weeks following
the daily  repeated exposures.   During exposure, subjects  alternately  rested
for 15 min  and exercised  for  15 min.   Minute  ventilation  was  30  L/min  for men
and  18  L/min  for  women.   Forced expiratory spirometry (FVC) was  performed
before and  5 min after the last exercise period.  Analysis of continued results
from all subjects  indicated that three consecutive daily exposures to a low 0-
                        3
concentration  (392 ug/m ;  0.20 ppm)  did  not alter  expected  pulmonary function
response to a  subsequent  exposure to  a  higher 0,  concentration (823 or 980
ug/m3; 0.42 or 0.50 ppm).
     Subjects  were divided into two groups based  on  the  magnitude of their
response to the  acute exposure to 823 or  980 ug/m  (0.42 or 0.50 ppm) 03.
Nine  subjects  were considered to be  responsive  (FEV-.  decrements averaged
34 percent), and   nine  subjects  were considered to  be  nonresponsive (FEV,
decrements  averaged less than  10 percent).   Statistical analysis based on this
grouping  indicated that  responsive  subjects   exhibited  pulmonary function
decrements  after both their first and second,   but not their third, exposure to
        3
392 ug/m   (0.20  ppm); decreases in  FVC  and FEV-,  were about 9 percent.   No
                                3
significant  effects  of 392-ug/m  (0.20-ppm)  0,  exposure  were found in the
nonresponsive  group.  In both  groups, repeated exposures to 0.20 ppm of 0, had
no influence on the subsequent response to the higher ambient 00 exposure (823
            3
or 980 ug/m ;  0.42 or 0.50 ppm).   Note that repeated exposures to the low 03
concentration  for  only three consecutive days  may have constituted insufficient
total  exposure (some combination of number of exposures, duration of exposures,
•
V^, and 03  concentration)  to  affect pulmonary  function decrements resulting
from exposure  to higher 0^ concentrations.   Additional studies, with considera-
tion of total  exposure  and component variables, are  needed to clarify this
issue.
     Haak et al. (1984) made  a similar observation as  Gliner  et al.  (1983)
that exposure  to a low  effective dose  of 03 did not attenuate the  response  to
a subsequent exposure at a higher effective dose of O,.   The pattern of pulmonary
function decrements was evaluated  following repeated daily 4-hr exposures to
784 ug/m  (0.40 ppm)  of 03 with two  15 min  periods of heavy exercise (VV =  57
L/min).   As expected,  pulmonary function decrements were greater on the second
of five consecutive days of 0, exposure; thereafter, the  response was attenu-
                                   3
ated.   Exposure at rest to 784 ug/m  (0.4 ppm) of 03 for  two consecutive  days

019PO/A                              11-49                               5/2/84

-------
had no effect on pulmonary function.  Ozone exposure on the next two succeeding
days with  heavy exercise produced pulmonary function  decrements  similar to
those observed  previously  in  this  study  for the first  two days of exposure  to
ozone.
     Kulle  et al.  (1984) studied 20 smokers with chronic  bronchitis  over a
3-week period.   The  subjects  breathed filtered air for 3 hr/day on Thursday
and Friday  of week 1 (control days), were exposed to 804 ug/m  (0.41 ppm) 03
for 3 hr/day on Monday through Friday of week 2,  and on week 3 breathed fil-
tered air  on Monday,  then  were re-exposed  to 0.41 ppm  0~ on Tuesday.  Bicycle
ergometer exercise was performed at  2 hr of exposure at an intensity of  100 W
for 15 min  (V£  ^ 4-5 times resting).  Spirometric measurements and recording
of symptoms were made at the  completion  of all exposures.  Small but signifi-
cant decrements  in  FVC (2.6 percent) and  FEV- (3.0 percent) occurred on the
first day only of the 5-day repeated exposures as  well  as on re-exposure 4 days
following cessation of the sequential exposures.   Symptoms experienced were mild
and did not predominate on any exposure days.   These results indicate that in-
dividuals with chronic bronchitis also have attenuated responses with repeated
exposures to 0,  that persist for no  longer than  4  days.   These results for
smokers with chronic bronchitis contrast to those  reported by the same investi-
gators for normal nonsmoking subjects exposed under nearly identical conditions
(Kulle et al., 1982b).  Their normal subjects demonstrated larger decrements in
FVC (8 percent)  after the  first and  second exposures;  thereafter the response
was attenuated.   This attenuation of response persisted beyond 4 days,  and only
with re-exposure  7 days  after repeated exposures did significant decreases  in
FVC once again appear.  These data also support the contention that persistence
cf an attenuated pulmonary response to 03 is related to the magnitude of the
initial  response.
     To determine  if nonspecific bronchial reactivity  is a factor involved  in
the attenuation  of  pulmonary  responses  to 0~, Dimeo et al. (1981)  evaluated
the effects of single and sequential 0- exposures  on the bronchomotor response
to histamine.   To determine the lowest  concentration  of  0-  that causes  an
increase in bronchial reactivity to histamine and to determine whether adapta-
tion to this  effect  of 0- develops  with repeated exposures, they studied 19
healthy, nonsmoking  normal  adult subjects.  Bronchial  reactivity was assessed
by measuring the rise in specific airway resistance (ASR  ) produced by  inhala-
tion of  10 breaths  of  histamine  aerosol  (1.6-percerit solution).   In five

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subjects, bronchial reactivity was determined on four consecutive days without
exposure to  (L (group I).   In  seven other  subjects  (group II),  bronchial
reactivity was  assessed  on two consecutive  days;  subjects were exposed to
        3
392 |jg/m  (0.2 ppm) of 0, on the third succeeding day and bronchial reactivity
was determined  after exposure.   Seven  additional  subjects (group III) had
bronchial reactivity  assessed  for two consecutive days  and then again on  the
                                                            3
next three consecutive days after 2-hr exposures to 784 ug/m  (0.4 ppm) of 0-,.
Exposures consisted  of alternating  15-min periods of rest and light exercise
(Vp = 2x resting VV).  Pre-exposure bronchial reactivity of the groups was the
same,  and no change in bronchial reactivity occurred in group I tested repeated-
ly but  not  exposed to 0^.  An  increase  in ASR   provoked by  histamine was
                        o                  Q   3W                          Q
noted after  the  first exposure to 784 ug/m   (0.4 ppm)  but not to 392 (jg/m
(0.2 ppm) of 0~.   With three repeated 2-hr exposures to 0.4 ppm on consecutive
days,  the ASR    produced by histamine progressively decreased, returning  to
             aW
pre-exposure values  after the  third exposure.  Their  results  indicated that
with intermittent light exercise,  the lowest concentration of ozone causing an
increase in bronchial reactivity in healthy human subjects was between 392 and
        3
784 ug/m  (0.2 and 0.4 ppm), and that attenuation of this effect of OT developed
with repeated  exposures.   The  lowest concentration of  0,  (identified  in other
studies using  light  or  moderate exercise) that caused  changes in  symptoms,
                                                                    3
lung volumes, or airway resistance was also between 392 and 784 ug/m  (0.2 and
0.4 ppm), and  the  time  course  for the  development  of attenuation of these
responses to 0,  was  similar to that observed  in  this  study.   These authors
propose that the  appearance of symptoms,  changes in pulmonary function, and
the increase in  bronchial  reactivity may  be  related and  caused by  a change  in
the activity of afferent nerve endings in the airway epithelium.
     Kulle et al. (1982b) also evaluated the effects of sequential  0., exposure
on bronchial reactivity.   Nonsmoking  subjects (n = 24) were exposed for 3 hr
on five  consecutive   days  each  week to  filtered  air  during week 1 and to
784 ug/m  (0.4 ppm) 0^ during week 2.   During week 3,  they exposed 11 subjects
                                                 3
to filtered  air  on the  first day and to 784 ug/m  (0.4 ppm) 0~ on the second
day,  while they  exposed  the remaining 13 subjects for 4 days to filtered air
                     3
and then  to 784 ug/m  (0.4 ppm) 03 on  the fifth day.    A  15-min  period  of
exercise at  100 W  (VV =  4 to 5 times resting VV) was performed 1 hr prior to
the end  of each  exposure.   After each exposure, a provocative  bronchial chal-
lenge test was performed to determine bronchial reactivity to methacholine,
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defined as the log of the methacholine dose that provoked a 35 percent decrease
in  SGaw  from control.   Bronchial reactivity to  methacholine  observed after
exposure to  03  on the iniital 2 to  3 days  was significantly increased over
that observed after  exposure  to  filtered air,  with no significant differences
on  the fourth and fifth days of exposure  or  with re-exposure 7 days later.
The  duration of the  attenuated bronchial reactivity  response  was  therefore
much longer  than  that observed for FVC and FEV,  Q  in the same subjects, as
noted earlier in this section.
     An issue that merits  attention  is whether  attenuated pulmonary  respon-
siveness is  beneficial  or  detrimental in that it may reflect the presence or
development  of  underlying  changes in  neural responses or basic  injury to  lung
tissues.   Whether the attenuation of  pulmonary function  responses after repeated
chamber exposures to 0.,  is  suggestive  of reduced  pulmonary responsiveness for
chronically  exposed  residents  of high-oxidant communities also remains unre-
solved.

11.4  EFFECTS OF OZONE ON VIGILANCE AND EXERCISE PERFORMANCE
     Results from animal studies  suggest  that 0., causes alterations  in motor
activity and behavior, but whether these responses result from odor perception,
irritation,  or  a  direct effect on the central  nervous system (Chapter 10) is
unknown.   In fact, modification of the inclination to respond was suggested as
possibly being  more  important than  changes in the physiological capacity to
perform simple or complex tasks.   Very few human studies are  available to help
resolve this issue.
     Henschler et al.  (1960)  determined  the olfactory threshold in 10 to 14
male subjects exposed  for  30  min to various 03 concentrations.   In a  subgroup
of 10 subjects,  9 individuals reported detection when the ambient concentration
                        o
was  as low  as  39.2 ug/m  (0.02 ppm of GO.   Perception  at this low level did
not  persist, being seldom  noted  after some 0.5  to  12 min of exposure.   The
                                                              o
odor of  Oo  became more intense  at concentrations of 98 ug/m   (0.05 ppm),
according to 13  of 14 subjects tested, and it  persisted  for a longer period of
time.  No explanation was provided for the olfactory fatigue.
     Eglite  (1968) studied the effects of low  0., concentrations on the olfactory
threshold and on  the  electrical  activity of the  cerebral cortex.  He  found  in
his 20 subjects  that  the minimum perceptible concentration (olfactory threshold)
                                      3
for 0» was between 0.015 and 0.04 mg/m  (0.008 and 0.02  ppm).   The few subjects

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on whom  electroencephalograms  (EEGs)  were recorded showed a 30 to 40 percent
                                                                               3
reduction of cerebral electrical activity during 3 min of exposure to 0.02 mg/m
(0.01 ppm) of  03-   The  data are presented inadequately and can be considered
only suggestive.
     Gliner et  al .  (1979)  determined  the effects of  2-hr  exposures  to 0.0,
490, 980,  or  1470 ug/m3 (0.0,  0.25, 0.50, or  0.75  ppm)  of 03 on  sustained
visual and auditory attention  tasks (vigilance performance).  Eight male and
seven female  subjects performed  tasks  consisting of judging  and responding to
a series  of 1-s light pulses which  appeared  every 3 s.  The  light  pulses were
either nonsignals  (dimmer)  or  signals (brighter).   When the ratio of signals
to nonsignals  was  low  (15 subjects),  approximately 1  out  of 30 performances
was not  altered regardless of  the  ambient level of 0,..   However, when the
ratio of signals was  increased (five subjects), a deficit  in performance
                                                                             3
beyond that of the  normal vigilance decline was observed during the 1470-ug/m
(0.75-ppm) 03  exposure.  The  results  obtained were interpreted within the
framework of an arousal hypothesis, suggesting that a high concentration of 0^
may produce overarousal.
     Five individuals (four men, one woman) served as  subjects (Gliner et al.,
1980) in  studies  designed to evaluate the effects  of 0,,  on the electrical
activity  of the brain  by monitoring the  EEC during psychomotor performance.
In the first experiment, a 2-hr visual sustained attention task was unaffected
by exposure to filtered air or 1470 ug/m  (0.75 ppm) of 0-.  The second experi-
ment involved  performing a divided-attention  task, which  combined a visual
choice reaction time situation with an auditory sustained attention task.   The
03 concentrations were either 0.0, 588, or 1470 ug/m  (0.0, 0.3, or 0.75 ppm).
Spectral  and discriminant function analyses were performed on the EEGs collec-
ted during these  studies.  There was no  clear  discrimination between 0., expo-
sure and  filtered  air  using the different parameters  obtained from  the EEG
spectral   analysis.   Given the  inability to  obtain  a  discrimination  between
                       3
clean air and 1470 (jg/m  (0.75 ppm) of 0, using these  techniques,  EEG analysis
does not  appear to  hold any promise as  a quantitative method of  assessing
health effects of low-concentration (i.e., <  1484-ug/m ;  0.3-ppm)  03 exposure.
     Mihevic et al.  (1981) examined the  effects of 0_ exposure (0.0, 588,
        3
980 ug/m  ; 0.00, 0.30,  and 0.50 ppm) in 14 young subjects  who initially rested,
then exercised  for  40 min  at heart  rates  of  124 to 130 beats/mi n,  and  finally
rested for an  additional  40 min.  Pulmonary  function measurements  (FVC, FEV
and MEFpryc-) were  made  during rest periods and after exercise.   The primary
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objective of the  study was to examine the effects of exposure during exercise
on perception of  effort  and  to evaluate perceptual sensitivity to pulmonary
responses.   As expected,  decrements  in  FVC,  FEV,,  and MEF25_75 were  signifi-
cantly greater (P <0.01)  immediately after exercise than in the rest  condition
                                   3
during either the  588- or 980-ug/m  (0.30- or  0.50-ppm)  0.,  exposures.   The
work  output  remained  the same in all conditions.   However,  the ratings of
perceived exertion revealed that the subjects  felt  they were working  harder or
making a greater effort when  exercising in the 0.50-ppm 03 condition  as  compared
to in-room  air.   The  increased effort was perceived  as a "central"  effect
(i.e., not  related to effort or fatigue in the  exercising muscles), which may
suggest the  perception of increased respiratory effort.  The  subjects  also
performed a  test  of magnitude estimation and production of inspired volume in
which they  either gave estimates of the percentage of  increase  in inspiratory
capacity or attempted to  produce breaths of a  given size.   From these tests an
exponent was derived  (by geometric  regression analysis),  which indicated the
"perceptual   sensitivity"  to  change  in  lung volume.   The  increase in  this
exponent following 0.,  exposure (588, 980 ug/m  ;  0.30,  0.50 ppm) indicated that
the subject's sensitivity  to  a change in lung volume  was  greater than  it was
following filtered-air exposure.
     Early epidemiological studies  on  high  school  athletes (Chapter  12) pro-
vided suggestive  information that exercise performance  in an oxidant environ-
ment  is  depressed.   The  reports  suggested  that the effects may  have  been
related to  increased  airway  resistance or to  the  associated discomfort in
breathing,  thus  limiting  runners'  motivation  to perform at anticipated  high
levels.   In  controlled human studies, exercise  performance has  been evaluated
during short-term maximal  exercise  or continuous exercise for  periods  up to
1 hr  (Table  11-6).  Folinsbee  et  al.  (1977a)  observed  that  maximal  aerobic
capacity (max V0?) decreased  10 percent, maximum attained work load was  reduced
oy 10 percent, maximum ventilation  (max Vp) decreased  16 percent, and maximum
                                                                 3
heart rate  dropped 6  percent  after a 2-hr 0.,  exposure (1470 pg/m ;  0.75 ppm)
with alternate rest and light exercise.   A psychological impact related  to the
increased pain (difficulty) induced by maximal  inspirations may have been the
important factor  in reduction  in performance.    Savin and Adams  (1979) exposed
nine  exercising  subjects  for  30 min to 294 and 588 pg/m  (0.15 and 0.30 ppm)
0_ (mouthpiece inhalation).   No  effects on maximum work rate or max  VO^ were
found, although  a significant reduction in max VF  was observed during  the
        3                                       . t
588-ug/m  (0.30-ppm) exposure.   Similarly, max VQ2  was not impaired in men and
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                                                            TABLE  11-6.   EFFECTS OF OZONE ON EXERCISE PERFORMANCE
en
Ozone
concentration
ug/m3
294
588
392
686
412
490
980
1470
1470
ppm
0.15
0.30
0.20
0.35
0.21
0.25
0.50
0.75
0.75
Measurement '
method
UV,
NBKI
UV,
UV
UV,
UV
CHEM,
NBKI
MAST,
NBKI
k Exposure
duration and
activity
30 min (mouthpiece)
R & CE (8xR)
@ progressive work
loads to exhaustion
1 hr (mouthpiece)
IE (77.5) @ vari-
able competitive
intervals
CE (77.5)
1 hr
CE (81)
2 hr
R (8) & CE
@ progressive work
loads to exhaustion
2 hr
IE (2.5xR)
@ 15-min intervals
Observed effect(s)
No effect on maximum work rate, anaerobic
threshold, or pulmonary function; max VV
decreased with 0.30 ppm 03.
FVC, FEV,.0) and FEF25_75 decreased,
subjective symptoms increased with 03
concentration at 68% max V02 ; f., in-
creased and VT decreased during CE;
decreased during V02 , HR, VE, or V..
No exposure mode effect.
Decreases in FVC (6.9%), FEV^o (14.8%),
FEF25.75% (18%), 1C (11%), and MVV (17%) at
75% max V02. Symptoms reported: laryngeal
and tracheal irritation, soreness, and chest
tightness on inspiration.
No effect on maximum exercise performance
(max V02 , HR, and total performance time).
HR , Vr, V,., V02 , and maximum workload
alT decreased. At maximum workload only,
fR decreased (45%) and VT increased (29%).
No. and sex
of subjects Reference
9 male Savin and Adams, 1979
(runners)
10 male Adams and Schelegle, 1983
(distance runners)
6 male Folinsbee et al., 1984
1 female
(distance cyclists)
8 male Horvath et al . , 1979
7 female
13 male Folinsbee et al., 1977a
     Measurement method:   CHEM  =  gas-phase  chemiluminescence;  UV  =  ultraviolet  photometry.
     Calibration method:   NBKI  =  neutral  buffered  potassium  iodide;  UV  =  UV  photometry.
     Activity  level:   R =  rest; CE =  continuous  exercise;  IE = intermittent  exercise;  minute  ventilation  (V.-) given  in  L/min or as  a multiple of  resting
     ventilation.                                                                                           b
     See Glossary  for  the  definition  of  symbols.

-------
women after 2-hr  exposure  and at-rest exposure to 0.0,  980,  and 1470 |jg/m
(0.00, 0.50, and 0.75 ppm)  of 0.. (Horvath et al. ,  1979).
     Six well-trained  men  and one well-trained woman  (all  except one male
being a  competitive distance cyclist) exercised  continuously on a bicycle
ergometer for 1 hr  while breathing filtered air or 412 [jg/m   (0.21 ppm) of 0~
(Folinsbee et al. ,  1984).  They worked at 75 percent max Vn_ with mean minute
ventilations of  81 L/min.   As previously noted (Section  11.2.2),  pulmonary
function decrements as well as symptoms of laryngeal  and/or tracheal  irritation,
chest soreness, and chest  tightness  were observed upon taking a deep breath.
Anecdotal reports  obtained from the cyclists supported the  contention that
performance may be  impaired  during competition at similar ambient 0~ levels.
     Adams and Schelegle (1983)  exposed  10 well-trained distance runners to
0.0, 392, and  686 ug/m3 (0.0, 0.20, and  0.35  ppm)  of 03 while  the runners
exercised on a bicycle ergometer at work loads simulating either a 1-hr steady
state training bout or a 30-min warmup followed immediately by a 30-min compe-
titive bout.  These exercise levels  were of sufficient magnitude (68 percent
of  their max Vn?)  to  increase mean Vp to 80 L/min.  In the last  30 min of the
competitive exercise  bout, minute  ventilations  were approximately 105 L/min.
Subjective  symptoms increased as  a  function of 0~ concentration  for both
continuous and competitive levels.   In the competitive exposure, four  runners
(0.20 ppm)  and  nine runners  (0.35 ppm)  indicated that  they  could not have
performed at their  maximal levels.   Three subjects were  unable  to  complete
either the  training or competitive simulation exercise bouts at 0.35 ppm 0^,
while a  fourth  failed to  complete the competitive ride.   As  previously noted
(Section 11.2.2),  the high ventilation volumes resulted  in marked pulmonary
function impairment and altered ventilatory patterns.   The decrements were the
result of physiologically  induced subjective limitations of performance due to
respiratory discomfort.  The authors found it necessary to reduce the 68 percent
max  Vn?  work  load by some 20 to 30 percent in two of their subjects for them
to  complete the  final 15 min (of the  30-min work time)  in their competitive
test.
     Although studies on athletes (not all top-quality performers) have sugges-
ted  some  decrement in performance, too  limited a  data base  is  available at
this  time  to  provide judgmental decisions concerning  the  magnitude  of such
impairment.   Subjective statements by individuals  engaged  in various sport
activities  indicate that  these  individuals may voluntarily  limit strenuous

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exercise during high-oxidant  concentrations.   Several  reviews on exercising
subjects have  appeared  in the literature  (Horvath,  1981;  Folinsbee,  1981).
11.5  INTERACTIONS BETWEEN OZONE AND OTHER POLLUTANTS
     An important  issue  is  whether or not 03 interacts with other pollutants
to produce  additive  as well as greater  than  additive effects beyond those
resulting from exposure  to  0_  or the other pollutants alone.   Also important
to determine  is  whether no  interactions  occur  when several pollutants are
present simultaneously.  Table 11-7 presents a summary of data on interactions
between 0- and other pollutants.
         O

11.5.1  Ozone Plus Sulfates or Sulfuric Acid
     Several studies  have  addressed the  possible interaction between 0., and
sulfur compounds.   Bates and  Hazucha (1973) and Hazucha  and  Bates (1975)
                                                              3
exposed eight volunteer  male subjects  to  a mixture  of  725  (jg/m   (0.37 ppm) of
0- and 0.37 ppm  of sulfur  dioxide  (S0«)  for 2 hr.   Temperature,  humidity,
concentrations,   and  particle  sizes  of ambient aerosols (if  any)  were  not
measured.    Sulfur  dioxide  alone had no detectable  effect  on  lung function,
while exposure to  03  alone  resulted in decrements in pulmonary function.  The
combination of gases resulted  in more severe respiratory symptoms and pulmonary
changes than did 0» alone.   Using the maximal expiratory flow rate at 50 percent
vital capacity as  the  most  sensitive  indicator, no  change  occurred  after 2 hr
                                                                          3
of exposure to 0.37  ppm SOp alone.   However, during  exposure to 725 ug/m
(0.37 ppm)  0, a  13 percent reduction occurred,  while exposure to the mixture
           3
of 725 ug/m  (0.37 ppm) 03 and 0.37 ppm S02 resulted in a reduction of 37 per-
cent in this measure of pulmonary function.   The effects resulting from 03 and
S0?  in combination appeared in 30 min, in contrast to a 2-hr time  lag for
exposure  to 0~ alone.
     Bell  et  al.  (1977) attempted  to  corroborate  these studies  using four
normal and  four  03-sensitive subjects.  They  showed that the 03  +  SO™ mixture
had  a greater detrimental  effect on all  pulmonary function measures than did
0- alone.   However, only one out of eight functional parameters showed statis-
tically significant decrements when compared with 03; FEV,  ~ decreased (4.7 per-
cent) in  the  sensitive subjects.   Four of the Hazucha and Bates  (1975)  study
subjects  were also studied  by Bell et al. (1977).   Two of these  subjects had
unusually large  decrements  in  FVC (40 percent) and FEV.. (44 percent) in the
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TABLE 11-7.   INTERACTIONS BETWEEN OZONE AND OTHER POLLUTANTS
Ozone
concentration
Mg/m3
ppm

Pollutant3

Measurement '
method
Exposure
duration and
activity

No. and sex
Observed effect(s)6 of subjects


Reference
A. 03 + S02:
294
393


725
970


725
970




V 725
en 970
CO 100

784
1048


784
1048


0.15
0.15


0.37
0.37


0.37
0.37




0.37
0.37

0.4
0.4


0.4
0.4


03
S02


03
S02


o3
S02




03
S02
H2S04

03
S02


03
S02


CHEM, NBKI
EC


MAST, NBKI
EC


CHEM, NBKI
FP




UV, NBKI
FP
1C

CHEM, NBKI
FP


CHEM, NBKI
FP


2 hr
IE(25)
@ 15-min
interval s
2 hr
IE(2xR)
@ 15-min
intervals
2 hr
IE(2xR)
@ 15-min
intervals


2 hr
IE(2xR)
@ 15-min
intervals
2 hr
IE(30)
@ 15-min
intervals
2 hr
IE(30)
@ 15-min
intervals
SG decreased; possible synergism is ques- 6 male
livable. Statistical approach is weak.


Decrement in spirometric variables (FVC, MEFR 8 male
50%); synergism reported. Interpretation com-
plicated by the probable presence of H2S04.

Decreased forced expiratory function 4 normal (L.A)
(FEV^o, FVC) relative to 0 exposure in 5 sensitive (L.A.)
combined group of normal and sensitive L.A. 4 normal (Montreal)
subjects more severe symptoms and greater
decrement of FEV^o in Montreal (5.2%) than
L.A. sensitive (3.7%) subjects.
Small decreases in pulmonary function (FVC, 19 male
FEVll2,3, MMFR, V 50, V 25) and slight
increase in symptoms due primarily to 03
alone; H2S04 was 93% neutralized. '
Decreased forced expiratory function (FVC, 9 male
FEV^o, FEF25 75~, FEFso,v) following expo-
sure to either 03 or 03 * S02; no differences
observed between 03 alone and 03 + S02.
Observed decrement in pulmonary function 8 male
(FEV^o, FVC, FEF25.75%, FEF50%, ERV, TLC)
and increase in symptoms reflected changes
due to 0^; no synergisni was found.
Kagawa and Tsuru, 1979c



Hazucha, 1973
Bates and Hazucha, 1973
Hazucha and Bates, 1975

Bell et al. , 1977





Kleinman et al. , 1981


Bedi et al. , 1979



Bedi et al . , 1982



B. Oj + H2S04-
294
200

588


100


0.15


0.3





03
H2S04

03


H2S04


CHEM, NBKI
1C

MAST, NBKI
& CHEM, NBKI

TS


2 hr
IE @15-min
intervals
2 hr
IE(35)
for 15 min
4 hr
IE(35)
for 15 min
SGaw decreased; no interaction reported. 7 male
Questionable statistics.

No significant 03-related changes in pulmo- 7 male
nary function or bronchial reactivity to 5 female
methacholine Bronchial reactivity decreased
following a 4-hr exposure to H2S04.


Kagawa, 1983a


Kulle et al. , 1982a






-------
                                                  TABLE  11-7.   INTERACTIONS BETWEEN OZONE AND OTHER POLLUTANTS  (continued)
 I
en
i-O
Ozone
concentration
(jg/m-5
784
100
133
116
80
ppm
0.4





Pollutant3
03
H2S04
(NH4)2S04
NH4HS04
NH4N03
b c
Measurement '
method
CHEM, NBKI




Exposure
duration and
activity
2-4 hr
IE
for two 15-min
periods



Observed effect(s)6
Decrement in pulmonary function due to
03 alone; more apparent after 4 hr than
2 hr; no interaction; recovery within 24 hr.



No. and sex
of subjects Reference
124 male Stacy et al., 1983
(divided into
10 exposure
groups)

C. 03 + CO:
588
115000



0.3
100.0



03
CO



MAST, BAKI
IR



1 hr (mouth-
piece) CE (51
for male and
34.7 for female
subjects).
Decrement in pulmonary function due to
03 alone: FVC, FEVj.0 and FEF25_75y
decreased; fg increased and V-, decreased
with exercise.

12 male DeLucia et al. , 1983
12 female
(equally divided
by smoking history)

D. 03 + N02:
196
9400


294

280




490-
980
560
35000
980
940





0.1
5.0


0.15

0.15




0.25-
0.5
0.3
30.0
0.5
0.5





03
N02


03

N02




03

N02
CO
03
N02





CHEM, NBKI
MAST (N02)


MAST, NBKI
and CHEM, NBKI
MAST, (N02)
and CHEM, C



CHEM, NBKI

CHEM, C
IR
CHEM, NBKI
CHEM, C





2 hr
IE(2xR)
@ 15-min
intervals
2 hr
IE(25)
@ 15-min
intervals



2-4 hr
R & IE(2xR)
@15-min
intervals
2 hr
IE (40)
for 30 min




Decreases in Pa02 and increases in Raw
due predominantly to N02 alone. No
interaction reported.

SGaw decreased in 5/6 subjects during 03
exposure, 3/6 subjects during N02 expo-
sure, and in all subjects during the
combined exposure. More than additive
effect reported in 3/6 subjects. Coughing,
chest pains, and chest discomfort related
to 03 exposure.
No interaction reported. Changes observed
in spirometry, lung mechanics, and small
airway function in non-reactors (IE) and
hyperreactors (R) at 0.5 ppm 03.
Decreases in FVC, FEVj.,,, FEF25_75%. and
FEFsiw. ventilatory and metabolic variables
were iSot changed; response was similar to
that observed in 03 exposure alone. Tight-
ness in the chest and difficulty taking deep
a breath was reported along with cough, sub-
sternal soreness, and shortness of breath.
12 male von Nieding et al., 1977
von Nieding et al. , 1979


6 male Kagawa and Tsuru, 1979b






16 normal and Hackney et al., 1975a,b,c
reactive subjects


8 male Folinsbee et al., 1981







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                                             TABLE  11-7.  INTERACTIONS BETWEEN OZONE AND OTHER  POLLUTANTS   (continued)
Ozone
concentration
ug/m3 ppm
980-
1372
940
1320
0.5-
0.7
0.5-
0.7
Measurement '
Pollutant method
N02
MAST, NBKI and
CHEM, NBKI
MAST (N02)
and CHEM, C
Exposure
duration and
activity
1 hr
(mouthpiece)
R
No. and sex
Observed effect(s)6 of subjects
No significant changes in SGaw, Vmax 50%, or 5 male
Vmax 25%.
Reference
Toyama et al . , 1981
E. 03 + N02 + S02:
49-
196
100-
9000
314
13000
157
£ 300
I 900

 See Glossary for the definition of symbols.
 Part of a larger study of 231 subjects.

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first  study (Bates  and  Hazucha,  1973),  while the other  two  had small but
statistically  significant decrements.   None of the  subjects  responded in a
similar manner in the Bell et al.  (1977) study.
     To determine  why  some of  the Montreal  subjects  were  less  reactive to  the
SOp-0- mixture when studied in Los Angeles compared to Montreal, Bell et al.
(1977) compared exposure  dynamics in the two chambers.  Analysis of the design
of the Montreal  chamber and pollutant delivery system indicated that concen-
trated streams of  S02  and 0_ could  have  reacted  rapidly  with  each  other and
with ambient  impurities  like olefins,  to  form  a large  number of  sulfuric acid
(h^SO^) nuclei which grew  by homogeneous condensation, coagulation, and absorp-
tion of ammonia (NHL) during their 2-min average residence time in the chamber.
A  retrospective  sampling  of the aerosol  composition used for the  original
S02~03 study in Montreal  (Hazucha and Bates, 1975) using particle samplers and
chemical  analysis in the chamber showed that acid sulfate particles could have
been 10-  to 100-fold  higher  (100  to 200 ug/m3),  and  thus  might have been
responsible for  the synergistic effects  observed.   However,  recent studies
conducted by  Kleinman  et al. (1981)  involving  identical concentrations  of  SO,
                                            3
and 03 showed  that  the presence of 100 ug/m H-SO. did not  alter the  response
obtained with the S0p-03 mixture alone.  (See later discussion in this section.)
     Bedi  et  al.  (1979)  exposed nine young healthy  nonsmoking men  (18  to  27
                      3
years old) to 784 ug/m  (0.4 ppm)  0_ and 0.4 ppm SO,, singly and in combination
for 2 hr  in an inhalation chamber at  25°C  and 45 percent rh.   The subjects
exercised intermittently for one-half of the exposure  period.   Pulmonary
function was measured before, during, and after the exposure.   Subjects exposed
to filtered air  or to  0.4 ppm SO- showed no significant changes in pulmonary
function.   When  exposed  to either 0-  or 0_ plus S0?, the  subjects showed
statistically  significant decreases  in  maximum  expiratory flow (FEV-. „,
FEF-c.ycy. ar|d FEFcryy)  ar>d FVC.   There were no significant differences between
the effects of 0_ alone  and the combination of 0., +  S0?;  thus, no synergistic
effects were discernible  in  their  subjects.  Although particulate matter was
not present in the  inlet  air, whether particles developed in the chamber at  a
later point is not known.
     Chamber studies were also conducted by Kagawa  and  Tsuru (1979c), who
exposed six subjects for 2 hr with intermittent exercise (50 W; i.e.,  ventila-
tion of 25  L/min)  for  periods  of  15 min of exercise separated by periods  of
15 min of rest.  The exposures  were performed weekly in the following sequence:
filtered air,  0.15 ppm  of 0 •  filtered air,  0.15 ppm of SO ; filtered air;  and
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finally 0.15 ppm  of  0_ + 0.15 ppm  of  SQ^.   Pulmonary function measurements
were obtained prior  to exposure, after 1 hr in the chamber, and after  leaving
the chamber.  Although a number  of pulmonary function tests were performed,
change in  SG    was  used  as the most sensitive  test  of change in function.
            dw
They reported a significant  decrease  in five of the  six young male  subjects
exposed to  0., alone.   In three of the subjects, they  reported a significantly
greater decrease  in  SG   after exposure to the combination of pollutants  than
                       Q W
with 03 exposure  alone.  Two other  subjects had similar decreases with either
03 or  03  + SOp  exposure.  Subjective  symptoms of cough and bronchial irrita-
tion were  reported to  occur  in subjects exposed to either 0,, or the 0_ + S0?
combination.  The authors suggested that the  combined effect of the  two gases
on SG   is more than simply additive in some exercising subjects.   This conclu-
     ciW
sion is questionable, however,  because  of the small number of subjects respond-
ing and the use of t-tests of paired observations  to  test the significance  of
pollutant-exposure effects.   The statistical  approach is weak despite the fact
that the  author selected a significance level of  P  <0.01.   The  question of
potential  synergistic interaction between S0? and 0~  therefore remains unresol-
ved by this study.
     Bedi  et al.  (1982)  attempted to explain  the conflict of opinion over the
cause  of  synergistic effects  reported  by Hazucha and Bates (1975) and Kagawa
and Tsuru  (1979c) for  humans exposed to the combination of 0- and SO,,.  While
intermittently  exercising (VF ~30  L/min),  eight young adult nonsmoking males
were randomly exposed  on separate occasions for 2  hr  to filtered air,  0.4 ppm
S02, 748 (jg/m3  (0.4  ppm)  of 03> and 0.4 ppm of S02 plus 784 ug/m3 (0.4 ppm) of
CL at  35°C  and  85 percent rh.   No  functional  changes in FEV, „ occurred as a
result of  exposure to  filtered air  or 0.4 ppm of SCL, but decreases  in FEV,  „
occurred  following exposure to either 784 ug/m  (0.4  ppm) of 0, (6.9 percent)
                              3
or the combination of  784 ug/m   (0.4 ppm) of  03 plus  0.4 ppm of SO^  (7.4  per-
cent).  Thoracic  gas  volume (TGV) increased and  FEE^y  decreased in the 0,
exposures, while  FVC,  ^^25-75%'  ^50%' ERV' and  TLC  a11  decreased in the
0~/S09  and  0, exposures.   However,  no  significant differences were found
 J   C-,       O
between the 0-, exposure and the 0, plus SO,, exposure.  In this study, statisti-
cal analyses were performed using ANOVA procedures.
     An analysis  of the data obtained  in  the  1982  study and a  prior  study
(Bedi et al., 1979) was also made using t-tests to  compare data from these  two
studies with  data obtained by  Kagawa  and Tsuru (1979c),  who  reported a  syner-
                                                                     3
gistic  effect  consequent  to exposure to  0.15  ppm of S02 and 294 ug/m   (0.15
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ppm) of 03 using t-tests.   The experimental designs of the Bedi et al.  and the
Kagawa and Tsuru studies were essentially  similar.  Reanalysis of the Bedi et
al.  data  using  t-tests  indicated that the SG   was not altered in the 25°C-
                                             aw
45 percent rh environment  but  decreased 10.6 percent (P <  0.05)  in  the S0?
exposure and 19 percent (P < 0.01)  in 0, plus S09  exposure  in  hot, wet condi-
                                        «J        L-
tions.  These investigators  concluded  that in one sense  they  confirmed the
findings (based on t-tests) of Kagawa and Tsuru,  but under different conditions.
This might suggest a small  potential effect on SG  .   They then stated,  "None-
                                                 dw
theless, we  believe  that  the use of a  more  stringent statistical approach
provides for better  analysis  of collected data and  that  we are correct  in
stating that synergism had not occurred."
     Few studies have been  reported in which subjects were exposed to 0,, and
H9SO..  Kagawa  (1983a)  summarized  some  results  obtained  on seven subjects
                                                                          3
intermittently  resting  and exercising during a  2-hr  exposure  to 294 ug/m
                              2
(0.15 ppm) of 0,.  and 0.2 mg/m  of H?SO,.  Using t-tests to analyze his  data,
he reported  a  highly significant (P < 0.01)  decrease (10.2 percent) in  SG  .
However, not enough details are provided to allow adequate analysis.
     Kleinman et  al. (1981) conducted  studies in  which 19 volunteers with
normal pulmonary function and no history of asthma were exposed on two separate
                                                                       3
days to clean air and to an atmospheric mixture containing 0~ (725 ug/m  , 0.37
ppm), S02  (0.37 ppm), and H2S04  aerosol  (100 ug/m3, MMAD =  0.5 urn; a  = 3.0).
Chemical speciation  data  indicated  that 93 percent of  the  H~SO. aerosol  had
been partially  neutralized  to  ammonium bisulfate.   Additional  data suggested
that the acidity of the aerosol in the chamber decreased as a function of time
during  exposure,  so that  at the beginning of the exposures  subjects were
exposed to higher  concentrations of H?SO, than they were at the end of  expo-
sures.  During this 2-hr period, the subjects alternately exercised for  15 min,
at a  level calibrated  to  double minute  ventilation,  and  rested for 15  min.
Statistical analysis of the  group average  data suggested that  the mixture may
have been  slightly  more  irritating  to the subjects  than  0., alone.   A large
percentage (13  of  19) of the subjects exhibited small decrements  in pulmonary
function following exposure  to  the  mixture.   The group average FEV,  Q on the
exposure day was depressed by 3.7 percent  of the control value.  However, the
magnitudes of the FEV,  „ changes were not higher than those observed in  subjects
exposed to 0-  alone  (expected decreases of 2.8 percent).   The authors  con-
cluded that  the  presence  of H^SO.  aerosols did  not  substantially alter the
irritability resulting from 0~-S09.
                             O   f-
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     Stacy et al . (1983) studied 234 healthy men (18 to 40 years old) exposed
for 4 hr  to  air,  03,  N02,  or S02; to  H2$04,  ammonium sulfate [(NH^SO^,
ammonium  bi sulfate  (NhLHSO.),  or  ammonium nitrate (NH.NO^) aerosols;  or  to
mixtures  of  these gaseous  and aerosol  pollutants.   The subjects  were divided
into 20 groups  so that each group contained 9 to 15 subjects.  The exposure
groups  of interest  were filtered  air (n = 10);  784 |jg/m   (0.4 ppm)  of 0^
(n = 12);   100 ug/m3 of H2S04  (n  = 11);  133 ug/m3 of  (NH4)2S04  (n - 13);
116 ug/m3  of NH4HS04  (n =  15);  80 ug/m3  of NH4N03 (n = 12); and  the mixtures
03 + H2S04  (n = 13), 03 + (NH4)2S04 (n = 15), QS + NH4HS04 (n = 11), and DS +
NH4N03 (n =  12).   Ambient conditions  were 30°C db, 85 percent rh because of
the need to  maintain  the  aerosol  particles in proper suspension.   Two 15-min
bouts of treadmill exercise were performed, one beginning at 100 min into the
exposure and the second beginning at 220 min.  Pre-exposure resting pulmonary
functions were  measured during a  rest period.   This battery  of  pulmonary
function tests was also made some 5 to 6 min  following the termination of the
exercise and repeated 24 hr later.   Unfortunately,  the minute  ventilations for
the exercise periods were  not  reported.   Data were analyzed by multivariate
analyses of variance.   All pulmonary functions (i.e.,  airway resistances,  lung
volumes, and flow rates) except ERV, FEV,/FVC, and FRC showed a statistically
significant effect of  the  gaseous  pollutant  (0~).   None of the particulates
significantly  altered  pulmonary functions  compared  with the  filtered-air
exposure, and there was no indication  of interaction  between 0_ and the parti-
culates.  Only 0,  exposure  affected pulmonary functions (16 of the 19 tests
administered) and no significant interactions occurred with the sulfate aero-
sols.   Interestingly,  after 4  hr  of exposure, SR   increased 27 percent with
                                                 clW
03; 41.7 percent with 03/H2S04; 28.5% with 03/(NH4)2S04;  and 34.7 percent with
0^/NH.HSO,.   Although  there was a trend toward  increased 03  effect in the
presence of  acid  sulfates,  it  did not reach  statistical  significance.   The
reductions  in  FVC  and  PEP™  were approximately equivalent.   At  24 hr post-
exposure, all  pulmonary values  had  returned to pre-exposure levels.  Exposure
to Q-, alone  and  with particles was associated with  symptoms  of irritation,
viz.  shortness of breath,  coughing, and minor throat  irritation.   This compre-
hensive  study  confirms  other  observations  that 0«  alone (at the levels of 0.,
and sulfate aerosol stated) produced significant changes in  pulmonary functions,
albeit  shortly after  an exercise period.   The data presented also  suggested
that 0-  induced greater changes at  4 hr than  at 2  hr  of  exposure and that the
      
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     Kulle  et  al.   (1982a)  studied the  responses  of  12 healthy nonsmokers
(seven men,  five women) exposed to 0_  and  H^SO.  aerosols.   Ozone  concentra-
                   3                 o       ^   4                     ,
tions were 588 |jg/m  (0.3 ppm) and HLSO. aerosol levels were 100 [jg/m  (MMAD =
0.13 pm; or  = 2.4).  These studies were conducted over a 3-week period; a 2-hr
exposure to  0_, 4-hr exposure  to  HLSO.,  and 2-hr  exposure  to 0~ were  followed
by a 4-hr  exposure to  H?SO..  The protocol  followed  in each of these  weekly
exposure regimes was day 1 -  filtered  air,  day 2 -  pollutant, and day  3  -
filtered air.  A methacholine  aerosol  challenge was made at  the completion of
each exposure  day.  Subjects  were exercised for  15  min 1 hr  prior  to the
completion of the exposure.  The work load was  100 W  at 60 rpm, with an assumed
V_ of approximately 30  to  35  L.   No discernible risk  was apparent  as  a conse-
quence  of  exposing the  nonsmoking healthy young  adults to  0~ followed by
respirable  HpSO. aerosol.   Bronchial  reactivity decreased with H~SO.  aerosol
exposure at a statistical  level  approaching significance  (0.05 < p <0.10).
Pulmonary function changes (SG  , FVC, FEV,, FEV-, and bronchial reactivity to
                              9W          JL     «3
methacholine) following  the  0~ exposure were not significant.   However, some
subjects did report typical symptoms observed in other 0,, exposures.

11.5.2  Ozone and Carbon Monoxide
     DeLucia et  al.  (1983) reported the  only  study  in which  subjects were
exposed to  carbon  monoxide  (CO) and 0~.   Subjects  exercised  at 50  percent max
•
V,.,, for 1  hr in  the following ambient  conditions:  filtered air,  100  ppm of
            3                                                  3
CO, 588 jjg/m  (0.30 ppm) of 03, and 100 ppm of  CO plus 588 ug/m  (0.30 ppm) of
0,.  These gas mixtures were administered directly, the subjects inhaling them
orally for  the entire  exposure period.  Twelve nonsmokers,  six  men  and six
women,  and  12 smokers  (not  categorized  as to smoking  habits),  equally  divided
by sex,  served as subjects.  There were relatively large differences  in fitness
between men  and women  as well as between smokers and nonsmokers,  which could
be responsible for some of the differences reported.   Cardiorespiratory perfor-
mance,  heart rate,  oxygen uptake, and minute ventilation were not substantially
higher during exercise  bouts where 0~ was present.  All  subjects exercised at
50 percent max Vn?, equivalent to  a mean VF  of  45.0 to  51.8  L/min  for  the men
and 29.7 to  36.8 L/min  for  the women.   The  women,  therefore, probably  inhaled
less 0_ than the men.   Carboxyhemoglobin  (COHb) levels  attained at the end of
the exercise period were similar for the two  sexes,  an average increase of
5.8 percent.  Smokers'  final COHb values were 9.3 ± 1.2 percent, compared with
nonsmokers' levels of 7.3 ± 0.8 percent.

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     Based on  the limited data available,  exposure  to CO and CL  does  not
appear to result  in any interactions.  The effects noted appear to be related
primarily to CL.

11.5.3  Ozone and Nitrogen Dioxide
     Studies describing the responses of subjects to the combination of these
two pollutants are  summarized  in  Table 11-7.   Hackney et al .  (1975a,b,c)  and
von Nieding et al .  (1977,  1979)  noted that no interactions were  observed  and
that the pulmonary function changes were due to 0^ alone for the  concentrations
present.  Kagawa  and  Tsuru (1979b) evaluated the reactions of six subjects
(one smoker) to  294 ug/rn^ (0.15  ppm) 0- and 0.15 ppm NO™,  singly and in com-
bination.  They  used  the  standard exposure time of  2 hr  with  alternating
15-min periods of rest  and exercise at 50 W.   SG    was determined prior  to
                                                  aw
flow volume measurements and prior to and at two intervals during the exposure
period.  A fixed  sequence of pollutant exposures was  followed at  weekly inter-
                                   3
vals,  i.e.,  filtered  air, 294 ug/m  (0.15 ppm) of 0_, filtered air, 0.15  ppm
of  N02,  filtered air, 0.15 ppm (03  +  N02),  and filtered air.  Statistical
analyses were  by t- tests.  Subjective  symptoms  were  reported  in some subjects
only when CL was present.  Significant decreases in  SG   occurred in five of
            O                                           dW
six subjects exposed  to 0,,  three of six subjects exposed to NO,,, and six of
six subjects exposed to 0^ + NO™.
     Kagawa (1983a) briefly reported that under the conditions of his exposure
(2  hr  to 0.15  ppm 0.,  + 0.15 ppm N02) SGaw, V5Q%, and VC decreased.  However,
no  significant differences were observed between  03  alone  and the  combination
of 00  +  NO,,.  Subjective  symptoms were equivalent in both 0- exposures.
    3     Z                                                -5
     Five  subjects  sitting in a  body plethysmograph  inhaled orally either
filtered  air,  0.7 ppm of N02, 1372 ug/m3 (0.7  ppm) of Og, or 0.5 ppm of 03 +
0,5 ppm  of  N02 for 1 hr  (Toyama  et  al . , 1981).   Specific  airway  conductance
and  isovolume  flows (V        and ^        ^  were measured before  and  at  tne
end of exposure, and 1 hr later.  No significant changes were observed for any
of  the  ambient conditions  and consequently no  interactions  could be detected.
     Folinsbee  et  al.  (1981) exposed  eight  healthy  men for 2 hr to  either
filtered  air  or 980 ug/m3  (0.5  ppm)  of GS plus 0.5 ppm of  N02  in filtered air
under  four different  environmental  conditions:   (1) 25°C, 45  percent rh;
(2) 30°C,  85  percent rh; (3)  35°C, 40  percent  rh;  and  (4) 40°C,  50  percent rh.
Subjects  rested for the first  hour, exercised  at  a V£  of 40 L/min  during the
 0190LG/A                            11-66                                 5/2/84

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next half hour,  and  then rested for the final 30 min of exposure.   Pulmonary
function measurements  were made  prior to exposure,  immediately  after the
exercise period,  and again  at the end  of the  2-hr period.   Significant
decreases occurred in  FVC,  FEV,  „, F^oc-ycy. and  FEF,-,,^  during  the 0..-NO_
exposure.  Ventilatory and  metabolic  variables,  expired ventilation,  oxygen
uptake, tidal volume, and  respiratory  frequency  were  unaffected by 0,,  and  N09
                                                                     O       C.
exposure.  Thermal  conditions modified  heart rate,  ventilation,  and FVC.
Greater changes  in pulmonary  functions were seen in  both groups following  the
exercise period  with recovery of  the decrements  toward  the pre-exposure value
during  the  succeeding  half  hour  of rest.   In this  study,  no synergism or
interaction between 0., and N0_ was observed over the entire range of ambient
temperatures and relative humidities.

11.5.4  Ozone and Other Mixed Pollutants
     Von Nieding et al.  (1979) exposed 11  subjects  to 0~, N0~, and S0«  singly
                                                        O    £-        c~
and in  various  combinations.   The subjects were exposed for  2 hr with 1 hr
devoted to exercise (intermittent), which doubled their ventilation.   The work
periods were of  15 min  duration  alternating with 15-min periods at rest.   In
the actual exposure experiments,  no significant  alterations were observed  for
PO,,, PCCL, and pH in arterialized  capillary blood or  in TGV.   Arterial  oxygen
tension  (PaO?) was decreased (7  to 8 torr) by exppsure to 5.0 ppm of NO^ but
was not further decreased following exposures to 5.0 ppm of N0« and 5.0 ppm of
                                                  3
S02 or 5.0 ppm of N02,  5.0 ppm of S02 and 196 ug/m  (0.1 ppm) of 03 or 5.0 ppm
of N09 and 196 ng/m  (0.1 ppm) of 0,.   Airway resistance increased significant-
ly (0.5  to  1.5  cm  H?0/L/s) in the combination experiments to the same extent
as in  the exposures  to N0? alone.  In  the 1-hr post-exposure period of the
N09, S00, and 0., experiment, R.  continued to increase.   Subjects were also
  <—    <_        3              \f                                  Q
exposed to a mixture of 0.06 ppm N02,  0.12 ppm of S02, and 49 (jg/m  (0.025 ppm)
of 0_.   No  changes  in  any of  the  measured parameters were observed.  These
    •3
same subjects were challenged with 1-, 2-, and 3-percent aerosolized solutions
of ACh  following control  (filtered-air)  exposure and  exposure  to 5.0-ppm NO
5.0-ppm S02, and 0.1-ppm 0,  mixture, as  well  as  after the 0.06-ppm N02, 0.12-
ppm S09, and 49-pg/m   (0.025-ppm)  0~ mixture  exposures.  Individual  pollutant
gases were not  evaluated separately.   ACh challenge caused the expected rise
in airway resistance in the control study.  Specific airway resistance (R   x
                                                                         dW
TGV) was significantly greater following the combined pollutant exposures than
in the control  study.
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     In  another  study  of simultaneous exposure to  SO-,  N09,  and 0.,, three
                                                      c.     £-       O
groups of  eight  subjects, each of different ages (<30, >49, and between 30 to
40 years) were exposed for 2 hr each day in a chamber on three successive days
(Islam and  Ulmer,  1979a).   On the first day, subjects breathed filtered air
and exercised  intermittently  (levels  not given);  on the second day they were
exposed  at  rest  to 5.0 ppm  of S02> 5.0 ppm of N02,  and 196  ug/m3 (0.1 ppm) of
0-; and  on  the third day the environment was again  5.0 ppm  of  S00, 5.0 ppm of
                 3
NO-, and 196 (jg/m  (0.1 ppm) of 0^, but the subjects  exercised intermittently
during the  exposure.  Statistical evaluation of data  for the 11 lung-function
test parameters and two blood gas parameters (PaO- and PaCO?)  was not reported.
These measurements were  made  before  exposure,  immediately post-exposure, and
3 hr post-exposure.  Individual  variability  was  quite marked.  The  investi-
gators concluded that no synergistic effects occurred in their healthy subjects.
However,  since they did not systematically expose these subjects to  the  indi-
vidual components  of  their  mixed pollutant environment,  the  conclusion can
only be  justified  in  that they apparently saw no consistent changes.  There
were some apparent changes in certain individuals  related to exercise (unknown
level) and age, but the data were not adequately presented or  analyzed.
     Islam and Ulmer  (1979b)  studied 15 young healthy males  during  chamber
exposures to 0.9 mg/m  (0.34 ppm) S02, 0.3 mg/m3 (0.16 ppm) N02,  and 0.15 mg/m3
(0.08 ppm)  0_.   Ten  subjects  were exposed to 1 day of filtered air  and four
successive days of the gas mixture.   Another group of five subjects was exposed
for 4 days  to  the  pollutant mixture followed by 1 day to filtered air.   Each
exposure lasted  8  hr.   Following  each exposure,  the subjects  were challenged
by an ACh aerosol.   Eight pulmonary function tests and four blood tests (PaO?,
PaCOp, hemoglobin, and  lactate dehydrogenase) were  performed before  and after
the exposure.   No impairments of lung functions,  blood gases,  or blood chemis-
try were found,  but  statistical  analysis of the data was  not  reported.  The
authors reported that some of the subjects exhibited unusual responses.
11.6  EXTRAPULMONARY EFFECTS OF OZONE
     The high oxidation potential of 0,, has led early investigators to suspect
that the major damage from inhalation of this compound resulted from oxidation
of labile components in biological systems to produce structural or biochemical
lesions (Chapter 10).  Initial studies by Buckley et al.  (1975) suggested that

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                                                  TABLE 11-8.   HUMAN EXTRAPULMONARY EFFECTS OF OZONE EXPOSURE
 I
CTi
Ozone b
concentrati on Measurement '
ug/m3
294
588
392
392
490
725
784
784
784
784
ppm method
0.15 UV,
0.30 NBKI
0.2 NO
0.2 CHEM,
0.25 NBKI
0.37 CHEM,
NBKI
0.4 CHEM,
NBKI
0.4 CHEM,
NBKI
0.4 CHEM,
NBKI
0.4 CHEM,
NBKI
Exposure
duration and
activity
1 hr (mouthpiece)
R (11) & CE
(29, 43, 66)
0.5-1 hr
2 hr
IE (2xR)
@ 15-min intervals
2 hr
IE (2xR)
@ 15-min intervals
4 hr
IE for two
15-min periods
4 hr
R
4 hr
IE for two
15-min periods
2.25 hr
IE (2xR)
@ 15-min intervals
Observed effect(s)d
No effect on NPSH, G-6-PD, 6-PG-D, GRase,
Hb.
Spherocytosis.
Hb levels decreased. RBC enzymes: LDH in-
creased, G-6-PD increased, AChE decreased.
RBC fragility increased. All observed
effects were stress related (heat).
RBC fragility increased and serum vitamin E
increased in Canadians only. RBC enzymes:
AChE decreased in both groups.
Mild suppression PHA- induced lymphocyte
transformation. Questionable decrease in
PMN phagocytosis and intracellular killing.
No statistically significant depression in T-
lymphocyte rosette formation. B-lymphocyte
rosette formation with sensitized human
erythrocytes was depressed immediately after
but not 72 hr and 2 weeks after ozone
exposure.
No detectable cytogenetic effect.
RBC fragility increased. RBC enzymes: AChE
decreased; LDH increased in new arrivals.
Serum glutathione reductase increased in
new arrivals.
No. and sex
of subjects Reference
6 male DeLucia and Adams, 1977
e Brinkman et al. , 1964
20 male Linn et al. , 1978
2 female
(asthma)
2 male (Toronto) Hackney et al., 1977b
2 female (Toronto)
3 male (L.A.)
1 female (L.A.)
21 male Peterson et al. (1978a,b)
8 male Savino et al., 1978
26 male McKenzie et al., 1977
6 female (L.A.) Hackney et al., 1976
7 female (new arrival)
2 male (new arrival)

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TABLE 11-8.   HUMAN EXTRAPULMONARY EFFECTS OF OZONE EXPOSURE  (continued)
Ozone £
concentration Measurement '
ug/m3 ppm method
784 0.4 CHEM,
NBKI
; 784 0.4 CHEM,
; NBKI
1176 0.6
980 0.5 CHEM,
NBKI
i
i — >
o 980 0.5 CHEM,
NBKI
980 0.5 CHEM,
NBKI
980 0.5 CHEM,
NBKI
980 0.5 UV,
NBKI
Exposure
duration and
activity
4 days
4 hr/day
IE for two
15-min periods
4 days
4 hr/day
2 hr
IE for two
15-min periods
2.5 hr
IE (2xR)
@ 15-min intervals
± Vit E
2.5 hr
IE (2xR)
@ 15-min intervals
intervals
2.75 hr
IE (2xR)
@ 15-min intervals
4 days
2.5 hr/day
IE (2xR)
@ 15-min intervals
2 hr
IE (2xR)
@ 15-min intervals
Observed effect(s)
RBC G-6-PD increased. Serum vitamin E
increased. Complement C3 increased.
No detectable cytogenetic effects.
No significant effects.
No significant effects.
RBC fragility increased. RBC enzymes: LDH
increased, G-6-PD increased, AChE decreased,
GSH decreased. Serum: GSSRase decreased,
vitamin E increased, lipid peroxidation
levels increased.
Hb decreased after second exposure. RBC
enzymes: GSH decreased after second expo-
sure, 2,3-DPG increased and AChE decreased
with successive exposures. Levels tended
to stabilize with repeated exposure but
did not return to control values.
No effect on circulating lymphocytes.
No. and sex
of subjects
74 male
(divided into
four exposure
groups)
30 male
29 male
and female
9 male
28 female
7 male
6 male (Atopic)
31 male and
female
Reference
Chaney et al. , 1979
McKenzie et al. , 1982
Hamburger et al. , 1979
Posin et al. , 1979
Buckley et al. , 1975
Hackney et al . , 1978
Gueri crn et al. , 1979

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                                             TABLE 11-8.   HUMAN EXTRAPULMONARY EFFECTS OF OZONE EXPOSURE  (continued)
Ozone
concentration
ug/m3 ppm
980 0. 5
1176 0.6
1960 1.0
Measurement3 >b
method
MAST,
NBKI
CHEM,
NBKI
NO
Exposure
duration and
activity
6-10 hr
R
2 hr
IE for two
15-min periods.
10 min
Observed effect(s)
Frequency of chromatid aberrations increased
immediately following exposure with a peak
in number 2 weeks after exposure (not statis-
tically significant); no change in number
of chromosome aberrations.
Suppression to PHA- induced lymphocyte
transformation is questionable.
Decreased rate of cutaneous HbOj, desaturation
No. and sex
of subjects Reference
6 male and Merz et al. , 1975
female
16 male Peterson et al., 1981
e Brinkman and Lamberts, 1958
 Measurement method:  MAST = Kl-coulometric (Mast meter);  CHEM = gas-phase chemiluminescence;  UV = ultraviolet photometry; NO = not described.

 Calibration method:  NBKI = neutral buffered potassium iodide.

 Activity level:   R = rest; CE = continuous exercise;  IE = intermittent exercise;  minute ventilation (Vf) given in L/min or in multiples of resting
 ventilation.

 Abbreviations used:  NPSH = nonprotein sulfhydryl;  G-6-PD = glucose-6-phosphate  dehydrogenase;  6-PG-D = 6-phosphogluconate dehydrogenase; GRase = glutathione
 reductase; Hb = hemoglobin; RBC = red blood cell;  LOH = lactate dehydrogenase; AChE = acetylcholinesterase;  PHA = phytohemagglutinin; GSSRase = glutathione
 reductase; GSH = reduced' glutathione; 2,3-DPG = 2,3-diphosphoglycerate;  HbOj, = oxyhemoglobin; PMN = polymorphonucl ear leukocytes.
&
 Details not given.

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statistically significant changes (P < 0.05)  occurred in erythrocytes  and sera
of seven young adult men following exposure to 980 ug/m  (0.50 ppm) of 0_ for
2.75 hr.   Erythrocyte membrane fragility,  glucose-6-phosphate  dehydrogenase,
and  lactate  dehydrogenase enzyme  activities  increased, while  erythrocyte
acetylcholinesterase activity  and  reduced gluthathione levels  decreased.
Serum gluthathione activity decreased significantly,  while  serum vitamin E and
lipid peroxidation levels increased significantly.   These changes were transi-
tory and tended  to  disappear within several  weeks.   Although  these  changes
were significant, that  the  alterations were  such as  to modify physiological
systems or mechanisms is doubtful (see later  reports in Table 11-8).
     In the  most comprehensive  studies  to date  concerning the  cytogenetic
effects of inhaled 0_ in human subjects, McKenzie and co-workers have investi-
gated  both chromosome  and chromatid aberrations (McKenzie  et  al.,  1977) as
well as sister  chromatid exchange (SCE) frequencies (McKenzie, 1982).  Blood
samples from  26 normal male volunteers  were  collected before 0~ exposure;
immediately after exposure; and 3 days, 2 weeks,  and 4 weeks after exposure to
        3
784 ug/m  (0.4 ppm)  of  0.,  for 4 hr.   Each subject served as his  own  control
since  pre-exposure  blood samples were  collected.   A total  of 13,000  human
lymphocytes were  analyzed  cytogenetically.   One  hundred well-spread,  intact
metaphase plates  were  examined per subject per treatment time for chromosome
number, breaks, gaps, deletions, fragments, rings,  dicentrics, translocations,
inversions,  triradials,  and quadriradials.  The data indicated  no apparent
detectable cytogenetic  effect  resulting from exposure to 0~ under the condi-
tions of the experiments.
     In  later  studies,  McKenzie  (1982)  investigated the SCE  frequency,  in
addition to the number of chromosomal  aberrations in peripheral  lymphocytes of
                                  3
human subjects exposed to 784 ug/m  (0.4 ppm) of 0, for 4 hr on one day and on
                                        3
four consecutive  days,  or  to  1176 \ig/m   (0.6 ppm)  for 2  hr.   One hundred
metaphases per  blood sample per subject for  chromosome aberrations,  and 50
metaphases per  blood sample per subject were  analyzed for  SCEs.   Each study
was conducted on  10 to 30 healthy, nonsmoking human subjects.  No statistically
significant  differences  were observed in the  frequencies of numerical  aberra-
tions, structural aberrations, or SCEs between 03 pre-exposure and post-exposure
values.  The  nonsignificant differences were observed  at  all  concentrations
and  durations  tested,  and in the multiple exposures  as well as  in the  single
0.,  exposures.
  O

0190LG/A                            11-72                                 5/2/84

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     Chromosome  and  chromatid aberrations were  investigated  by  Merz et al.
                                                                  3
(1975) in  lymphocytes  collected  from subjects exposed to 980 |jg/m  (0.5 ppm)
of Do  for  6  to 10 hr.   Increases  in  the  frequency of chromatid aberrations
(achromatic  lesions  and chromatid  deletions)  were observed  in  lymphocytes
after  0_ exposure, with a peak in  the  number  of aberrations 2  weeks after
exposure.  No  increase  was observed in the number of chromosome aberrations.
While  these  results  suggest  human  genotoxicity after CL  exposure, the results
did  not  differ  significantly  from pre-03 chromatid aberration  frequencies
because of the small  number (six) of subjects investigated.
     Guerrero  et al.  (1979)  exposed 31 male and female  subjects to  filtered
air  followed on  a  second day by 2-hr exposure to  980 [jg/m   (0.5 ppm) of 0.,.
Subjects "lightly" exercised  15 min out of  every 30 min.  Blood  samples were,
unfortunately,  obtained only at the termination of  the exposures.   An SCE
analysis performed on  the  circulating lymphocytes  showed no  change in lympho-
cyte  chromosomes  in  either  condition.  However, SCE  analysis performed on
                                                                               •3
diploid human  fetal lung cells (WI-38) exposed to 0.0,  490,  1470, and 1960 ug/m
(0.0,  0.25,  0.75,  and  1.00 ppm)  of 03 for  1 hr  j_n vitro was  shown to have a
dose-related increase  in  SCEs.   The investigators suggested that the lack of
SCE  changes  in lymphocytes j_n vivo was attributable to the protective effect
of serum and/or another agent.
     Peterson  and  co-workers  conducted three studies designed to evaluate the
influence  of  0_  exposures on  leukocyte and lymphocyte function.  In 1978,
Peterson et al.  (1978a) evaluated  bactericidal  and phagocytic rates  in poly-
morphonuclear  leukocytes  from blood obtained before each exposure, 4 hr after
exposure, as well as  3  and 14 days post-exposure.  The 21 subjects were exposed
for  4  hr to  to 784 ug/m  (0.40 ppm) of 0,  at rest with  the  exception of two
15-min periods of  exercise (700 kgm/min, resulting in  a doubling of heart
rate).   The  phagocytic rate  and  intracellular  killing  of  respirable-size
bacteria (Staphylococcus  epidermis) was  significantly reduced 72 hr  after 0,
exposure.  No  significant effect  on  the phagocytic rate  or intracellular
killing was  observed  immediately  after 0_ exposure, or  at  2 weeks  after 0-
exposure.  The nadir of neutrophil  function was  observed at  72 hours after 0,,
exposure.  Since the neutrophil has an average lifespan  of 6.5 hr, the mecha-
nism by  which  0, produces an effect on the neutrophil  at 72 hr is  open to
speculation.   Ozone may produce indirect effects on neutrophils  through toxicity
to granulocytic  stem cells,  or by altering humoral factors  that facilitate
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phagocytosis.   A similar experimental protocol was used in a subsequent study
on 11 subjects with  the addition of a clean-air exposure with four subjects
(Peterson et al., 1978b).  The experimental description is confusing, because
variable numbers of  subjects were studied under different conditions.  In the
           3
0» 764-ug/m   (0.39-ppm) exposure (20 subjects),  lymphocyte  transformation
 •3
responses to  2 ug/ml and 20 ug/ml  of phytohemagglutinin  (PHA) in cultures
indicated significant (P < 0.01)  suppression to 2 ug/ml  of PHA in blood obtained
immediately post-exposure  but  no effects with  20 ug/ml of  PHA.   The data,
presented only in graphical  form,  suggested a wide variability  in response,
and consequently the significance of the observations may be minor.   A third
study was  conducted by  these  investigators (Peterson et al., 1981)  on  16
                             3
subjects exposed to  1176 ug/m  (0.6  ppm) of 03<  The protocol of rest, exercise,
and blood sampling  was  similar to that  used in their earlier  studies except
that one additional   blood sample was obtained at least 1 to 2 months after the
exposure.  The relative  frequency of lymphocytes in blood and the i_n vitro
blastogenic response of  the  lymphocytes  to  PHA, concanavalin A (con A), pole-
weed mitogen  (PWM),  and  Candida  albicans were  determined.  In  the  second- and
fourth-week blood samples,  a significant (P < 0.05) reduced response to  PHA
was observed.  No  other alterations in  function were observed.  The signifi-
cance of these findings remains somewhat tenuous.
     Savino et al.  (1978)  observed  that while peripheral blood  T-lymphocyte
rosette  formation  was  unchanged  following exposure of  human subjects to
784 ug/m3 (0.4 ppm)  0,  for 4 hr, B-lymphocyte rosette formation was signifi-
                      O
cantly  depressed.   Rosette  formation is an j_n vitro method that measures the
binding of antigenie red blood cells with surface membrane sites on lymphocytes.
Different antigenic  red cells are used to distinguish T from B lymphocytes.  A
normal  B-lymphocyte  response was restored by 72 hr after 03 exposure.
     Biochemical parameters  (erythrocyte fragility, hematocrit,  hemoglobin,
erythrocyte  glutathione,  acetylcholinesterase, glucose-6-phosphate  dehydro-
genase,  and  lactic  acid dehydrogenase)  were determined  in blood  obtained  from
subjects given  either vitamin E or a placebo  (Posin et al. , 1979).  Exposure
                                                    3
conditions were  filtered air on day 1  and 980 ug/m  (0.50 ppm)  03 on day 2;
2  hr  of exposure alternating  with  15 min  of  exercise  (double the resting
minute  ventilation)  and 15 min of  rest.   Vitamin E  intakes  for  nine or  more
weeks were  800 or  1600  III.   The  number  of subjects  and  the percent of men and
women differed in each  of the  three  studies  conducted.  No significant differ-
ences between the  responses of  the  supplemented and placebo groups to the  03
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exposure were  found for any  of  the  parameters measured.   Hamburger et al.
(1979) obtained blood  from the 29 subjects in one of the above three experi-
ments (800 IU vitamin E and placebo).  Blood was obtained before and after the
                                          3
2-hr exposures to filtered air or 980 ug/m  (0.5 ppm) of 0_.   No statistically
significant change in erythrocyte agglutinability by concanavalin A was found.
     In summary,  the overall  impression of  available human data  raises doubts
that cellular  damage  or altered function to  circulating  cells occurs as a
consequence of  exposure  to 0_ concentration under 980  to 1960 yg/m  (0.5 to
1.0 ppm).
11.7  PEROXYACETYL NITRATE
     Subjects exposed to peroxyacetyl nitrate (PAN) complain of eye irritation,
blurred vision,  eye  fatigue,  and of the compound's distinctive odor.  Smith
(1965) had  32  young  male subjects breathe orally  0.30  ppm  PAN for 5 min at
rest and continue to inhale this pollutant during a subsequent 5-min period of
light exercise.  Oxygen  uptake  during exercise was found to be statistically
higher while breathing PAN than  while breathing  filtered air.  These observa-
tions were  not  confirmed in  subsequent studies  (Table  11-9).  Gliner et al.
(1975) studied  10 young  men (22  to 26 years  of age) and nine older men (44  to
45 years) while they walked at 35 percent max V0? for 3.5 hr of a 4-hr exposure
to PAN.  The ambient conditions in the chamber  were either 25°C or 35°C dry
bulb at 30  percent  rh  and the PAN concentration was either 0.0 or 0.24 ppm.
Various measures of  cardiorespiratory  function were similar in both PAN and
filtered-air exposures.  A study of  16 older men  (40 to 57 years) breathing
0.27 ppm PAN for 40  min  found no changes  in oxygen uptake during light work
(Raven et al.,  1974a).
     The potential influence  of  PAN on V0?     was determined  in 20 young men
who undertook a 20-min progressive modified Balke test while inhaling 0.27 ppm
at ambient  conditions of either  25°C (Raven  et al. 1974b) or 37°C (Drinkwater
et al. , 1974).    Total exposure time was 40 min.  No alterations in cardiores-
piratory functions  or maximal aerobic capacity  due  to  the pollutants were
observed regardless  of the ambient temperatures.   Raven et al. (1974a) evalu-
ated  metabolic,  cardiorespiratory,  and body temperature responses  of  seven
middle-aged (40  to   57 years) smokers  and nine  nonsmokers  during  tests  of
maximal aerobic  power.   Ambient conditions were 25°C or 35°C  dry bulb and

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                                               TABLE 11-9.   ACUTE HUMAN EXPOSURE TO PEROXYACETYL NITRATE
 i
-^j
cr>
Concentration
ug/mj ppm
1187 0.24
1187 0.24
1336 0.27
1336 0.27
1336 0.27
1484 0.30
Exposure
duration and
activity
4 hr
IE (20-30) for
50 min of each hr.
4 hr
IE (20-30) for
50 min of each hr
40 min
IE (progressive) for
20 min
40 min
IE (progressive) for
20 min
40 min (mouthpiece)
IE (progressive) for
20 min
10 min (mouthpiece)
IE for 5 min
. No. and sex
Observed effect(s) of subjects
FVC decreased 4% in 10 young subjects after 19 male
exercise. No significant change in pulmonary
function in nine middle-aged subjects. No in-
teraction between exposure, temperature (25° &
35°C), or smoking habit.
No significant changes in submaximal work at 19 male
35% VOpmax in 10 young and nine middle-aged
subjects. No interaction between exposure
and temperature (25° & 35°C).
No significant change in V0~ x in young non- 20 male
smokers (n = 10) or smokers \n = 10) during
treadmill walk at 35°.
No significant change in V0~ in middle- 16 male
aged nonsmokers (n = 9) or sffloKers (n = 7)
during treadmill walk at 25°C and 35°C.
No significant change in V02 in 20 male
young nonsmokers (n = 10) or smokers
(n = 10) during treadmill walk at 25°C.
Oxygen uptake increased with exercise. 32 male
Maximum expiratory flow rate decreased
after exercise.
Reference
Raven et al. , 1976
Gliner et al. , 1975
Drinkwater, 1974
Raven et al. , 1974a
Raven et al. , 1974b
Smith, 1965
         Activity level:   IE = intermittent exercise; minute ventilation (VV) given in L/min.

         See Glossary for the definition of symbols.

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25 percent rh.  These  subjects  inhaled either filtered air or air containing
0.27 ppm PAN  for  40  min.   No effects of PAN were found.   Effects related to
age, smoking history, and ambient temperatures were as anticipated.
     In his studies  of young men orally inhaling 0.30 ppm PAN, Smith (1965)
found a small  reduction in MEFR following light exercise but no change in this
function during resting  exposures.   Raven  et al.  (1976) observed a small but
significant (4  to 7  percent) reduction in standing  FVC  in young men after
3.5 hr of light exercise (35 percent V00    ) during a 4-hr exposure to  0.24 ppm
                                       £ max
PAN.
     The interaction of PAN and CO was also evaluated in the series of studies
on  healthy young  and middle-aged  men  exercising on a  treadmill (Raven et al.,
1974a, 1974b;  Drinkwater et al., 1974; Gliner et al., 1975).   Both smokers and
nonsmokers were exposed to 0.27 ppm PAN and 50 ppm CO.  No interactions  between
CO  and  PAN  were found.  Metabolic, body temperature,  and cardiorespiratory
responses of  healthy middle-aged  men,  nine smokers and seven  nonsmokers, were
obtained during tests  of maximal  aerobic power (max V^p) at ambient tempera-
tures of 25°C and 35°C, rh = 20 percent (Raven et al., 1974a).  These subjects
were randomly exposed  for  40 min in an environmental chamber to  each of four
conditions,  i.e.,  filtered  air, 50  ppm  CO, 0.27 ppm  PAN,  and  a combination  of
50 ppm of CO  and  0.27  ppm of PAN.  Carboxyhemogl obi n  was measured in these
subjects.   There was no significant change in maximal aerobic power related to
the presence  of  these  air  pollutants, although total  exercising time  was
lowered in the  25°C  environment while exposed to CO.  A decrement in max VQ2
was found in  middle-aged smokers breathing 50 ppm of CO.  Another study con-
ducted under  similar pollutant  conditions  at an ambient temperature of  35°C,
20 percent rh was  carried  out on 20  young male subjects (10 smokers and 10
nonsmokers)  (Drinkwater et al.,  1974).  Maximal aerobic power was not affected
by  any pollutant  condition.   Exposure to CO was effective in reducing  work
time of the  smokers.   The same subjects were also involved in a study conducted
at  25°C, 20 percent  rh under similar pollutant conditions  except that  they
inhaled the pollutants  orally for 40 min (Raven et al. , 1974b).   Exposure to
the two pollutants singly or in combination produced only minor,  nonsignificant
alterations  in  cardiorespiratory  and  temperature  regulatory parameters.   The
influence of  PAN  and CO, singly or in combination, was evaluated in 10  young
(22 to 26 years) and nine middle-aged (45 to 55 years) men performing submaxi-
mal work (35 percent max V-?) for 210 min (Gliner et al., 1975).   Five subjects

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in each  age group were  smokers.   Studies were conducted  at  two different
ambient  temperatures,  i.e.,  25°C  and  35°C,  rh 30 percent.   The pollutant
concentrations were  0.25 ppm of  PAN  and 50 ppm of CO.   Two  physiological
alterations were  reported.   Stroke volume decreased  during  long-term work,
being enhanced in the higher ambient temperatures.   Heart rate was significant-
ly (P <0.05) higher when exercise was being performed  during the CO exposures.
No other alterations were found in relation to the pollutants.   There were  no
differences in response related to age.

11.8  SUMMARY
     A number of  important  controlled  studies  discussed in this chapter have
reported significant  decrements  in pulmonary  function associated  with 0,
                                                                          O
exposure (Table 11-10).  Results from studies of at-rest exposures  to 0^ have
                                                                        O
demonstrated decrements  in  forced  expiratory  volumes  and  flows  occurring  at
                   3
and above 980 ug/m  (0.5 ppm) of 03 (Folinsbee et al., 1978;  Horvath et al.,
1979).   Airway resistance is not clearly affected at  these 0Q concentrations.
                     3
At or below  588  ug/m  (0.3  ppm) of 0~, changes in pulmonary  function do not
occur during at rest exposure (Folinsbee et al., 1978), but the  occurrence  of
some 03 pulmonary symptoms has been suggested  (Kb'nig et al. ,  1980).
     With moderate intermittent exercise at a  VV  of 30 to 50 L/min,  decrements
in forced expiratory  volumes  and  flows have been  observed at and above 588
    3
ug/m  (0.30  ppm)  of  03  (Folinsbee et al. ,  1978).   With heavy  intermittent
exercise (VV = 65 L/min), pulmonary symptoms  are present  and decrements  in
forced expiratory volumes and flows are  suggested  to occur following  2-hr
exposures to 235  ug/m   (0.12 ppm) of 03  (McDonnell et al. , 1983).   Symptoms
are present and decrements  in forced expiratory volumes and flows definitely
                        3
occur at 353 to 470 ug/m  (0.18 to 0.24 ppm)  of 0., following 1 hr of continuous
very heavy exercise  at a VV of 80  to  90 L/min  (Adams and Schelegle, 1983;
Folinsbee et al.,  1984) and  following 2 hr of  intermittent heavy exercise at a
VF of 65 L/min (McDonnell et al.,  1983).   Airway resistance is only modestly
                                                                             3
affected even with heavy exercise while exposed at levels as high as 980 ug/m
(0.50 ppm) 03 (Folinsbee et al., 1978; McDonnell et al., 1983).   Increased  fR
and decreased VT,  while  maintaining the same VP, occur with  prolonged  heavy
               i                        ,      t
exercise when exposed  at 392 to 470 ug/m   (0.20 to 0.24 ppm)  of 03  (McDonnell
et al. ,  1983; Adams  and Schelegle, 1983).  While an  increase in RV has been
                                             3
reported to result from exposure to 1470 ug/m   (0.75 ppm) of 0^  (Hazucha et al.
                                                                            3
1973), changes in RV  have not been observed following exposures to 980 ug/m
0190LG/A                           11-78  .                              5/2/84

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                                                     TABLE 11-10.   SUMMARY TABLE:  CONTROLLED  HUMAN  EXPOSURE  TO OZONE
c Exoosure
ug/i^
HEALTHY
627
1960
980
980
1470
ppm method duration
ADULT SUBJECTS AT REST
0.32 MAST, NBKI 2 hr
1.0
0.5 CHEM, NBKI 2 hr
0.50 CHEM, NBKI 2 hr
0.75
Activity
level (V,) Observed effects(s)

R Specific airway resistance increased with
acetylcholine challenge; subjective symptoms
in 3/14 at 0.32 ppm and 8/14 at 1.0 ppm.
R (10) Decrement in forced expiratory volume and
flow.
R (8) Decrement in forced expiratory volume and
flow.
No. and sex
of subjects Reference

13 male Konig et al . , 1980
1 female
40 male Folinsbee et al . ,
(divided into four 1978
exposure groups)
8 male Horvath et al . ,
7 female 1979
EXERCISING HEALTHY ADULTS
235
353
470
588
784
392
686
0.12 CHEM, UV 2.5 hr
0.18
0.24
0.30
0.40
0.20 UV, UV 1 hr
0.35 (mouth-
piece)
IE (65) Decrement in forced expiratory volume and
@ 15-min intervals flow suggested at 0.12 ppm with larger
decrements at > 0.18 ppm; respiratory
frequency and specific airway resistance
increased and tidal volume decreased at
> 0.24 ppm; coughing reported at all
concentrations, pain and shortness of
breath at £ 0.24 ppm.
IE (77.5) @ vari- Decrement in forced expiratory volume and
able competitive flow with IE and CE; subjective symptoms
intervals increased with 03 concentration and may
CE (77.5) limit performance; respiratory frequency
increased and tidal volume decreased with
CE.
135 male McDonnell et al.,
(divided into six 1983
exposure groups)
10 male Adams and Schelegle,
(distance runners) 1983

-------
 I
00
o
                                               TABLE 11-10.   SUMMARY TABLE:   CONTROLLED HUMAN EXPOSURE TO OZONE  (continued)
Ozone3
concentration Measurement >c Exposure Activity
ug/m3 ppm method duration level (V£)
392
823
980
412
588
980
0.2 UV, UV 2 hr
0.42
0.50
0.21 UV, UV 1 hr
0.3 CHEM, NBKI 2 hr
0.5
IE (30 for male,
18 for female
subjects)
@ 15-min intervals
CE (81)
R (10). IE (31,
50, 67)
@ 15-min intervals
Observed effects(s)
Repeated daily exposure to 0.2 ppm did not
affect response at higher exposure concen-
trations (0.42 or 0.50 ppm); large inter-
subject variability but individual
pulmonary function responses were highly
reproducible.
Decrement in forced expiratory volume and
flow; subjective symptoms may limit per-
formance.
Decrement in forced expiratory volume and
flow; the magnitude of the change was
related to 03 concentration and Vr-
No. and sex
of subjects
8 male
13 female
6 male
1 female
(distance cyclists)
40 male
(divided into four
exposure groups)
Reference
Gliner et al. , 1983
Folinsbee et al. ,
1984
Folinsbee et al . ,
1978
                                                    capacity decreased with IE (50,  67);  no
                                                    change in airway resistance or residual
                                                    volume even at highest IE (67).   No
                                                    significant changes in pulmonary function
                                                    were observed at 0.1 ppm.
     725    0.37
     980    0.50
    1470    0.75
MAST, NBKI      2 hr
R (11) & IE (29)
@ 15-min intervals
Good correjation between dose (concen-
tration x Vp) and decrement in forced
expiratory volume and flow.
20 male
8 female (divided into
six exposure groups)
Silverman et al.,
1976
     784
            0.4
                      UV,  NBKI
                2 hr
                              IE (2xR)
                              @ 15-min intervals
                      Specific airway resistance increased with
                      histamine challenge;  no changes were
                      observed at concentrations of 0.2 ppm.
                                                                                                                          12  male
                                                                                                                          7 female
                                                                                                                          (divided  into three
                                                                                                                          exposure  groups)
                                                                         Dimeo et al.,  1981
     784
            0.4
                      CHEM,  NBKI  &    3 hr
                      MAST,  NBKI
                              IE (4-5xR)
                      Decrement in forced expiratory volume was
                      greatest on the 2nd of 5 exposure days;
                      attenuated response by the 4th day of
                      exposure.
                                                10 male
                                                4 female
                         Parrel!  et al.,  1979

-------
TABLE 11-10.   SUMMARY TABLE:   CONTROLLED HUMAN EXPOSURE TO OZONE  (continued)
   Ozone
concentration    Measurement >c    Exposure         Activity
M9/""3   ppm         method         duration         level  (V£)
                                       Observed effects(s)
                                                     No. and sex
                                                     of subjects
                                                                                                                                                   Reference
784    0.4       CHEM, NBKI      3 hr
     IE (4-5xR)
     for 15 min
Decrement in forced expiratory volume was
greatest on the 2nd of 5 exposure days;
attenuation of response occurred by the
5th day and persisted for 4 to 7 days.
Enhanced bronchoreactivity with
roethacholine on the first 3 days;
attenuation of response occurred by
the 4th and 5th day and persisted
for > 7 days.
                                                                                                                     13 male
                                                                                                                     11 female
                                                                                                                     (divided into two
                                                                                                                     exposure groups)
                                                                                                                                               Kulle et a!.,  1982b
>-> 823 0.42 UV, UV
oo
I—1
921 0.47 UV, NBKI
1176 0.6 UV, NBKI
1470 0.75 MAST, NBKI
2 hr IE (30)
2 hr IE (3xR)
2 hr IE (2xR)
(noseclip) @ 15-min intervals
2 hr IE (2xR)
@ 15-min intervals
Decrement in forced expiratory volume and
flow greatest on the 2nd of 5 exposure
days; attenuation of response occurred by
the 5th day and persisted for < 14 days with
considerable intersubject variability.
Decrement in forced expiratory volume and
flow greatest on the 2nd of 4 exposure
days; attenuation of response occurred by
the 4th day and persisted for 4 days.
Specific airway resistance increased in 7
nonatopic subjects with histamine and
methacholine and in 9 atopic subjects
with histamine.
Decrements in spirometric variables
(20%-55%); residual volume and closing
capacity increased.
24 male
8 male
3 female
11 male
5 female (divided
by history of atopy)
12 male
Horvath
Linn et
Holtzman
1979
Hazucha
1973
et al . . 1981
al . , 1982b
et al. ,
et al. ,

-------
                                          TABLE 11-10.  SUMMARY TABLE:  CONTROLLED HUMAN EXPOSURE TO OZONE  (continued)
Ozone3
concentration Measurement Exposure
ug/m3
ppm method duration
Activity
level (VJ
Observed effects(s)
No. and sex
of subjects
Reference
ASTHMATICS
392
490
0.2 CHEM, NBKI 2 hr
0.2S CHEM, NBKI 2 hr
IE (2xR)
@ 15-min intervals
R
No significant changes in pulmonary func-
tion. Small changes in blood biochemistry.
Increase in symptom frequency reported.
No significant changes in pulmonary func-
tion.
20 male
2 female
5 males
12 female
Linn et al . , 1978
' Silverman, 1979
SUBJECTS WITH CHRONIC OBSTRUCTIVE LUNG DISEASE
_ 235
h—"
1
co
ro
353
490
392
588
784
0.12 UV, NBKI 1 hr
0.18 UV, NBKI 1 hr
0.25
0.2 CHEM, NBKI 2 hr
0.3
0.41 UV, UV 3 hr
IE (variable)
@ 15-min intervals
IE (variable)
@ 15-min intervals
IE (28) for
7.5 min each
half hour
IE (4-5xR)
for 15 min
No significant changes in forced expiratory
performance or symptoms. Decreased arterial
oxygen saturation during exercise was
observed.
No significant changes in forced expiratory
performance or symptoms. Group mean arterial
oxygen saturation was not altered by 03
exposure.
No significant changes in pulmonary function
or symptoms. Decreased arterial oxygen
saturation during exposure to 0.2 ppm.
Small decreases in FVC and FEV3.0.
18 male
7 female
15 male
13 female
13 male
17 male
3 female
Linn et al. , 1982a
Linn et al . , 1983
Solic et al. , 1982
Kehrl et al. , 1983
Kulle et al. , 1984
Ranked by lowest observed effect level.
Measurement method:  MAST = Kl-Coulometric (Mast meter); CHEM = gas phase chemiluminescence; UV = ultraviolet photometry.
Calibration method:  NBKI = neutral buffered potassium iodide; UV = ultraviolet photometry.
Minute ventilation reported in L/min or as a multiple of resting ventilation.   R = rest; IE = intermittent exercise; CE = continuous exercise.

-------
(0.50 ppm)  of 0» or less, even with heavy exercise (Folinsbee et al., 1978).
Decreases  in  TLC and 1C have  been  observed  to result from exposures to 980
ug/m  (0.50 ppm) of 0, or less, with moderate and heavy exercise (Folinsbee et
al. , 1978).
     Group  mean  decrements  in pulmonary function can  be  predicted  with  some
degree  of  accuracy  when expressed as a function of effective dose of 0~, the
simple  product  of  0- concentration, VV, and  exposure  duration  (Silverman  et
al., 1976).   The relative contribution  of  these variables to  pulmonary decre-
                                                *
ments is  greater for 0-  concentration than for VF,  which  is greater than that
for exposure duration.   A greater degree of predictive accuracy is obtained if
the contribution  of these  variables is appropriately  weighted  (Folinsbee  et
al., 1978).   However,  several  additional  factors make the interpretation  of
prediction  equations more  difficult.   There  is  considerable intersubject
variability in  the  magnitude  of  individual pulmonary function responses  to  0^
(Horvath et al., 1981;  Gliner  et al, 1983; McDonnell et al., 1983).    Individual
responses to a given 0- concentration have been shown to  be quite reproducible
(Gliner et al., 1983; McDonnell et al., 1984),  indicating  that some individuals
are consistently more  responsive to 0- than  are  others.   No  information is
available to account for these differences.  Considering  the great variability
in  individual  pulmonary  responses  to 0_ exposure,  prediction equations  that
only use some form of effective dose are not adequate for  predicting  individual
responses to 0,.
     In addition to overt changes  in pulmonary  function,  enhanced nonspecific
bronchial reactivity has been  observed following exposures to 0~ concentrations
                   3                                                       3
as  low  as  588 ug/m  (0.3 ppm) (Konig et  al.,  1980).   Exposure to 392 |jg/m
(0.2 ppm)  of  0-  with intermittent light exercise does not affect nonspecific
bronchial reactivity (Dimeo et al., 1981).
     Changes in forced expiratory volumes 'and flows resulting from 0,, exposure
                                                                    O
reflect reduced maximal inspiratory position (inspiratory  capacity)  (Folinsbee
et  al., 1978).   These  changes, as well  as  altered ventilatory control and the
occurrence of  respiratory symptoms,  most  likely result from sensitization or
stimulation of airway  irritant receptors (Folinsbee et al. , 1978; Holtzman  et
al., 1979; McDonnell et al., 1983).   The increased airways resistance observed
following 03 exposure  is probably initiated by  a similar  mechanism; a modula-
tion of this  pathway,  however, has been proposed to account  for the  lack of
0190LG/A                           11-83                                5/2/84

-------
correlation between  individual  changes in SR    and  FVC (McDonnell et al.  ,
                                             aW
1983).   The increased responsiveness of airways to histamine and methacholine
following 0,,  exposure  most  likely  results from an 0_-induced  increase  in
airways permeability or  from an  alteration of  smooth muscle characteristics.
     Decrements in pulmonary function were not  observed for asthmatic  subjects
exposed for  2 hours at  rest (Silverman,  1979) or with  intermittent  light
exercise (Linn et al. , 1978) to 0, concentrations of 490 ug/m   (0.25 ppm)  and
less.   Although this result  indicates  that asthmatics are not more sensitive
to 0-  than are normal subjects,  experimental-design considerations  in  reported
studies suggest that this  issue  is  still  unresolved.   For patients with  COLD
performing light to moderate intermittent  exercise,  no decrements in pulmonary
function are  observed  for  1-  and 2-hr exposures  to  03 concentrations of
588 ug/m3 (0.30 ppm) and less  (Linn et al.,  1982a;  Solic et al., 1982; Kehrl
et al., 1983;  Linn et al.,  1983)  and only  small decreases in forced expiratory
                                                  3
volume are observed  for  3-hr exposures to 804  ug/m  (0.41 ppm)  (Kulle  et al.,
1984).   Small  decreases  in SaO~  have also  been  observed, but interpretation of
these  decreases and their clinical significance is  uncertain.
     Many variables have not been adequately addressed in the available clini-
cal data.  Information derived  from 0- exposure of smokers and nonsmokers  is
sparse and  somewhat inconsistent,  perhaps  partly  because  of undocumented
variability in smoking histories.   Although some degree of attenuation appears
to occur in  smokers,  all current results  should be interpreted with caution.
Further and more  precise studies  are required  to answer the complex problems
associated with personal  and ambient pollutant  exposures.  While a few studies
have investigated  sex  differences,  they  have  not  conclusively demonstrated
that men and women respond differently to  03, and consideration of differences
in pulmonary capacities  have not been adequately taken into account.  Environ-
mental conditions  such as  heat  and relative humidity  may enhance  subjective
symptoms and  physiological  impairment  following 0- exposure, but the results
so far  indicate  that the effects are no more than  additive.  Other variables
such as  seasonal  effects and age, particularly  the very young  and the aged,
need to  be  considered.   In addition, there  may  be  considerable interaction
between  these  variables  that may result  in  modification of interpretations
made based on available   information.
     During repeated daily  exposures  to 0~, decrements  in pulmonary function
are greatest on the second exposure day (Farrell et al. , 1979; Horvath et al.,

0190LG/A                           11-84                                5/2/84

-------
1981; Kulle  et  al. ,  1982b;  Linn  et  al.,  1982b);  thereafter,  pulmonary  respon-
siveness to  03  is attenuated with  smaller  decrements  on  each  successive  day
than  on  the day  before  until  the fourth or  fifth  exposure  day when small
decrements or no changes are observed.  Following a sequence of repeated daily
exposures,  this attenuated pulmonary  responsiveness  persists for 4  (Kulle
et al., 1982b;  Linn et al., 1982b) to 7 (Horvath et al., 1981) days.   Repeated
daily exposures to a given low effective dose of CL does not affect the magni-
tude  of decrements  in  pulmonary function resulting from exposure at a higher
effective dose  of 0  (Gliner et al., 1983).
                   <3
     There is some evidence suggesting that exercise performance may be limited
by exposure  to  03-   Decrements in  forced  expiratory  flow occurring with 0~
exposure  during prolonged heavy exercise  (Vp =  65  to 81 L/min) along with
increased fR and decreased V,. might be expected to produce ventilatory limita-
tions at  near  maximal  exercise.   Results from exposure to ozone during high
exercise levels (68 to 75 percent of max VO^) indicate that discomfort associ-
ated with maximal  ventilation  may be an important factor in limiting perfor-
mance (Adams and  Schelegle, 1983; Folinsbee et al., 1984).   However, there is
not enough data available to adequately address this issue.
     No consistent cytogenetic or functional changes have been demonstrated in
circulating  cells  from  human subjects  exposed to  0, concentrations as  high as
                3
784 to 1176 (jg/m  (0.4 to 0.6 ppm).   Chromosome or chromatid aberrations would
therefore be unlikely at lower 0., levels.   Limited data have indicated that 03
can interfere with  biochemical  mechanisms  in blood erythrocytes and sera but
the physiological significance of these studies is questionable.
     No significant  enhancement  of  respiratory effects has been consistently
demonstrated for  combined exposures of 03 with SOp, N02,  and sulfuric  acid or
particulate  aerosols or  with multiple  combinations  of  these pollutants.   Most
of the available  studies with  other photochemical oxidants have been limited
to a series of  studies on the effects of peroxyacetyl  nitrate (PAN) and carbon
monoxide  (CO)  on healthy young  and middle-aged  males during intermittent
exercise on  a treadmill.  No significant effects  were  observed  at  PAN  concen-
trations of  0.25  to  0.27 ppm, which are  higher than the daily maximum  concen-
trations of  PAN reported for  relatively high oxidant areas (0.037 ppm).   Two
additional studies at 0.24 and 0.30 ppm of PAN suggested a possible limitation
on forced expiratory volume and flow but there are not enough data to evaluate
the significance  of  this effect.   Further  studies  are  also  required on the
more complex mix of pollutants  found in the natural  environment.
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-------
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Guerrero, R.  R. ;  Rounds,  D.  E.;  Olson,  R.  S.;  Hackney,  J.  D.  (1979) Mutagenic
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        12.  FIELD AND EPIDEMIOLOGICAL STUDIES OF THE EFFECTS OF OZONE
                       AND OTHER PHOTOCHEMICAL OXIDANTS
12.1  INTRODUCTION
     This  chapter  critically assesses  field  and epidemiological  studies of
health effects linked to ambient air exposure to ozone and other photochemical
oxidants.  In order to characterize the nature and extent of such effects, the
chapter  (1) delineates  types  of health effects associated with ambient ozone
or  photochemical  oxidant exposures;  (2)  attempts  to determine quantitative
relationships  between  exposures to  these agents and observed effects;  and
(3) identifies population  groups at greatest risk  for  such health effects.
Studies of both acute and chronic exposure effects are discussed.
     Many  of  the available  epidemiological  studies  used  exposure data or
health endpoint measurements inadequate or unreliable for quantifying exposure-
effect relationships.   Also,  results from these studies have often been con-
founded by factors such as variations in activity levels and time spent out of
doors, cigarette smoking,  poor hygiene, coexisting  pollutants, weather,  and
socioeconomic status.   Thus,  selection  of those studies thought  to be most
useful in  attempting  to derive health  criteria  for  ozone  or oxidants is of
critical  importance.  To  judge the relative scientific  quality of  epidemio-
logical  studies  for  standard-setting purposes,  the  following  guidelines  (as
modified from  U.S.  Environmental  Protection  Agency, 1982) were set  forth:

     o    The aerometric data  are  adequate to characterize geographic or
          temporal   differences in pollutant  exposures  of  study  popula-
          tions  in  the range(s)  of pollutant  concentrations  evaluated.
     o    The study populations  are  well  defined and allow for statisti-
          cally adequate comparisons  between  groups or temporal  analyses
          within groups.
     o    The  health  endpoints  are  scientifically plausible  for  the
          pollutant being  studied; and the measurement  methods  are ade-
          quately characterized and implemented.
     o    The  statistical   analyses  are  appropriate  and  properly per-
          formed,  using  data  subjected   to  adequate  quality  control.
     o    Potentially  confounding  or   covarying  factors are  adequately
          controlled for or taken into account.
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     o    The reported findings  are  internally coherent and biologically
          plausible.

     For present purposes,  greatest  emphasis is placed here on discussion of
studies  that provide useful  information on  exposure-effect  or exposure-
response relationships associated with  ambient air levels of ozone or photo-
chemical oxidants  likely to occur in  the United States  during  the  next 5
years.   Accordingly, the  following additional guidelines were used to select
studies  for  detailed discussion:  (1)  the  results provide  information on
quantitative  relationships  between health effects and ambient  air ozone or
oxidant concentrations with  emphasis  on concentrations less than or equal to
0.5 ppm (measurement methods and calibrations are reported when available) and
(2) the report has been  peer reviewed and is in the open literature or is in
press.   Some  studies not  meeting the above  guidelines but  considered to be
sources  of  additional  supportive information are also summarized  below and
their limitations noted.
12.2  FIELD STUDIES OF EFFECTS OF ACUTE EXPOSURE
     Field studies  of symptoms and pulmonary  function combine features of
controlled human exposure  studies  (Chapter 11) and epidemiological studies.
These studies employ the more rigorous methods and better experimental  control
typical of controlled  exposure  studies with observations made  in  the  field
(Morris, 1970; Mausner and Bahn, 1974; American Thoracic Society,  1978; World
Health Organization, 1983, 1984).   Some  attempt to mimic chamber  conditions
but include  exposures  of  subjects  to  ambient air containing the pollutant(s)
of interest  as well as exposures to clean  air  as a control.  They  thus  form  a
bridge or continuum between studies discussed in Chapter 11 and epidemiological
studies assessed here.

12.2.1  Symptoms and Pulmonary Function in General  Field Conditions
     Some early studies of symptoms and pulmonary function under field oxidant
exposure conditions were  previously reviewed by the Environmental  Protection
Agency (1978).  For example,  Richardson and Middleton (1957, 1958)  studied eye
irritation in subjects under both air-filtration and nonfiltration  conditions.
They reported increased complaints to  be associated with oxidant concentrations


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of 0.1 ppm, measured by the potassium iodide (KI) method, but not with nitrogen
dioxide (N0?) or suspended particles.
     Balchum (1973) reported  an  expansion of a  study by Remmers and Balchum
(1965).  Pulmonary function changes were observed in 15 patients with moderately
severe chronic obstructive  lung  disease (COLD), who spent one week in a room
without air  filtration and  a  second  week  in a room with  filtered air.   In the
unfiltered room, mean daily oxidants (KI  method) averaged 0.11 ppm and  ranged
up to 0.2 ppm,  but ranged from 0.02 to 0.03 ppm in the filtered room.   Decreases
in airway  resistance  and increases  in  arterial  partial  pressure of oxygen
(PaOp) appeared in both smokers and nonsmokers after 48 hours in filtered air,
both when  at rest  and during exercise  in about  75 percent of subjects.  Re-
examination of the 1965 data by Ury and Hexter (1969) showed airway resistance
decreases to be more strongly correlated wi^h oxidant concentrations than with
either N02 or nitric oxide  (NO) levels.
     More  recent field  studies  of pulmonary function have employed pre- and
post-exercise function measurements  (often used in controlled human exposure
studies) in  comparing the  effects  of  short-term exposures  to  ambient air
containing ozone and  oxidants versus clean air  (sham control) exposures.  For
example, in  a  series  of studies carried out in a mobile laboratory, Linn and
coworkers  have  shown  pulmonary  function  decrements to  be  associated with
exposure of  Los  Angeles  area residents to ambient  air  containing ozone and
other  photochemical oxidants.   The  subject characteristics and experimental
conditions employed in  different studies  by Linn and collaborators are  sum-
marized in Table 12-1 and associated pollutant levels in Table 12-2.
     Linn  et al.  (1980,  1983) evaluated  30 asthmatic and 34  normal subjects
exposed to ambient and purified air in a mobile laboratory in Duarte, CA (near
Los Angeles) during two  periods separated by 3  weeks.   Only  5  subjects  were
smokers, and the two  groups  were similar in  age,  height,  and sex ratio.
Asthmatic  subjects had  heterogeneous disease characteristics, determined by
questionnaire responses.  Of  the "normal" group, 25 subjects were considered
allergic based on  a  history of upper respiratory allergy or reported undiag-
nosed  wheeze which they called  "allergic."   Ozone,  nitrogen oxides  (NO ),
                                                                         /\
sulfur dioxide (S0?),  sulfates,  and total suspended particulate matter (TSP)
were monitored inside and outside the chamber at 5-min  intervals, and  valida-
tion studies were  performed at the mobile laboratory.   Measurements of 0,, by
the ultraviolet  (UV)  method were calibrated against California Air Resources

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                TABLE 12-1.   SUBJECT CHARACTERISTICS  AND  EXPERIMENTAL  CONDITIONS
                              •  OF THE  MOBILE  LABORATORY  STUDIES
Subjects
Number
%Males
%Asthmatics
%Smokers
Age6
Height, cm
Weight, kg
Exercise
Exposure time
Location
Atmosphere
1978a
64
41
47
8
30110
170110
70114
light intermittent
2 hr. (p.m. )
Duarte
oxidant
1979b
64
41
33
22
34111
170112
69+16
light intermittent
2 hr. (a.m.)
Hawthorne
primary pollutant
1980C
60
75
12
13
30111
173+15
69110
heavy continuous
1 hr. (p.m. )
Duarte
oxidant
1981
98
58
51
7
28±8
172+9
67111
d







heavy continuous
1 hr. (p.m
Duarte
oxidant
. )


 Linn et al.  (1980,  1983).
bLinn et al.  (1982,  1983).
cLinn et al.  (1983), Avol  et al.  (1983).
dLinn et al.  (1983).
eMean + standard deviation.
        TABLE 12-2.   POLLUTANT LEVELS (MEAN 1 S.D.)  MONITORED INSIDE A MOBILE LABORATORY
                                  DURING AMBIENT AIR EXPOSURES
Subjects
03 (ppm)e
S02 (ppm)
N02 (ppm)
CO (ppm)
Parti cul ate:
Total (ug/m3)
S04_(Mg/m3)
N03 (tag/m3)

19783
. 174+ . 068
.0121 .003
.069+ .014
2.9

182
1§

1 1.1

+42
1 7


1979b
. 022+ . Oil
. 0181 . 099
.056+ .033
1.6

112
13
19
1 0.9

145
1 6
+10

1980°
.165+ .059
.099+ .005
.050+ .028
3.1

227
17
22
1 2.0

+76
112
1 9

1981d
.156+ .055
.005+ .033
.062+ .023
2.2

166
9
32
1 0.7

±52
1 4
±10
aLinn et al.  (1980, 1983).
bLinn et al.  (1982, 1983).
cLinn et al.  (1983), Avol  et al.  (1983).
dLinn et al.  (1983).
eUltraviolet photometer calibration method.
 Measurements unsatisfactory due to artifact nitrate formation on filters.
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Board (CARB) reference  standards  and corrected to those  obtained  by the KI
method.   The mobile  laboratory  has been described previously  (Avol  et al.,
1979), as  have the  methods  for  studies of  lung function.   Lung  function
measures before and  after exposure were compared by t-tests and nonparametric
methods.   Intermittent  periods  of exercise were combined with the exposure.
     Ozone and particulate pollutants predominated in the ambient air mixture,
as shown  in Table 12-1  for the  1978  Duarte study.  Ozone  levels (corrected  to
                                  3
the  KI  method) averaged 427 pg/m  (0.22 ppm)  inside the mobile laboratory
                     3
chamber and  509 p.g/m  (0.26  ppm)  outside the  laboratory  during  ambient air
                        3
exposures, and 7.8 (jg/m (0.004 ppm) during purified  air  exposures.  Matching
                                                         3
peak 0~ concentrations, respectively, were 498 ± 186 pg/m  (0.025 ± 0.10 ppm);
597 ± 217 pg/m3 (0.31 ± 0.11 ppm); and 19 ± 17 pg/m3  (0.01 ± 0.009 ppm).  TSP
                        3                                3
levels averaged 182 pg/m  inside the chamber and 244 pg/m  outside the labora-
                                                3
tory  during  ambient  air exposures,  but 49 pg/m   inside the chamber during
purified-air exposures.  Average  NOp,  S0»,  CO, and sulfate levels inside the
chamber were uniformly low during ambient-air exposures (as shown in Table 12-1)
and were  even  lower  during purified-air exposures (i.e., 0.015 ppm  for  NO  •
0.009 ppm for S0?; 2.8 ppm for CO; 0.9 ppm for sulfates).   Gases were monitored
continuously, alternatively inside and outside the mobile laboratory for 5-min
periods.   Particles were measured during testing inside and outside the labora-
tory.  Temperature and humidity were controlled inside the laboratory.
     During the  exposure studies  (Tuesday through  Friday),  four subjects
(maximum) were tested  sequentially in the morning at 15-min intervals,  each
first breathing purified air at rest followed  by "pre-exposure" lung-function
tests.  Ambient-air chamber tests were performed in the early afternoon (after
masking odors  by  a  brief outside exposure).   The ambient-air exposure period
lasted 2  hr  (and  included  exercise on bicycle  ergometers  for the first 15 min
of each half-hour),  followed  by "post-exposure" lung function testing during
continuing ambient-air  exposure.   Ergometer  workloads ranged from 150 to 300
kg-m/min  and were  sufficient  to approximately double the respiratory  minute
ventilation  relative to resting  level.   The purified-air control  study for
each  subject took  place at least three weeks  after  the ambient-air  exposure
session,  with  identical  procedures except for purified-air  in  place of the
ambient.   Note that Linn et al.  (1980, 1983) also separately tested 12 healthy
subjects  from  the  project  staff  in  order  to validate various  aspects  of the
study.  The validation tests indicated insignificant variability in the measure-
ment methods for healthy normal  subjects.
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     In the main  set  of experiments $  The asthmatic group experienced greater
changes from baseline  in residual volume (RV) and peak flow measurements with
exercise than  did the  "normals,"  based on data adjusted  for  subject age,
height, and weight.   The  magnitude of these changes  did not  correlate with
age.  Both groups  showed  similar changes in most of  the other lung-function
measurements.    Regression  analysis showed  no  significant associations  of
functional  changes with TSP, total  sulfate, total NH3, or  NO™.  Increasing  0_
was correlated with decreasing  peak flow and 1-sec forced expiratory  volume
(FEV ).  No explanation was  given for an association of increasing CO with
increasing RV and  with the slope of the alveolar plateau (SBNT).   Increasing
SQy was significantly  associated with increasing RV  and total lung  capacity
(TLC).   In multiple regression  analysis, 0~ was the variable contributing the
most variation  in  FEV, and maximum expiratory flow (V   75%^' as we^ as  in
the FEV, normalized for forced  vital  capacity (FEV.,/FVC%), TLC, and  pulmonary
resistance (R )  in the normal/allergic  group.  Although  other pollutant vari-
ables  contributed  to  the  observed effects, none did  so  consistently.  Apart
from 0_,  functional  changes on  control  days  (intraindividual  variability),
smoking habits, and age appeared to explain the functional changes in normals/
allergies during  exposure.   In  asthmatics,  all pollutant variables  except TSP
were significant  in one or more analyses,  but  not  all  consistently.  Asth-
matics and normals/allergies also had significantly  increased symptom scores
during ambient  air exposure  sessions.  This increase appeared to last later
into the day in asthmatics but not  in normals/ allergies (Figure 12-1).
     Nine of 12  highly reactive subjects (four from the  normal/allergic group
and five asthmatics—a similar proportion from each group), who had experience^!
a fall in FEV  greater than 200 ml  during ambient exposure (compared to purified-
                                                                            3
air exposure),  underwent  a controlled 2-hr exposure  experiment at  392 ug/m
(0.2 ppm) with  intermittent exercise (see Chapter 11).   Among  these nine
reactive subjects, the mean FEV, change in the ambient exposure was -273 ±  196
ml  (-7.8 ±6.3 percent of pre-exposure).  This change was  significantly greater
than the mean  change  of -72 ±  173  ml (3.1 ±6.6 percent pre-exposure) in the
control  setting.   The authors   suggested that ambient exposures  had greater
effects than chamber  exposures.  Normal/allergic subjects in  the validation
studies  showed similar findings  in  the exposure  chambers compared to the
outside ambient air when the levels were similar inside and out.
     Linn et al.  (1982, 1983)   repeated  the  initial experiment (Linn et  al. ,
1980)  with  64  different  subjects,  ages 18 to 55,  at a different  location
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             30
          LU
          §  20

          g
             10
                   1   I    I

                    	AMBIENT AIR
                    	PURIFIED AIR
1    \    T
                   I	I
     I
 I	I
I
                   PE   1C   LO

                      ALL
PE  1C  LD

 NORMAL
PE   1C  LD

ASTHMATIC
                Figure 12-1. Mean symptom score changes with
                exposure for all subjects, normal and allergic sub-
                jects, and asthmatic subgroup of subjects. PE =
                pre-exposure; 1C = in chamber (near end of ex-
                posure period); LD = later in day. Circles (Oor®)
                indicate total symptom scores; triangles (AorA)
                indicate lower-respiratory symptom  scores. Solid
                symbols indicate that ambient exposure score is
                significantly higher for indicated time period
                and/or increased significantly more relative to
                pre-exposure value. Open symbols indicate non-
                significant difference between ambient and
                purified air scores.
                Source: Adapted from Linn et al.  (1980).
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(Hawthorne) with  low CL levels  (0.04  ±  0.02 ppm, 82 ±  39  pg/m  )  but with
elevated levels of  other  pollutants.   They found no meaningful lung-function
or symptom  changes,  and they concluded that 0~ was primarily responsible for
the effects seen in the original study.
     A third  experiment (Linn  et al . ,  1983; Avol et al . , 1983) was conducted
at the original oxidant-polluted location (Duarte) with 60 subjects, ages 18
to 55, exercising heavily  (four  to  five  times  resting minute ventilation) and
                                                               o
continuously  for 1  hr.  The  mean 0- concentration was 314 pg/m   (0.16 ppm)  in
ambient air (measured by the UV method).   Total  reported symptoms did  not
differ significantly  between exposure  and control (purif ied-air) conditions.
For the complete group, small  functional decrements in FEV  were  found  (3.3
percent loss,  P < 0.01),  more  or less comparable  to  those  in the original
study.  A number of the subjects showed functional losses during exposure that
were  still  present  after  a  1-hr recovery period at rest in  filtered air.
Those  in  the  most  reactive  quartile (those  who  experienced 320 to 1120-ml
"losses, versus control) were  compared  with  the least  reactive quartile
(increases of 60 to 350 ml).   They did not differ by age, height, sex, smoking,
medication  use, prevalence of atopy, or  asthma.   Negative FEV, changes seemed
to occur more frequently (34 of  47  cases) at 0,  exposure concentrations  above
        3                           3
235 pg/m  (0.12 ppm), up to 549 jjg/m  (0.28 ppm) in the  total  study group (P =
0.02).  The authors  stated  that the considerable functional  losses  in this
study were not  necessarily  accompanied by symptoms, nor were they related to
obvious prior physical or clinical status.
     A fourth study  in  the  original location (Duarte)  studied  98 subjects,
including 50 asthmatics (Linn et al . ,  1983; Avol et al . , 1983).   Mean exposure
            3                             3
was  306 pg/m   (0.156 ppm) 0, and 166 pg/m  TSP  (lower  than in 1980).  The
                                           3
highest exposure concentration was  431 |jg/m  (0.22  ppm), which was lower  than
in 1982.  The  subjects  were exposed to heavier, continuous  exercise  (though
lower exercise ventilation levels than in 1980), and those showing the largest
changes in pulmonary function (positive and negative)  were the asthmatics.
The  mean  decreased  values  remained depressed  for   up to 3  hr  post  ambient
exposure.   Maximum mean  changes  in FVC and FEV, for asthmatics after ambient
exposure were 122  ml  and 89 ml,  respectively,  with the former returning more
quickly to control  levels.   The value for V    5Qo/  was  more variable with a
maximum mean change  of  132  L/s  after ambient exposure.   The only significant
mean changes after exposure were for FVC in normals (P < 0.003).   There were
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 significant  interactions  of  ambient and purified air after exposure  in asthma-
 tics  for  FEV.. and V    cr.v.
             1      max50%
      In  summary,  the Linn et al.  (1980,  1982,  1983) and Avol et al. (1983)
 studies  have demonstrated respiratory effects  in  Los  Angeles area  residents
 related  to  CL  concentration and  level of  exercise.   Such effects  include
 pulmonary  function decrements seen at 0~  levels as low as 0.16 ppm and increased
 symptoms  observed  at levels  as  low as  0.12  ppm  03-   The  effects  are  typically
 mild  and  generally do not differ substantially  between asthmatics  and persons
 with  normal  respiratory health,  although  symptoms  last for  a few hours  longer
 in  asthmatics.   However,  many of the  normal  subjects had a  history  of allergy
 and appeared to be more  sensitive to 0_  than "non-allergic"  normal  subjects.
                                       O
 The relative importance of exercise level,  duration  of  exposure,  individual
 variations in  sensitivity, and effects of coexisting pollutants in  producing
 the observed effects  remains to be more fully investigated.
      Lebowitz et al.  (1974)  demonstrated  an  association  between pulmonary flow
 and volume  changes  (measured  by a water-filled  spirometer) in exercising
 children  under  ambient exposure conditions.   However, no effects of  exercise
 or  diurnal shifts  in function during the day were observed  under controlled
 temperature  and humidity  conditions in  filtered rooms; later, Lebowitz et al.
 (1982b) verified  the lack of diurnal  effect in normal subjects and  validated
 the use of the  Mini-Wright   Peak Flow Meter  for field use.
      Lippmann et  al.  (1983)  studied  83  nonsmoking,  middle-class,   healthy
 children  (ages  8  to 13)  during a  2-week  summer day  camp program  in  Indiana,
 PA.   The children exercised outdoors most of the time.   Afternoon measurements
 included baseline  and post-exercise  spirometry  (water-filled, no noseclips).
 Peak  flow  rates were obtained by Mini-Wright  spirometer at  the beginning of
 the day or at lunch,  both adjusted for  age and  height.   No day-of-week effect
was seen.  Ambient  air levels of TSP, hydrogen ions, and sulfates were moni-
 tored by a high-volume sampler in the day camp building  rooftop.   Ozone concen-
trations were estimated as a weighted  average  of  data  extrapolated  from a
monitoring site 20  mi south and a  site 60  mi  west,  using  two models that
yielded 03 estimates  within  ±16 ug/m  (0.008 ppm) on  average.  Estimated 1-hr
peak  03 levels  (early afternoon) varied from 90 to 249 ug/m3  (0.046 to 0.122 ppm),
whereas TSP  levels  were low (6-hr samples <103 ug/m ),  as were sulfuric acid
                                                       O
 (H2S04)  equivalent  concentrations (maximums <6.3  ug/m  ).   Lippman  et al.
 (1983) reported significant inverse correlations  between FVC and FEV-.  and
estimated maximum 1-hr 03 levels for 4 or more days covering a twofold
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range in 0,..   Differences  in  correlations  (i.e.,  slopes)  were not related to
other pollutants  (TSP,  H?SO.) or ambient temperatures.   Qualitatively,  the
Lippmann et al.  (1983)  study  results suggest low-level 0~ effects; however,
because exposure modeling  (rather  than  on-site  monitoring)  was used to esti-
mate CL levels, much uncertainty surrounds quantitative interpretation of the
      O
study results.  The uncertainty about appropriate quantitative interpretation
of these findings may be reduced by consideration  of the results  from a similar
study conducted the next summer by Lippmann and  Lioy (1984).
     A similar group of children  was studied at  a  day camp in Mendham,  NJ.
Preliminary analyses of the  Mendham data,  as summarized by Lippmann and Lioy
(1984), indicates  a  significant  association  between peak hour CL  levels  and
decrements  in  peak expiratory flow rate (PEFR).  In order to provide  better
air monitoring data, CL concentrations were  measured (UV) at  the  Mendham  camp
                      <3
site, as were concentrations of HUSO,.   The highest peak 1-hr CL  concentration
measured on a study day was 0.143 ppm;  values ranged from 0.02 to 0.18 ppm O^-
     Several comparisons can  be  made between the data  reported  by Lippmann
et al. (1983) and  Lippmann and Lioy (1984).   There were 39 children (22 girls,
17 boys)  in the  follow-up study with sufficient  data  for analysis;  however,
the children were  not  as physically active  as  the  children studied in the
previous study in  Indiana, PA.  While marked (^-dependent changes in PEFR were
,-eported,  Lippmann and  Lioy  (1984) did not observe an Q3-dependent change  in
FVC,  as was found  previously.  Also, the change in  FEv^ Q with 03 was  smaller
in girls.   However, in  both studies, the 03-related decrements were greater in
girls  than boys.  Both  studies also reported low concentrations  of acidic
aerosol,  suggesting  that the response was primarily attributable to 03-    A
final  analysis  of  the  two  studies  cannot be  made  until  a  complete description
of the results obtained in Mendham, NJ, has been published.

12.2.2  Symptoms and Pulmonary Function Under High-Altitude Conditions
     Young  et  al.  (1962) noted high average CL levels  in passenger cabins  of
aircraft  flying  between 27,000 and 39,000 feet.   In  1973,  Bischof reported
that  0,, concentrations  (Comhyr  ECC meter)  during  14  spring polar flights
(1967-71)  varied from  0.1 to 0.7 ppm, with  1-hr peaks  above  1.0  ppm,  despite
ventilation.   More recently,  Daubs  (1980) reported 03  concentrations in Boeing
747  aircraft  ranging  from 0.04 to 0.65 ppm, with  short-term (2 to 3 min)
 019DC/A                               12-10                         6/18/84

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levels as  high as 1.035 ppm.  Other reports (House of Representatives, 1980;
Broad, 1979)  indicate that 0- concentrations  in  high-altitude aircraft can
reach excessively high  levels;  for example, from  New York to Tokyo a time-
weighted concentration  of  0.438  ppm was  recorded,  with a  maximum  of  1,689 ppm
and a 2-hr exposure of 0.328 ppm.*
     Anecdotally,  flight attendants  and  passengers in high-altitude aircraft
have complained of certain symptoms (chest pain, substernal pain, cough) which
were most  prevalent during  late  winter  and early spring  flights.   Similar
symptoms have  been observed in more systematic studies of such effects, such
as  (1) the study  by  Reed  et al. (1980), which found symptoms among 1,330
flight attendants to be related to aircraft type and altitude duration but not
to  sex,  medical  history,  residence,  or years of  work;  and  (2) the Taskin
et al.  (1983)  study,  which  found increased 0_-related  symptoms  in flight
attendants on Boeing 747SP (higher-altitude) flights in comparison to attendants
on  lower-flying  747 flights.  Neither  of these two studies,  however, measured
03 concentrations in the aircraft studied.
     Two recent studies by Lategola and associates attempted more quantitative
evaluation of  problems  associated with 0- exposures of flight attendants and
passengers.  Lategola et al.  (1980a) exposed 55 young subjects  (29 men  and 26
women) to ambient air and to an 0- environment in an altitude chamber maintained
at 1829 m (6000 ft).   Subjects served as their own controls in each experiment.
Two major  studies were  conducted on 27  (15 men and 12 women)  and 28 (14 men
and 14 women) subjects.
     In the first study,  (1) 0_  concentrations were 0 and 315 ng/m  (0.0 and
0.2 ppm),  (2)  exposure  time was  4 hr (with four 10-min exercise periods, the
first three  being at lower  levels of  activity and the fourth  at a higher
level) and  (3) pulmonary function and subjective  evaluations  were  obtained
pre- and post-exposure.  These  measurements were  made near  sea  level before
and 10 min after the altitude exposures.   Other studies,  on vision parameters,
     *Note that, as ambient pressure decreases at high altitude, 03 concentra-
tions remain the same as expressed in terms of ppm levels, but 0,, mass concen-
trations  (in  (jg/m  )  decrease in direct proportion  to increasing altitudes.
Therefore,  knowledge  of prevailing  atmosphere pressure and temperature  is
generally needed for correct conversion of ppm 03 readings to pg/m  03 concen-
trations under specific measurement conditions.
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hand steadiness, and  Wechsler  memory tests, were conducted during the  high-
altitude exposures.   Male  subjects  exercised with minute ventilations  of 20
L/min in the  first three exercise periods  and  30 L/min for the last period
just prior to descent;  for female subjects,  exercise ventilations were  13 and
17 L/min, respectively.   No  alterations in  the measured pulmonary functions
were found and although slight discomforts were reported, they were not signi-
ficantly related to 0-  exposure.  The second study differed from the first  in
                                  3
that the 0«  exposure  was 475 \JQ/n\  (0.3 ppm) and only three exercise periods
were used.  Again,  men  exercised at ventilations of 24.9 L/min for the first
two periods and 38.6 L/min for the last, and the women at 16.4 and 20.9 L/min,
respectively.   Significantly greater symptom scores were found  after both the
last exercise period  and the termination of the  study.  In this experiment,
differences between the  no-0_  and the 0  responses for all  spirometry param-
eters [FVC, FEV-p  forced expiratory flow (^^25-75°^'  and ^^75-957-^ Wltnin
each sex group were statistically significant (P < 0.05).  The two lung-volume
measures manifested smaller changes than did flow-rate flow measures.   Symptom
scores were greater in  men than  in women  during the last treadmill tests, but
were not statistically  significant.   The results indicate increased symptoms
and pulmonary function  decrements  among normal subjects at 0.30 ppm,  but not
0.2 ppm under light exercise conditions.
     Lategola et al.  (1980b) also studied 40 middle-aged men, 20 smokers and
20 nonsmokers, again exposed in an altitude chamber (1829 m),  resting for 3 hr
in environments containing 0 or 475 pg/m  (0.0 or 0.3 ppm) 0_.  Eye discomfort
was the most frequently reported symptom; headache and nose and throat irrita-
cion were also reported.  All subjects combined manifested small but statisti-
cally significant spirometric decrements in  FVC, FEV   and FEF-,5_g5o,» primarily
due to  changes within the  nonsmoking group.  Smokers reported fewer or  dimin-
ished symptoms, confirming  observations reported by others.   The study tends
to confirm small but significant respiratory effects observed at 0.3 ppm among
nonsmoking normal  adults  under high-altitude conditions.  The 0_ levels used
                                                                O
in the  Lategola  studies are, however, generally lower than 0_ concentrations
reported to occur  in  certain aircraft at  high  altitudes, as are the simulated
altitudes employed by Lategola and coworkers.
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12.3  EPIDEMIOLOGICAL STUDIES OF EFFECTS OF ACUTE EXPOSURE
     Effects of acute exposure to photochemical oxidants are generally assessed
in communities by  comparing  functional  or clinical status during periods of
high and  low  0_  or oxidant concentrations.   Occasionally,  communities  with
different concentrations are  compared.  The concentrations measured have been
24-hr averages, maximum hourly averages, or instantaneous peaks.

12.3.1.   Acute Exposure Morbidity Effects
     For purposes of this document, indices of acute morbidity associated with
photochemical  oxidants  include  the incidence  of acute respiratory illnesses;
symptom aggravation  in  patients with asthma and other chronic lung diseases;
eye  irritation;  headache;  respiratory  irritation; and  effects  on pulmonary
function, athletic performance,  auto accident rates,  school  absenteeism, and
hospital admissions.
12.3.1.1.   Respiratory  and Other Symptoms  of  Irritation.   Various symptoms,
including eye  irritation,  have  been  reported during  ambient air exposure.
However, eye  irritation  has generally not  been associated with 0- exposure  in
controlled  laboratory studies (Chapter  11).   This  symptom has been associated
with formaldehyde, acrolein,  and other organic photochemical  reaction products
such as peroxyacetyl  nitrate (PAN) (National Air Pollution Control Association,
1970; Altshuller, 1977;  Environmental Protection Agency, 1978; National  Research
Council, 1977; Okawada  et al.,  1979).   Of  the  biological effects  caused by  or
aggravated  by  photochemical air pollution,  eye irritation appears to  have one
of the lowest thresholds; however, it also appears to be a short-term, revers-
ible effect,  since damage  to conjunctiva  and  subjacent  tissue  has  not been
reported.
     Regression analyses by Renzetti and Gobran (1957), as reviewed previously
(Environmental Protection Agency, 1978), has indicated increases in eye irrita-
tion over a wide range  of average  oxidant values  in  the Los Angeles area,
suggesting  that  severity increased  above  hourly oxidant concentrations of
about 0.1 ppm.
     The U.S.  Environmental  Protection Agency (1978)  also  reviewed  several
studies on  850 Japanese schoolchildren  by Shimizu (1975) and Shimizu et al.
(1976), by the Japanese Environmental Agency (1976),  and by Makino and Mizoguchi
(1975) and Mizoguchi  et al.  (1977).  The Shimizu et al. studies  did not segre-
gate the  effects of oxidants,  although they  found that acrolein (0.5 ppm,

019DC/A                              12-13                        6/18/84

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5 min) produced  eye irritation.  The  Japanese  Environmental  Agency (1976)
study reported complaints  from  a survey conducted at oxidant concentrations
>0.15 ppm, but without  denominators.   In  the studies by Makino and Mizoguchi
(1975) and Mizoguchi et al.  (1977),  no yearly symptom-pollution correlations
were significant for SO-,  N0?,  or NO alone,  whereas  some symptoms were posi-
tively correlated with  temperature  (alone and with  other  pollutants).   The
highest correlations were  reported  between symptoms  and oxidants.   On days
when maximum  hourly oxidant levels  exceeded 0.10 ppm,  significantly higher
rates of  eye  irritation,  cough,  headache, and sore throat were reported.
Analyses of further studies, which measured oxidants  (KI) and  07 (chemilumines-
                                                               O
cence) on  a  schoolground,  yielded  similar results.   When maximum oxidant
concentrations exceeded  0.15 ppm, eye  irritation, sore throat, headache, and
coughing were greater than  on lower-oxidant-level days.  Infectious  illnesses
were not  distinguished.  Symptom rates in  74 allergic students were  generally
higher than rates  in  nonallergic or all students on days  when the  maximum
hourly oxidant  level  was 0.23 ppm or  greater.   These  and other  subjective
symptoms were reported  during episodes of  acute smog in Japan, although  rates
(i.e., denominators) were  unknown,  and other pollutants were  present at high
concentrations (Kagawa,  1982; Kabayama,  1971;  Fujii, 1972; Mikami and Kudo,
1973a,b; Adachi  et  al., 1973;  Adachi and  Nakajima,  1974;  Matsumura  et al.,
1973; Sugita et al., 1976; Masuda, 1977).   Weather variables were not controlled
in the analyses  of  data from these  studies.   Effects seen at  different times
of the day during  episodes in Japan may be due to different pollutant mixes.
     In the more recent literature,  Okawada et al. (1979) examined the associa-
tions between eye  irritation  and photochemical  oxidants in Tokyo high school
students  7 days  during  two summer  sessions  (n  = 28  and 43,  respectively).
Tests were  performed between 1:00  and 4:00 p.m., during  periods of daily
maximum oxidant  levels  (measured by KI method at test  site).   Tear  lysozyme
and  pH values were  measured,  and eyes were examined with  a slit-lamp.   Tear
lysozyme and  pH  values  decreased on  2  days when the  oxidant concentration was
nighest (0.175  and  0.210 ppm),  in comparison to 2 days  when the  concentration
was  lowest (0.020  to  0.033 ppm).  Eye irritation incidence rates (determined
from questionnaire  responses each day)  increased  proportionately with  oxidant
concentrations above 0.1 ppm.   The irritation was produced experimentally with
the  following pollutants individually:  formaldehyde  >0.2 ppm,  PAN >  0.05 ppm,
and peroxybenzoyl nitrate (PBZN) > 0.01 ppm.

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     Several studies have also reported respiratory and other symptoms associ-
ated with photochemical oxidant pollution.  One such U.S.  study was performed
by Hammer et  al.  (1974)  on similar groups of freshman  student nurses at two
hospitals in  Los Angeles, as previously  reviewed  (Environmental  Protection
Agency, 1978).  Symptom rates from daily diaries (a daily average of 61 students)
were obtained from October 1961 through June 1964.   Simultaneous daily measure-
ments  of  oxidants  (KI method) and other  pollutants  and maximum daily tem-
perature were available on more than 90 percent of the  days  in the  study from
Los Angeles Air  Pollution Control District monitoring  stations located 1.5  to
3.0 km  from both hospitals.   Both before and  after  adjusting the  rates by
excluding days  on which  subjects  reported fevers (to  minimize  effects  of
infections),  Hammer  and coworkers  found  eye discomfort  at oxidant levels
                        3                                              3
between 294 and 372 jjg/m  (0.15 and 0.19 ppm), cough at 588 to 764 ug/m  (0.30
                                                       3
to 0.39 ppm), and  chest  discomfort at 490 to  568  ug/m  (0.25 to 0.29 ppm)
maximum hourly  oxidant  levels.   These adjusted rates were related to oxidant
levels more closely  than to CO, NO-,  or  daily  temperature.  The rates are
shown in Figure 12-2.
     Symptoms of cough, chest discomfort, and headache  have been both (1) asso-
ciated  with occupational  exposure to  oxidants  (see  below) and (2) in some
community studies cited above appear to have resulted from exposure to ambient-
air  oxidants.   Some  of  these effects may  have  resulted from interactions
between  oxidants and other  pollutants (National  Research Council, 1977).
Various oxidants  may produce irritation at  levels  found in smog  (Dimitriades,
1976;  U.S.  Environmental  Protection Agency, 1978; National Research Council,
1977).
12.3.1.2  Alterecj  Performance.   To  determine the possible  effects  of photo-
chemical  oxidant pollution  on athletic performance, Wayne et al.  (1967) and
Herman  (1972)  studied a group of cross-country track runners during meets  in
Los Angeles.  Their results indicated that  NO  ,  CO,  and particulate matter
were not  related to performance.  They did not examine  SO,,.  The proportion of
runners  failing  to improve their times during the track season significantly
rose  as concentrations  of  oxidants measured by  the  Air  Pollution Control
District  increased  to the range of 0.06  to  0.37 ppm in the  hour before the
race.   Subsequent  analysis  of this study has  yielded  estimates of impaired
athletic  performance above 0.12 ppm oxidant  (Hasselblad  et al. , 1976; U.S.
Environmental  Protection Agency, 1978; World  Health  Organization,  1978) or
0.065  ppm (National  Research Council, 1977).  Analysis of an extended set  of
019DC/A                              12-15                        6/18/84

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    35
 £  30 h
 0
 o
 
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data by  Herman  (1972)  showed  an  inverse  association between running speed and
oxidant  measured  1  hr  before  the meet, after correcting for average speeds,
time, season, and temperature.
     Some investigators have hypothesized that photochemical oxidant pollution
may create poor daytime driving  conditions.  Ury  (1968) found that concentra-
tions of oxidants monitored by the Air Pollution  Control Districts correlated
positively with  the frequency of weekday daylight motor vehicle accidents in
Los Angeles during August through October.  Accident rates were higher on days
when hourly  oxidant levels exceeded  0.15 ppm than  on days below 0.10 ppm.
Other pollutants  were  not evaluated,  but are low in summer.  As for weather,
only days  of rain  and fog were  excluded from data analyses.   In  a  second
study,  Ury et  al. (1972)  investigated CO concentrations during winter months
with the same  analytical  methods.   A statistically significant difference in
frequency of accidents above and below 0.10 ppm was again noted in relation to
oxidant  concentrations, but  no  consistent relationship was noted with lagged
oxidant  or  CO  concentrations.   Morning  (9:00 a.m.  to 12:00 noon) peaks  in
accidents may implicate 0_ precursors or other pollutants, but do not implicate
traffic  density.  Reduced visual acuity  (according to results of Lagerwerff,
1963),  increased  eye  irritation, or reduced visibility may have been partly
responsible (U.S. Environmental   Protection Agency, 1978).
12.3.1.3  Acute Effects on Pulmonary  Function.   Previously reviewed studies
(U.S.  Environmental  Protection Agency, 1978) showed significant differences in
children's peak flow  rates related to  oxidants in two  Los  Angeles communities
(McMillan et al., 1969) but  no   differences in pulmonary  function  in office
workers  in Los  Angeles and San  Francisco (Linn et al., 1976).   Neither study
measured  pollutant  exposures sufficiently  or  accounted for meteorological
variables; also,  within-study populations appeared to differ between commu-
nities.
     Kagawa  and Toyoma (1975) and Kagawa et al.  (1976)  reported consistent
effects  of 0«  on the pulmonary  function  of  children  in Japan.   First,  they
studied  21 children 11 years of age  (in 1975) for 29  weeks (June-December).
Hourly average  concentrations of 0,. (measured by chemiluminescence) at their
                                 3
school  ranged from 20 to 294 ug/m  (0.01  to 0.15 ppm).  Maximum hourly concen-
                                                       3                     3
trations of NOS N0?, and S0? were approximately 98 ug/m  (0.08 ppm), 432 ug/m
                        3
(0.23 ppm), and 133 ug/m  (0.05  ppm), respectively, and particulate matter was
         3
350 ug/m .  The overall significance of the association between 0. and pulmonary

019DC/A                              12-17                        6/18/84

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function tests was accounted for by 25 percent of the subjects,  in whom airway
resistance (R  )  was  positively correlated  with 0_  concentrations  during
testing, specific conductance  (SG   )  was  negatively correlated, and maximum
                                 aw
expiratory flow rates  (V    5Q^,  V    25^)  were inconsistent.   These measures
also correlated with temperature  (more than with any other variable) and SO,,
levels, but not with N0» levels.
     The same students  were studied during a low-temperature  period (November-
March) and a  high-temperature period  (April-October).  Hourly average 0_ con-
                                            3
centrations ranged from about 20 to 588 ug/m  (0.01 to 0.30 ppm);  NO, N0?,  and
                                                            3
S0? concentrations were approximately 220, 563, and 418 ug/m   (0.18,  0.30,  and
0.16 ppm) respectively, and the concentration of particulate  matter was approxi-
mately 450 pg/m .   Again,  concentrations of 0, were positively correlated with
R  , V   rrio/5 and V   OI-o/ and negatively correlated with SG  , in  both periods,
 aw'  max50%'      max25%       y      •*                   aw'         K      ,
and more consistently  in the low-temperature period when 0^ was lowest  (<0.10
              3
ppm, 196  ug/m ).   As  in the previous  study,  associations  of function  with
pollutants were confounded  by temperature, which acted differently in the  two
seasons.   Excluding  the effect  of temperature yielded  several 0~-R   and
                                                                  o  dW
0.,-V   r-no/ partial  correlations of statistical  significance  in  the  low-
 3  max50% r                                      a
temperature  (low-0,) period.   Analysis of multiple correlation coefficients
indicated a  few  likely pollutant interactions.  R   and SG   correlated with
multiple environmental   variables  in nine subjects.  There were linear  rela-
tions  of  health  effects with 03 concentrations  occurring  up  to the maximum
concentrations:  0.15 ppm in the first study, (high-0~ period) and either 0.10
(as the  effects  were  seen in the  low-03  period) or  0.30 ppm  (in  the  high-03
period)  in the second  study.   Another Japanese study (Shishido et al. , 1974)
showed similar results, but did not control for other pollutants.
     Lebowitz et al. (1982a, 1983)  and Lebowitz (1984) studied 24 children and
young  adults,  ages  8 to 25, from  middle-class backgrounds for an 11-month
period in 1973 and 1980 in Tucson,  AZ.  Every day, in the late afternoon (3:00
to 7:00  p.m.,  usually  4:00 to 6:00 p.m.) peak flow was measured with a Mini-
Wright®  peak flow meter (Wright,  1978; Williams, 1979;  van As,  1982;  Lebowitz
et al., 1982b).  Subsets of the group, chosen randomly, underwent measurements
during  different  seasons  of the year.  After  age  and height correction,  no
peak flow differences  in baseline data were seen among the subjects by  analysis
of  variance  (ANOVA), and  all were  within  the  published normal  range  (within  1
standard  deviation  of  100 percent  of  prediction).  Daily peak flows for each

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child were transformed  into  a standard normal variable (x = 0,  s = 1), using
the formula z. =  (x.  - x)/s. The  seasonal  mean and standard deviation were
used to  generate  daily values (z-scores) that  were standardized deviations
from seasonal  averages, with similar units for all individuals.   This procedure
adjusts  for  seasonal  effects and  differences between individual means and
variances.
     Ozone (measured by  chemi1uminescence),  CO (infrared), and NO- (chemilu-
minescence) were monitored outdoors at three stations.  Daily TSP level (6-day
high-volume samples) was  measured at 12 locations, including stations at the
center of  each cluster of  subjects within a  1/4-  to 1/2-mi  radius).   Previous
inventories by  the Pima County Air  Quality  Control District (1978)  showed
significant homogeneity  of 0., in  the basin.   The  central  station data  and the
                             *J
average  basin  data were  used in  the analysis.   Comparisons  of  these data
showed no  significant  differences  in results  between  the  two.  In this  study,
indoor 0,,  (chemiluminescent  method)  showed very  low  levels  (<0.035  ppm,  69
    3
ug/m ) as  reported  previously (National  Research Council, 1981).  Indoor and
outdoor  CO levels were  less  than  2.4 ppm  (2736  g/m  )  and  3.8  to  4.9  ppm (4332
           3                                                            3
to  5586  g/m ),  respectively, as  was  N0?  (median of  0.03 ppm,  34 ug/m ).
Indoor CO  was correlated with gas-stove use  only.   Outdoor  TSP ranged  between
                3                                                        3
20  and 363 ug/m   for all  monitoring days  and between 27.5 and 129 ug/m  on
days of  indoor monitoring.  Indoor TSP and respirable suspended particle (RSP)
                                                           3
ranges for 41  representative houses were 5.7  to  68.5 ug/m  and 0.1 to 49.7
    3
ug/m , respectively, and were correlated with indoor cigarette smoking but not
gas-stove use (Lebowitz et al.,  1983; Lebowitz, 1984).
     Initial  analysis showed that 0- and TSP levels were negatively correlated
with peak flow, after correcting for season and other pollutants.  Multivariate
analysis  of variance was  conducted to control  for person  days of observation,
meteorological variables,  CO, N02,  and TSP, after which the 0- concentration
coefficient was  still  shown  to  be  independently significant (P < 0.001).
There were significant,  independent  interactions  between  03 and  TSP  with  peak
flow (see Table 12-3).
     When  the contributions  from  each of the  other factors were removed by
adjustment (using multiple regression), the  0_  concentration  correlation  with
                                              »j
peak flow  was  still  significantly negative (Lebowitz et al., 1983).  The mean
z-score  for  the person  days with a maximum  hourly 03 level  of 157  ug/m
(0.08 ppm) or greater (21  days)  was -0.31 (P < 0.007); it was -0.38 for a mean
                    3
0-  level of 157 ug/m  (0.08 ppm) or greater between 3:00 and 7:00 p.m.
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     TABLE 12-3.   THE RELATIONSHIP BETWEEN AVERAGE STANDARDIZED DEVIATIONS
               OF PEAK FLOW AND OUTDOOR CONCENTRATIONS OF OZONE
                    AND TOTAL SUSPENDED PARTICULATE MATTER3
Maximum hourly
ozone concentration
ug/m3
<75

75-100

102-155

157-235

All

ppm
<0.038

0.038-0.051

0.052-0.079

0.08-0.12



Daily total suspended particulate matter,
(ug/m3)
<56 56-76 >77 All
+0.108,
(167)d
+0.042
(71)
+0.242
(40)
-0.088
(9)
0.115
(298)
+0.239
(53)
-0.162
(39)
-0.021
(94)
-0.196
(31)
-0.027
(244)
+0.156
(61)
-0.061
(39)
-0.474
(67)
-0.804
(27)
-0.227
(223)
0.069
(663)
0.024
(363)
-0.115
(419)
-0.310
(148)


Source:   Lebowitz (1983a).

 Analysis of variance for total  explained effect,  for the interaction,  and
 for each pollutant,  P < 0.0001.
 Sample size was reduced because total  suspended particulate matter (TSP) levels
 were not available for all  days.
cRepresents all  days  when data were available for each pollutant.
 Person days of observation.

Note:  Peak flow decreases with increasing TSP,  becoming statistically  signifi-
cant only at ozone >  0.052 ppm.   Peak flow also  decreases with increasing
ozone, becoming significant at TSP > 77 ug/m3 (the decrements at ozone  >^ 0.08
ppm are significant for TSP levels of 57-76 ug/m3).   There is a very significant
interaction of ozone  and TSP.   Decrements in peak flow of -0.474,  -0.804, and
-0.310 represent 18,  28, and 12% changes respectively, when compared to normal
day-to-day variability in a comparable group of  children previously studied by
Lebowitz et al.  (1982b).


(P < 0.0001).  The z-scores represent  decreases in peak  flows of 12.2 percent

and  14.8  percent, respectively,  and the percent  changes are  significant
(P < 0.05),  based on published  data for normal  day-to-day variability in
another, comparable  group  of  children (Lebowitz et al., 1982b).  This  study,

because of the small  number of subjects, needs to be repeated to determine the

consistency  of  the  relationships  found.   Personal  monitors, had they  been
available, would  have provided more  accurate  exposure  estimates. Children are

likely to spend much time outdoors, especially in the afternoon.
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12.3.1.4  Aggravation of Existing Respiratory Diseases.  Several studies have
examined photooxidant  pollutant effects on  symptoms  and lung functions of
patients with  asthma,  chronic bronchitis,  or emphysema.   Most  earlier ones
were evaluated in the predecessor criteria document (U.S. Environmental Protec-
tion Agency,  1978).   Schoettlin and Landau  (1961)  reported  increased daily
asthma  attacks  in 137  subjects from September to  December,  1956,  on high
oxidant days  in  Los  Angeles,  but did not control for  age, sex, temperature,
season, or medication use.   Schottlin (1962), using regression analyses, found
no relationship between oxidants (KI) and symptoms in 200 chronic lung disease
patients and  200  matched  controls  from a Los Angeles Veterans Administration
hospital.    Rokaw  and Massey  (1962)  performed a pilot  study  on  31 chronic
pulmonary patients and a control group in Los Angeles over an 18-month period,
using pulmonary function tests  four  times per week.  Only  six patients  showed
negative changes  associated with higher oxidant concentrations (X = 0.06 ppm,
max. =0.42 ppm).
     Zagraniski et al.  (1979) studied a group of 82  asthmatic  and allergic
(i.e.,  hay fever) patients and a group of 192 normal telephone company employ-
ees in New Haven, CT, from July to September 1976.   Of the two groups studied,
57 percent  were  female,  90 percent white,  61 percent over age 30,  35 percent
current smokers (20  percent more  than one pack per day),  and 22 percent ex-
smokers.  The  clinic group (i.e.,  asthma and allergic  patients)  had higher
proportions of ex-smokers and persons who had never smoked, whereas the employee
group  had  significantly more  women, persons over 30,  and persons who  held
clerical or technical jobs.  All these variables were controlled in statistical
analyses of data  from daily diaries (completed weekly  over  a 10-week study
period).
     Air monitoring  occurred  at two sites 1.2 km apart and within 0.8  km  of
where  the  subjects  were recruited;  however, distances from residences and
workplaces  were  not  reported.  Concentrations of  S0?, TSP,  sulfates  (from
dried  glass-fiber filters),   and 0_  (by chemiluminescence) were monitored;
previous monitoring  had shown low N02 and CO levels.  Meteorological  variables,
specifically maximum daily temperature  (mean of 27°C, from 19 to 34°C), were
used as covariables.  Average daily  windspeed varied  little and was not used.
Sulfates and  0.,  often had coincident peaks; few daily sulfate concentrations
                 3                                                   3
exceeded 24 pg/m  .   Ozone maximum hourly readings  averaged  157 |jg/m  (0.08
                                      3
ppm), and  the  range  was 8 to 461  ug/m   (0.004 to  0.235 ppm), with maximum

019DC/A                              12-21                        6/18/84

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                                                                  3
concentrations  in  the  afternoon.   Eight-hour  mean TSP was 83 ug/m  (range:  24
to  169 [jg/m ), and 24-hr  mean  TSP was 73 ug/m3 (range: 20  to  147 ug/m3).
Reported  outdoor  exposure, working, and  home conditions  were  judged to  be
equivalent for most subjects for most pollutants.
     Daily symptom prevalence rates were used as dependent variables.  Patients
had  higher  symptom rates,  except for cough,  than did  controls.   Smokers in
both groups  reported  more  episodes of illness  and  chronic  productive cough
than did  nonsmokers.   Data from participants  who returned five or fewer daily
records per  week  or missed four or more  consecutive weeks of the study were
excluded from analysis, and 23 percent of the participants (10  percent controls;
50 percent  patients)  dropped  out of the study.  The dropout rate was related
to  smoking  in  both groups and  to  asthma and  allergy exacerbations in  the
patients.   Symptoms rarely correlated  with pollution variables,  using paired
and  multiple  analyses.   Maximum hourly 0- levels correlated with cough  and
nose irritation in heavy smokers (r = 0.24 and  0.32, respectively,  P  < 0.05),
and  significant positive,  pairwise correlations (P  < 0.05)  of  maximum hourly
03 levels were  found  with  cough in hay  fever patients  (r = 0.22), and  with
nose irritation in asthmatics (r = 0.17).  When subjects were  regrouped  by
smoking and illness status  for multiple regression  analyses,  0,  level signifi-
                                                              O
cantly  (independently)  correlated  with  cough and   eye  irritation in heavy
smokers, and with  cough  in hay fever patients (independent of  season).  Cough
frequency increased linearly  with  hourly 0_ concentrations  in  the range  of 8
            3
to 461  ug/m   (0.004 to 0.235 ppm,  a mean of 0.08 ppm),  especially in smokers
and  in  those  with  predisposing  illnesses (independent  of season).  No other
symptoms were associated with 0- in any of the  groups,  nor were other pollut-
ants associated with symptoms.  Negative pH changes  of TSP over  8 hr and  24 hr
were positively and independently associated with eye,  nose,  and throat  irrita-
tion in most groups,  but  not with other symptoms.   Pollen  was  associated
positively only with frequent sneezing in hay fever  patients.
     A  major problem with  this  study is that  daily  prevalence data  were used,
rather  than  incidence  data,  and no correction  for  auto regression was  made
(see below).  Misinterpretation and misuse of diaries were limited in frequency,
as determined from comparisons with clinical  data, and were  not  likely to  have
substantially influenced symptom data.   However,  bias  may have been  induced
(in  either direction)  by the  selective dropout  of the more heavy  smokers, the
patients with symptoms, and persons who did not report symptoms.   These  factors
should have been evaluated.
019DC/A                              12-22                        6/18/84

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     Whittemore  and  Korn (1980) reported newly developed statistical methods
by which  they evaluated daily  asthmatic  attack  rates  recorded  in  diaries  by
asthmatics residing in the Los  Angeles area for 34-week periods (May to December)
during  1972  to 1975.   The panels  were  recruited by the U.S. Environmental
Protection Agency (EPA)  as part of the Community Health Environmental Surveil-
lance System  (CHESS),  and  participants were  asked  to complete weekly  diaries.
Diaries not  received within  16  days  after each week were discarded.   (The  EPA
data sets  used have  undergone  quality control to  ensure  accurate coding of
health  responses.)   The 16  location-specific panels  were  chosen  by local
consulting physicians,  differed from one  another in size and composition,  and
were not expected to be  representative of the asthmatic population.  Information
on demographic variables,  smoking, occupational  exposures,  and other factors
potentially related to asthmatic attacks indicated great interpersonal variabil-
ity.   Air pollution measurement (24 hr; midday to midday) periods were derived
from EPA  monitors  in  each of the  six communities  for all  pollutants except
oxidants.   Daily maximum hourly averages  for  oxidants  (KI) were used, as mea-
sured by  the  County Air Pollution  Control  Districts.   Each  individual in each
34-week period was considered separately in multiple logistic analyses (without
respect to place).   Many individuals were therefore counted in more than one
34-week period.  There were  444 such person periods (166 males under 17, and
65 males  over 17;  94 females under 17, and 119 females over 17).   Homes were
within 1 to 8 mi (average of 3  mi) from the monitoring sites.  Since RSP, NO ,
                                                                            )\
and SO  were  highly  correlated with  TSP,  TSP was  chosen as  an  index  for the
      yV
mix of other pollutants.  Weather variables, i.e.,  temperature,  relative humi-
dity (rh), and average wind  speed, were included in the regressions, as were
day-of-week indicators.
     Daily oxidant  levels  ranged  from  0.03 to 0.15 ppm between  areas  and
between times.   Each daily attack rate was  regressed  by multiple  logistic
regression function against  the presence  or absence of attacks  on  the preced-
ing day (to  correct  for an autocorrelation effect), the daily representative
levels of oxidant and  TSP, minimum temperature,  rh, and average windspeed, as
well  as against  variables  representing  time since the start of the study and
day of  week.  Days with  missing attack  data,  as  well   as days with missing
pollutant data, were  not included in the regressions.   The  autocorrelations of
asthma were the  most  significant variables in the logistic regressions.   The
other air pollution and weather variables were also independently significant,

019DC/A                              12-23                        6/18/84

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except  for  windspeed (which was later dropped).   Baseline  probabilities of
attacks were  determined, dependent upon whether or not an attack had occurred
on the previous day.  Relative risk probabilities for attacks being associated
with specified  increases  in oxidant  levels were also estimated by the model,
holding all other variables constant.   Counts of expected (from the model) and
observed  attacks  (from the  Los  Angeles  diary data) were then  compared to
determine how well  the model predicted actual data.  Although the panel  coef-
ficients  obtained for oxidant and TSP indicate a number of  consistent effects
(not all  panels  show such effects),  intrapanel variability with  respect to
temperature and  humidity  suggests  high  individual  variability  in responses.
Also, days  of cool  temperature elicited significantly high  attack rates.  The
relative  importance  of day  of week, day of  study, and attack on preceding day
indicate  that panel  studies  should include  these factors in the study design.
Results obtained  indicated, for example,  that  panelists  having a baseline
attack probability of 0.10 following  an  attack-free day and an attack probabil-
ity of  0.41 on  the  day after an attack day, would have the  attack probability
on a given day raised to 0.13 or 0.44,  respectively,  if oxidant levels increased
by 0.2  ppm.   Similarly,  even smaller increments (<0.01)  in relative risk for
attacks were estimated to be associated with  increases of 0.10 ppm in oxidant
levels.    No consistent departures from  the model  were noted  in  examining
deviations  of observed  from expected  values, indicating  that the  actual data
fit the model  quite well.   However,  caution is demanded before fully accepting
the obtained quantitative findings.   Use  of daily averages  of pollutant concen-
trations  from monitors distant from the subjects may not have been sufficient
or appropriate,  and  the  analyses  did not use data on medication use, pollen
counts,  daily  emotional  stress, other pollutants, exercise (e.g.,  in  cool
weather),  or respiratory  infections  (because these data  were not  collected).
The effects of such omissions could not  be tested.   Also,  the ascertainment of
attack was based on subjective appraisal,  without clinical  validation,  leading
to possible biases  in  reporting.   Last,  some data on  attacks  were missing,
and, as with  most  epidemiological  studies,  information on actual  subject
exposure  can  only  be inferred.   Shy and Mueller  (1980),  commenting on  the
study,   further  indicated that a repeated  measure  design  using analyses of
variance  would  have allowed an evaluation  of the  interaction  of  group  and
time, with  fewer comparisons necessary, and reduced cases where an individual
occurs  in more than one panel.

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     In  another  study of  exacerbation of preexisting  respiratory  disease,
Lebowitz et  al.  (1982a,  1983) and  Lebowitz  (1984)  studied 117  families  (229
subjects) from a stratified sample of  families in three geographic clusters in
a  community  study  population.   Families were chosen  to be representative  of
the  Anglo-white  population, stratified  by symptoms,  and monitored over a
                                                                           ®
2-year  period,  using daily symptom and  medication  diaries and mini-Wright
peak flow meters (Wright, 1978; Williams, 1979; Lebowitz  et al. 1982b; van As,
1982).   Daily  response  rates  were acceptable for a majority of days in all
seasons.  Checks by telephone and visits ensured proper use  of diaries, and
visits were made to calibrate peak flow meters.   All families provided informa-
tion on  their  houses, heating, cooling, and  appliances,  and smoking in the
household.
     Twenty three  adult  asthmatics in one cluster,  and a total of 35 adult
asthmatics, provided  daily  peak flows.  There were  353 days  with  sufficient
information  (>5  individuals/day) for  analysis.  There were additional  days
with  sufficient  information (n >  5)  on  separate  subgroups:  544 days from
adults with  reported  chronic  symptoms of airway obstructive  diseases (ADD),
494  days from  adults  with reported allergies, and 312 days from asymptomatic
adults.  For adults,  z-score  transformation (see above)  of peak flows  used
sex-,  age-,  and  height specific values.  Thus, all  peak flows  (V   ) were
                                                                  fflclX
adjusted for covariables and were in the same relative units. When the individ-
ual  was  the  unit of  study, a person-days dummy variable was used in analysis
to  eliminate  effects  of the different number  of  individual person days of
observation.   Hultivariate  analyses  of variance and regression  methods were
used to examine interactions and to control for colinear variables.
     Indoor and  outdoor  (around the residence) monitoring was conducted in a
random cluster sample of  study  households  (n = 41)  for air pollutants, pollen
bacilli, fungi,  and algae.   Monitoring for pollen  and TSP (measured by the
high-volume method) was conducted simultaneously in the center of each cluster,
and  pollutants were measured  regionally  in the basin  (see previous  discussion
for  details).  Symptom  rates  per 100  person days were calculated  from daily
diary data for asthmatics and nonasthmatics within exposure groups for compara-
tive purposes.   Attempts  to estimate  concentrations in  houses  not  monitored
yielded  a classification  based on gas-stove use and  smoking  in the houses.
Scanning electron  microscopy  showed that indoor dust  differed  from outdoor
dust, which was  generally almost all  silica quartz  (mass median aerodynamic

019DC/A                              12-25                        6/18/84

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diameter, MMAD, of ~ 5 pm), and rapid fall -off was observed for outdoor parti-
cles and pollen  as  participants  entered their houses (decreasing 100 to 200-
fold).
     For adults,  smoking  had  the biggest effect on V   .In adults with AOD
                                                     nicix
symptoms, 0- was significantly related to V    (P < 0.01) after adjustment was
           o                               nicix
made for smoking  and  relative humidity as covariables, and TSP and gas-stove
use  as  other main  effects.   Concentrations of  TSP were also significant
(P < 0.01), and the 03-TSP interaction had a P of 0.104 (n = 258 days).  Using
the  same variables  in multiple regression yielded a  regression coefficient of
-5.946 for  0,  (P <  0.005  by t-test) and  a  regression  coefficient  of + 0.004
(P < 0.0025) for TSP.
     In 23  asthmatics  in  one  geographic cluster where indoor monitoring was
most complete, 0., and temperature had a significant interaction in relation to
                <5
V    ; high  temperature  had an effect when 0^ was low, and 0., had an associa-
 iRSX                                        *3               o
tlon with  V  .   only in low temperatures  (Table  12-4).   However, 0^ was not
           max                                                     o
independently related  to  V    after adjustment was made for outside CO, tem-
                           max
perature,  humidity,  age,  smoking,  gas-stove use, indoor TSP, and residential
pollen  (fungi were  not independently important).  There was also an interac-
tion of 0~ and  temperature with prevalence  rates  of  acute  symptoms  in  these
asthmatics.  Temperature  was  more  important, since 0~  had  an  effect (though
not statistically significant) only within the high- temperature range.  (Since
only 75  incidence days of asthma attacks occurred in 3820 person days,  incidence
rates could not be evaluated.)  Ozone was associated with prevalence of rhini-
tis, but only  in those living in houses using gas stoves (P < 0.015) in this
group,  with  multivariate analysis  of  variance  controlling for temperature.
Daily medication was correlated highly with exacerbations of symptoms.
     The  0_  level  at which V    effects  were  seen,  although consistent, is
           o                  nicix
 lower  than expected.  After  controlling for other  variables, the  authors
speculated that the effects  in asthmatics were occurring  primarily at 0^
concentrations  > 0.052 ppm, with  0- acting either as  a surrogate for  other
oxidants  or in  conjunction with  other environmental conditions  (i.e.,  low
temperature, high TSP).
     A  study of health- related responses  to air pollution  in persons  with
chronic obstructive  pulmonary disease was conducted in  Houston,  TX,  by  Johnson
et  al.   (1979).   Javitz  et al .  (1983) recently  presented  the  results  of a
reanalysis of  this  study.  Logistic  regression  of a selected set  of self-
reported health symptoms  from oxidant exposure  revealed that the incidence of
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     TABLE 12-4.   THE RELATIONSHIP BETWEEN AVERAGE STANDARDIZED DEVIATIONS.
   OF PEAK FLOW IN ASTHMATICS AND THE INTERACTION OF OZONE AND TEMPERATURE"

   Maximum hourly
ozone concentration                             Temperature (°F)
ug/m3
<75

75-100

<102

ppm
<0.038

0.038 to 0.051

0.052 to 0.122

<61
-1.94
(217)°
-1.99
(327)
-2.11
(30)
61-80
-1.85
(219)
-1.78
(490)
-1.71
(549)
80-96
-2.17
(174)
-1.75
(388)
-1.57
(794)
Source:   Lebowitz et al.  (1983b).
 Analysis of variance for total explained variation and interaction,
 P < 0.0001.
 Person days of observation.
chest discomfort, eye  irritation, and "feeling worse than  usual"  increased by
10.1, 7.5, and 2.9 percent, respectively, as PAN concentrations increased from
0 to 0.012 ppm.  Incidence of nasal  symptoms and respiratory symptoms and use of
medication for respiratory  symptoms  increased by 6.0,  3.4,  and 5.2  percent,
                                                  3
respectively,  as  0~ increased from 0 to 412 ug/m  (0.0 to  0.21  ppm).   No
increased incidence of any specific nasal or respiratory symptom or of moderate
or severe nasal  or  respiratory symptoms were noted.   Linear regressions of
spirometry measurements on  daily peak 0,, revealed that  average FEV-.  decreased
                                        o                          .L
by 1.6 percent and  FVC decreased by 2.8 percent  as  0_  increased from 0  to 412
    3
jjg/m  (0.0 to 0.21 ppm).   The FEV1 and FVC changes with total oxidants (0  and
PAN) were similar to  those found for 0,. alone,  but were larger in magnitude
(FVC and FEV1 decreased 4.3 percent and  3.2 percent, respectively).  Considering
the relatively small  sample sizes  and test to test variability of 5 percent,
the magnitude of the effect is small  and of questionable significance.
     A major  shortcoming  of this study was that 0- measurements were missing
for about 40  percent  of  the study's 1026  site  days;  also, NO , hydrocarbon
(HC), CO, sulfur oxides (SO ), particulate matter,  PAN, and aeroallergens were
                           /\
measured only at some of the sites.   Daily maximum  hourly concentrations of 0-
were measured at the  monitoring station nearest each  subject's  residence.
However,   in  two  zones, 0- measurements  were  substituted from the  next nearest
019DC/A
12-27
6/18/84

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zone and the average reading of six continuous 0~ monitors was substituted in
                                                O
a third zone.  Thus, the  number of 0- measurements appears insufficient for
appropriate exposure information.  Personal  exposure  information was thought
to be the weakest link  in  the analyses (Javitz et al.,  1983).   Other difficulties
arise from the study's design:  (1) sample size (286) was not large enough to
allow for sufficient subclassification (Javitz et al.,  1983);  (2) over one-third
of the subjects  (total  grouped/ indexed) reported respiratory symptoms on 100
or more of this  study's 114 days, and over two-thirds reported nasal symptoms
on 10 or  fewer  days.   This apparent extreme  skewing of symptom behavior may
have made such  information relatively insensitive to any detected pollution
effect.   Also,  Finally, the number (114) of  monitoring  days  may have been
insufficient to allow enough variation in exposure variables or effect variables
for relationships between  the two to be discerned.  A low correlation between
spirometry and questionnaire variables may indicate low validity of one or the
other  (Helsing  et  al., 1979),  and the possibility of a differential attack
rate based on  lags  was not studied.   Finally, a  number  of variables (e.g.,
age, sex, socioeconomic status,  migrant pattern,  smoking, occupation) may have
been interacting  in  a  colinear  or confounding fashion,  but were not suffi-
ciently assessed in the analyses.
     In regression  analyses  of  questionnaire variables,  the health endpoint
was a proportion  of subjects reporting symptoms  at each site  rather than the
presence or  absence  of symptoms in individual subjects.   These analyses were
usually pooled across  all  sites,  although sometimes they were pooled across
only three sites.   Site-specific  regression  of questionnaire variables does
not appear to have  been performed.  Only  in  regression analysis  of the spiro-
metric variables did the individual serve as  his  or her own control.   Half the
spirometric  regression analyses appear to have been limited to only one site.
Therefore, the type of health endpoints and the methods of analyses are incom-
olete and  Inappropriate.   Furthermore, insufficient information  was available
on  daily  pulmonary function with which  to correlate  or perform  regression
analyses against daily pol'iutant measurements.
12.3.1.5  Incidence of Acute Respiratory Illness.  Table 12-5 describes studies
relating  oxidant levels with the incidence  of acute  respiratory illnesses.
These studies,  however, did not meet the criteria  necessary  for developing
quantitative exposure-response relationships.
12.3.1.6  Physician, Emergency Room, and Hospital Visits.  Previously reviewed
studies (Environmental Protection  Agency,  1978)  have indicated  that  oxidant
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                                       TABLE 12-5.  STUDIES OF ACUTE  RESPIRATORY  ILLNESS
        Reference
             Subject matter
                                                                                                   Findings
   Nagata et al.  (1979)
   Durham (1974)
   Pearlman et al.  (1971)
ro
ro
to
   Wayne and Wehrle (1969)
   Cassell et al. (1969)
   and Mountain et al.
   (1968)
Health insurance records from two locations
in Japan, July-September 1975.
Health service visits for respiratory
illness in students at five Los Angeles
and two San Francisco colleges.
Incidence and duration of influenza-
like illness, December 1968-March 1969,
among elementary school children in five
southern California communities.
Absenteeism in two elementary schools, 1962-
1963.
Frequency of cough, sore throat, colds,
eye irritation, and headaches in a New
York City population near the monitoring
station.
No relationships between oxidant levels
(average hourly max = 0.066 ± 0.041 ppm)
and new acute respiratory diseases.   Other
pollutants were not studied.

Pharyngitis, bronchitis, and colds associ-
ated with oxidant levels on same day and on
7 preceding days.  Stronger associations
in Los Angeles than in San Francisco.
Oxides were measured about 5 mi away.   Other
pollutants and climatic variables were not
control led.

No relationship between photochemical  oxi-
dant gradient and illness rates during an
influenza epidemic occurring in a low-
oxidant period; all the communities had
similar levels.

No consistent association between oxidant
level and absenteeism.  Other pollutants
were not considered.

In summer, symptoms in children <8 years old
were related to carbon monoxide (surrogate of
ozone and particulate matter).   In adult
heavy smokers, eye irritation and headache
were related to carbon monoxide.  Maximum
effect often occurred 1 to 2 days after the
peak of pollution.  Summer pollution was
associated with symptoms in the total  popu-
lation.  No ozone or oxidant concentrations
were monitored.

-------
concentrations are insufficient for hospital  admissions,  with no clear separa-
tion of  oxidant  effects  from effects of other  pollutants.   The effects of
social  factors, which produce day-of-week and weekly cyclical variations, and
holiday and seasonal variations,  are rarely removed (and then with possible
loss of  sensitivity).  Attempts  to relate  time of visit to time of exposure
are also very difficult.   Any visit to medical  facilities usually lacks appro-
priate denominators  (the  number  of those at risk), since they are generally
not available, and  the  catchment area is unknown  (Bennett,  1981;  Ward and
Moschandreas, 1978).  In  addition,  with  the increased use of  the  emergency
room as  a  family  practice center, visits are becoming  less  associated with
acute  exposure  or attack  than  they once were.   Emergency room  data, like
hospital record  data,  often lack, information  on  patients'  smoking habits,
ethnic  group,  social  class,  occupation,  and even  other  medical  conditions.
     A study  by  Namekata  et  al.   (1979) of emergency room visits for  cardiac
and respiratory diseases  in  two hospitals  in Chicago must be considered in-
adequate because:   (1)  information  collected from the medical  records is
insufficient to identify sources of variability in the data and to control  for
confounding factors of the types noted above; (2)  the 0~ data are insufficient
and  incomplete;  and (3) the linear  models  used could not determine  effect
levels of the pollutant.
     Goldsmith et al. (1983)  studied emergency room visits  in  four Southern
California  communities  (Long Beach,  Lennox,  Azusa, and  Riverside)  during
1974-1975.    Logbook  data  on  total  admissions were  taken  from two hospitals  in
each of  the first three communities  and from three  hospitals  in the  fourth.
The  hospitals were  £ 8 km from  Southern California Air Quality Management
District stations monitoring TSP, GX> CO,  NO,  N02>  S02>  sulfate (SO^, and
aldehyde (COH).   Catchment areas and air monitoring  data  from  residential  and
work sites were unknown for the  subjects included  in the study.  The  data were
adjusted for  day-of-the-week and  long-term trends, but not for seasonal trends.
Maximum  hourly averages of oxidants  and temperature were reported to  be associ-
ated with  daily  admissions in the high-oxidant area (Azusa) after correction
for other variables  using  correlation coefficients from path analysis  (although
the  more complete path analysis explained  less variance than  the standard
regression  model).   Humidity had a  positive effect  and  sulfates a negative
effect when these variables  were  included  in  the  model.   Unfortunately,  the
lack  of population denominators  and characteristics,  the lack of admission

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characteristics, and poor  characterization  of exposures seriously limit the
use of these findings.
     Bates and  Sizto (1983) studied admissions to all 79 acute-care hospitals
in Southern Ontario (i.e.,  the whole catchment area) during 4 months  (January,
February, July, August)  in each year (1974,  1976-1978, and 1979-1980).  Air
pollution data  for CO, N02> 03>  and COH were  obtained from 15 stations mostly
along the prevailing wind direction.   Temperature was controlled.   In July and
August, highly  significant associations (Pearson r,  1-tailed, P < 0.001) were
found between  excess (percent  deviations  from day-of-week and seasonal means)
respiratory admissions  and average maximum hourly  SO- and  0~  (KI  method)
concentrations, and temperature (with 24- and 48-hr  lags between the variables).
Nonrespiratory  admissions  showed no relation to pollution.   Ozone  (maximum
hourly average  = 62.8 ppb) was independently  related to admissions, as repli-
cated in 1979 when S03 was greatly reduced.   Temperature was also independently
important (-5.3°C average  on winter days  in study).   Admissions, and admission
correlations with  pollutants,  were consistent  from year to year.  Further
analysis  showed that asthma was the most  significant  respiratory  problem
driving  the  admissions  up,  especially  in  younger  people.   Bronchitis and
pneumonia admissions were  not  significantly related  to pollutants.  The authors
state that  effects  of  sulfates could  not  be separated from 03 effects.  Since
the number of separate people  admitted was  unknown,  a "sensitive" subpopulation
could have  affected  the  results.  Improvements in the monitoring data (i.e.,
exposure) would help interpret these findings.
     Whether changes in  hospital use reflect  changes in either illness experi-
ence  or  illness perception and  behavior  is still  uncertain.  A  person may
behave differently  according to perceptions of  environmental  challenges.   The
response  of the medical  care  system  is  also  determined by several  factors,
including insurance and  availability of physicians,  beds, and services (Bennett,
1981; Ward and  Monchandreas, 1978).  Artifacts may arise from changing defini-
tions of classifications and  varying diagnostic or  coding practices as well.
Another  frequent problem is that repeated admissions or attendance by  a small
number  of patients can  cause  tremendous  distortions in the data (Ward and
Moschandreas,  1978).   Furthermore,  hospital statistics  often lack reliability
and  validity  since determining incidence is  difficult, insufficient clinical
data  are available to support resolution of  diagnostic category in grading
severity, and  a number of  potential subclassifications of patients may require
separation and  attention in the  analysis  (Ward and Moschandreas,  1978).
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12.3.1.7  Occupational Studies.   Studies  of acute effects from  occupational
exposure are summarized in Table 12-6.  These studies did not meet the criteria
necessary for  developing quantitative  exposure-response relationships  for
ambient ozone/oxidant exposures.

12.3.2  Trends in Mortality
     The possible association  between exposure to 0  and increased mortality
                                                    *5
rates  has  been investigated a  number of times, and the results have been
reviewed at  length  in previous documents  (National  Research  Council, 1977;
U.S. Environmental  Protection  Agency, 1978; World Health Organization, 1978;
Ferris, 1978).  In  1978,  the U.S. Environmental Protection Agency published
data on the  average number of deaths attributed  to  cardiac  and respiratory
causes among residents of  Los Angeles County for different temperature ranges
and days with low and high oxidant concentrations.   This report suggested that
a positive  relationship  might  exist  between oxidant exposure  and mortality
between 70°  and 79°F.   However,  only five  of  the  seven curves plotted from
data in the  range of  70° to 79°F  have positive  slopes.   This proportion  could
show positive  slopes  simply  by chance,  with a  probability of  P = 0.16 by a
sign test (as recalculated from the data), thus failing to support a relation-
ship between oxidant concentrations and mortality.   This failure is especially
probable in  light of  the inconsistent slopes  in the  range  of 80° to 89°F.
Since  high  temperature  and  elevated  oxidant  concentrations tend to occur
simultaneously in the Los  Angeles Basin, Oechsli  and Buechley (1970) studied
the effects  on mortality  of  heat waves among the  elderly (in 1939, 1955, and
1963).   They could not find evidence that high photochemical  oxidant concentra-
tions could  augment the mortality effect  of high temperature.  Biersteker and
Evendijk (1976) reached  similar  conclusions about heat-related  mortality in
July and August of 1975  and 1976 in Rotterdam,  the Netherlands.
     Sensitive subpopulations  studied have  included elderly  residents  of
nursing homes  and individuals  with cardiopulmonary disease.   The California
Department of Public Health (1955, 1956, 1957)  survey of nursing homes attempted
to correlate daily mortality and patient transfers to the hospital with maximal
daily temperatures and 0.-  concentrations (>0.3 ppm).   Heat had a significant
effect on mortality,  but  no  correlation could be  found between mortality and
high-03 days (Breslow and Goldsmith, 1958; Tucker,  1962).
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                              TABLE 12-6.  STUDIES OF ACUTE EFFECTS FROM OCCUPATIONAL EXPOSURE
      Reference
             Subject matter
                    Findings
 Fabbri et al. (1979)
   Sarto et al. (1979a,b)
 Truche (1951)
 Kleinfeld et al.  (1957)
ro
i
CO
CO
 Kudrjavceva  (1963)
  Poloskaya  (1968)
Pulmonary function in workers in a plastic
bag factory (31 exposed and 31 controls
of same age,  height,  smoking habits).
Reported symptoms in tests of electric
insulators with prolonged exposure to
ozone >0.1 ppm.

Clinical findings and symptoms in welders
using inert gas-shield consumable electrodes
in three plants with ozone measured at
breathing zones.
Symptoms in hydrogen peroxide production
workers employed 7-10 years.
Symptoms in welders and nearby workers
(controls) ages 25-35, with less than
than 5 years employment.
Decreased expiratory flow in 8 of 31 subjects
at ozone levels of 196 to 1803 pg/m3 (0.10 to
0.92 ppm) during workshift.   Lower flows in
exposed smokers than control smokers.   Acute
changes to acetylchol inesterase, peroxidase,
and lactate dehydrogenase.   Other pollutants,
including formaldehyde (0.18 to 0.20 ppm, 220
to 245 pg/m3), were not controlled.

Reports of thoracic cage constriction, in-
spiration difficulty, and laryngeal  irritation.
Other pollutants were not controlled.

Increase in chest constriction and throat
irritation at 1-hr concentrations of 588 to
1568 pg/m3 (0.3 to 0.8 ppm); no complaints
or clinical findings below 490 pg/m3 (0.25
ppm).  Nitrogen dioxide and total suspended
particulate matter were not measured or
control led.
At 348 to 556 MQ/m3 (0-25 to 0.40 ppm) head-
ache, weakness, increased muscular excitability,
and decreased memory.   Other gases were possibly
important.

More frequent complaints of respiratory irri-
tation, headache, fatigue, and nosebleeds in
welders; exams were normal.  Ozone averaged
3332 pg/m3 (1.7 ppm), with maximum of
4900 ug/m3 (2.5 ppm); carbon monoxide and
nitrogen dioxide were below permissible levels.
Total suspended particulate matter was not
studied.

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                        TABLE 12-6.  STUDIES OF ACUTE EFFECTS FROM OCCUPATIONAL EXPOSURE  (continued)
     Reference
             Subject matter
                                    Findings
von Nieding and Wagner
 (1980)
Oxhoj et al. (1979)
Challen et al.  (1958)
Young et al.  (1963)
Nevskaja and Diterihs
  (1975)
Health effects in male German metallurgical
plant workers, as measured by questionnaire,
absenteeism, insurance records, vital capa-
city measures, plethysmographic measures,
blood pressure, and airway resistance.
Ozone nitrogen oxides, and sulfur oxides
were sampled.

Pulmonary function in electric arc
welders (n = 119, 5-38 years exposure)
and clerical controls matched on smoking
and age.

Symptoms in 14 helio-arc welders.
Lung function in seven welders
argon-shield.
using
Illness in hydrogen peroxide production
workers measured by questionnaire and
pulmonary function.
                Group exposed to high ozone had more absen-
                teeism and more episodes of bronchitis and
                pneumonia, more cough and phlegm, and higher
                airway resistance than did controls.  However,
                high total suspended particulate matter levels
                and temperature-induced volatilized metals
                obscured effects of ozone.

                No acute effects found.   Chronic pulmonary
                function changes thought to be related to par-
                ticles only (not controlled).
Upper respiratory symptoms in 11 of 14 welders
exposed daily to ozone (0.8 to 1.7 ppm, 1568
to 3332 (jg/ m3), which disappeared with expo-
sure to 392 |jg/m3 (0.2 ppm).   Pulmonary
congestion was seen at 3920 \ig/m3 (2 ppm).
Nitrogen dioxide was present, but not studied.

No changes in function from ozone (0.2 to
0.3 ppm, 392 to 588 pg/m3).  Nitrogen dioxide
was probably present, but not controlled.

Increased prevalence of bronchitis and
emphysema and decreased expiratory flow rates
reported.  Ozone concentrations were between
78 and 98 pg/m3 (0.04 and 0.05 ppm)  Sulfuric
acid was also present.

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     Massey et al.  (1961) compared daily mortality in two areas of Los Angeles
County with similar temperatures but different photochemical pollution levels
by multiple correlation and regression.   No statistically significant relation-
ships were observed.   Buell  et al.  (1967) studied  lung  cancer mortality in
different  areas  but  could draw no meaningful conclusions.   Mills (1957a,b)
compared  nursing  home deaths with an index  of  photochemical pollution and
found a positive association between  the index and excess deaths; other in-
vestigators who analyzed the data observed no associations (California Depart-
ment of Health,  1955,  1956,  1957; Breslow and Goldsmith,  1958).   Studying the
effect of  pollution concentrations on cardiac and respiratory  diseases in Los
Angeles County,  Hechter  and  Goldsmith (1961) found  no significant correlation
between pollutants and mortality, either on the same day  or  after 1  to 4 days
of higher concentrations.  Hechter and Goldsmith (1961)  also failed to identify
a contribution of  oxidant levels to daily mortality in Los Angeles from 1962
to 1965.
12.4  EPIDEMIOLOGICAL STUDIES OF EFFECTS OF CHRONIC EXPOSURE
     Only a  few prospective  studies  of  the  chronic effects  of 0., exposure are
available.  These  studies  are  usually concerned with symptoms,  lung function,
chromosomal effects,  and mortality rates.   Mortality from chronic  respiratory
diseases and lung cancer has not been observed following oxidant exposures and
is not  likely  to  occur given  the relatively  low  levels of oxidants and the
proposed mechanisms of action.

12.4.1  Pulmonary Function and Chronic Lung Disease
     Cohen et al.  (1972) found no difference in ventilatory function or chronic
respiratory symptoms in nonsmoking adults in the San Gabriel Valley and in San
Diego,  but  their  findings are limited  by  the similarity of annual average
ambient levels of oxidants in the two areas.  From 1963 through 1967 arithmetic
mean oxidant levels were 0.047 ppm in San Gabriel Valley and 0.038 ppm  in San
Diego.  Average daily maximum  hourly oxidant levels during the period of the
study were  0.12 ppm and 0.07 ppm, respectively, and other  pollutants (TSP,
S02, and RSP) were equivalent  in both areas.
     The University of  California at Los Angeles (UCLA) population studies  of
chronic obstructive  respiratory diseases in  communities with  different air

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pollutant exposures have  been  reported by Detels and colleagues  (Detels  et
al., 1979; Rokaw et al., 1980;  Detels et a!.,  1981).   Three areas were exposed
to  photochemical  oxidants (Burbank, CA); SO  ,  particulates,  and HCs (Long
Beach, CA); and low levels of gaseous pollutants (Lancaster, CA).   The prevalence
of  symptoms was  reported  to  be increased in the residents of polluted areas.
Lung  function was generally better among residents of the  low-pollution areas
according to measurements of FEV,,  FVC, maximum expiratory flow rates, closing
volume, thoracic volume,  and  airway resistance.  Maximal  mid-expiratory flow
rate, considered to be  sensitive  to changes in small  airways, was similar in
all areas, while  the  mean AN_ was slightly decreased among residents of the
low-pollution areas.  Although the  results  suggest that  adverse  effects  of
long-term exposure to photochemical  oxidant pollutants may occur primarily in
the larger airways, their usefulness is limited by a number of problems.  For
example,  testing of subjects  was  not concurrent and occurred over a 4-year
period between areas; the authors presented no  information on such matters as
self-selection and migration in and out of these areas.
     Additional comparisons between  mobile  laboratory and  hospital laboratory
test  results  did not always show adequate reproducibility.  The study popula-
tions had mixed  ethnic  groups, and completion rates were approximately 70 to
79  percent in the three areas.   Comparisons  of participants with census informa-
tion  were fairly close.   Analysis of the comparisons of the three  communities
for symptoms  and  pulmonary function results used age- and sex-adjusted data
only  from white  residents who  had no history  of change of  occupation  or resi-
dence because  of  breathing problems.  Those with occupations  that may have
involved  significant exposure  were  not necessarily excluded.  Analyses were
often made by smoking status and compared means or proportions that fell above
or  below  certain levels.
      A major  difficulty in the analyses is that the exposure data presented
are not adequate.  Control of migration effects on chronic exposure was insuf-
ficient,  and  recent exposure  information was provided only by ambient levels
from  only one monitor,  located as far  as 3 mi away.  A  further  problem  is
that,  as  in most geographical  comparisons,  analysis of results  assumes  no
differences by place,  date, or season.   This assumption is especially important
since  the study  periods in each community were quite different.   Furthermore,
over  the  4-year period  of the  study  there were  many changes,  including amounts
and types of cigarettes  smoked, respiratory  infection  epidemics, and other

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undeterminable influences  that  could have affected the  results.   Also,  the
numbers of subjects changed  from one report to another and from one analysis
to another.
     The major problem in interpreting the pulmonary function data is that the
results do not appear to have been validated, as judged by the poor correlations
between function and chronic symptoms and the fewer than expected smokers with
abnormal lung function.  In  tests such as  interpretation  of  flows  at  low  lung
volume or the single-breath nitrogen study, there do not appear to be appropri-
ate comparisons  for determining observer  differences  or biases, which are
critical for these difficult tests.
     Another major  problem is  that  the investigators  used  cutoff points to
examine the  differences  among the areas.   Why  cutoffs  that were  three to  five
standard deviations below  the  mean  were chosen  is  unclear,  especially since
many of the  variables  examined were not normally distributed.  By performing
the analysis in the manner described, very few people were left with abnormal-
ities  in any group.  Inconsistencies  first surfaced when  the authors  examined
such variables  as total proportions of subjects  with  symptoms or the mean
percent predicted lung function, and these inconsistencies grew worse.  Further-
more,  the method  was  inadequate to determine differences between one case in
one area and two  cases  in another  area.   Insufficient numbers of cases were
available, and the trends were in the wrong direction, especially those of the
single-breath nitrogen ANp.  Whether the covariables and confounding variables
were sufficiently handled  in the analysis  is not clear.  Thus, this study must
be  treated  as an  insufficiently quantitative  study  for present purposes.
     Additional studies  of chronic  morbidity are shown in Table 12-7.  These
studies also do not provide  information useful for  quantitative exposure-effect
assessment.    Thus,  to  date,  insufficient information  is available in the
literature on possible exposure-effect relationships between 0_ and the preva-
lence  of chronic lung disease.   These relationships need  further  study.

12.4.2 Chromosomal Effects
     The importance of chromosomal  damage depends  on  whether the effect  is
mutagenic or cytogenetic,  and,  thus, whether  it occurs  in autosomal  cells or
peripheral  lymphocytes.  Translocations  and trisomies are important  forms of
genetic damage, whereas minor  chromosomal breakage (e.g., as  associated with
caffeine) are  of  questionable  significance.   Interest  in chromosomal damage

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                                      TABLE  12-7.  ADDITIONAL  STUDIES  OF  CHRONIC  MORBIDITY
         Reference
             Subject matter
                    Findings
    California  State  Depart-
      ment  of Public  Health
      (1955-57)
    Hausknecht  (1960,  1962)
    Deane  et  al.  (1965),
     Goldsmith and  Deane
     (1965)
co  Peters et  al.  (1973)
    Linn  et al.  (1976)
    Ulrich et al.  (1980)
Illness onsets throughout California in
various age groups, measured by weekly
surveys.
Prevalence of illness in survey of 3445
households throughout California.  Chronic
pulmonary disease studied four times, 1957-
1959.

Symptoms, measured by questionnaire and
ventilatory function, in outdoor tele-
phone workers 40-59 years of age in San
Francisco and Los Angeles.

Illness in 61 welders, 63 pipefitters, 61
pipecoverers, and 94 new pipefitters,
measured by questionnaires,  pulmonary
function, partial physicals, and X-rays.

Respiratory symptoms and function in office-
workers in Los Angeles and San Francisco,
Summer of 1973.
Immunological  values in 30 workers (mean
age 34) exposed for 2 to 9 years (mean of
4.3) to ozone,  compared to reference values.
No relationship between incidence of illness
and area in the young.  Elderly showed some
increases in Los Angeles.  Pollutants other
than ozone were also higher.

Higher prevalence rates in Los Angeles and
San Diego.  No quantitative ozone data.
No differences in symptom prevalence between
cities, although particulate concentrations
were about twice as high in Los Angeles.  No
aerometric data.

Lung function obstruction in smokers in first
two groups; third group had restrictive func-
tion.   Otherwise, no differences were
observed.   Many pollutants were also involved.

No difference in chronic respiratory symptom
prevalence between cities.   More frequent
reports of nonpersistent (<2 years) produc-
tion of cough and sputum by women in the more
polluted community.   Different populations
and different aerometric characteristics
complicate the analysis.

Increased immunoglobulins (IgG, IgA, and
IgM),  transferrin a, antitrypsin, apparently
associated with 39 to 588 ug/m3 (0.02 to
0.3 ppm).   Other pollutants were not
evaluated.

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from 0, derives  from in vitro and i_n vivo studies (Chapter 10).  Findings in
      «5               J   ————     Mm  ,•—«••«.
In v.1vo numan  studies  are conflicting, but generally  negative  (Chapter 11).
     Four epidemiological  studies have investigated chromosomal  changes  in
humans exposed to  0_.   None indicate any evidence that 0- affects peripheral
lymphocytic chromosomes in humans at the reported ambient concentrations.   For
example, Scott and Burkart (1978) studied chromosome  lesions  in peripheral
lymphocytes of students  exposed to air pollutants  in  Los Angeles.   In their
study of  256 college  students who were  followed  continuously, they found
chromosomal changes  that  were  almost entirely  of the simple-breakage type and
not more numerous than is usual in a population study.
     Magie et al. (1982) studied chromosome aberrations and peripheral lympho-
cytes in college students:   209 nonsmoking freshmen at a campus with higher
                                    3
smog levels (>0.08 ppm 0~; >160 ug/m ) and 206 freshmen at a campus with lower
                                     3
smog levels  (<0.08  ppm  O^; <160 ug/m ).  Both campuses were  located in Los
Angeles.  Students were enrolled in the study after completing questionnaires,
and were assigned  to groups on the basis  of  campus and previous residence.
Blood samples  and  medical histories (obtained at the beginning of the school
year, in November, in April, and at the beginning of the next school year) were
analyzed for chromosome and chromatid  aberrations,  but no significant effects
were found for chromosomal structure of peripheral lymphocytes.
     Bloom (1979) studied military recruits before and after welding training.
No effects were  seen (03 levels were  negligible  and  N0«  was high).  Fredga
et al.  (1982) studied the incidence of chromosome changes in men occupationally
exposed to automobile fuels and exhaust gases in groups of drivers, automobile
inspectors, and a reference group matched with respect to age, smoking habits,
and  length of  job employment.   Chromosome preparations from lymphocytes were
made and analyzed  by standardized routine methods.  Analysis of the data gave
no evidence for an occupational effect.
12.5  SUMMARY AND CONCLUSIONS
     Field and epidemiological studies, when properly executed, offer a unique
view of health effects research because they involve the real world, i.e., the
study of  human  populations in their natural setting.  However, these studies
also have attendant limitations that must be considered in a critical evaluation
of their results.  One major problem in singling out the effects of one pollutant

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in field studies of either morbidity or mortality in populations has been the
interference of other critical  variables in the environment.   Limitations also
exist for epidemiological  research on the health effects of oxidants,  including
interference or interaction between oxidants and other pollutants;  meteorological
factors such as temperature; proper exposure assessments including individual
activity patterns  and location  of pollutant monitors;  difficulty in identifying
oxidant species responsible  for  observed effects;  and characteristics of the
populations such  as  hygiene practices,  smoking habits, and  socioeconomic
status.
     Investigative approaches comparing  communities with high 0~ concentra-
                                                                O
tions and  communities with low 0_ concentrations have usually been unsuccess-
ful, often because actual  pollutant levels have not differed enough during the
study and  other important variables have  not been adequately controlled.  The
terms  "oxidant" and  "ozone"  and their  association  with health effects  are
often insufficiently clarified.   Moreover, our knowledge about the measurement
and calibration methods used is  still  lacking.  Also,  as  our knowledge and
skills in  epidemiology  improve,  the incorporation  of new  key variables  into
the analyses is required.   Thus,  the incorporation  of  individual exposure data
(e.g., from the home and workplace) becomes more of a  necessity.
     Both  acute and  chronic exposure situations have  been reported in  the
literature on photochemical oxidants.   Relevant studies providing quantitative
information on effects associated with acute exposure  include those on irrita-
tive  symptoms,  pulmonary  function, and  aggravation of  existing respiratory
disease (Table 12-8).  A  few studies,  of limited quality,  have been reported
on  morbidity,  mortality,  and  chromosomal effects   from chronic exposures.
     Studies on the  irritative effects of  0,  have  been complicated by  the
presence of other  photochemical  oxidants and their precursors in the ambient
environment.  That 03 causes the eye irritation  normally associated with smog
is  doubtful.   Nevertheless,  studies  indicate that eye  irritation is likely to
occur at oxidant levels of about 0.10 ppm.  A shown in Table 12-8, associations
between oxidant levels  and symptoms  such  as eye, nose,  and throat  irritation,
chest  discomfort,  cough,  and headache have  been  reported at >0.10  ppm  in both
children and young adults (Hammer et al.,  1974; Makino and Mizoguchi,  1975;
Okawada et al., 1979).  Zagraniski  et al.  (1979) also  reported  an  association
                                             3
of these symptoms with approximately 157  ug/m  (0.08 ppm)  ozone in adults with
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                         TABLE 12-8.   SUMMARY TABLE:   ACUTE  EFFECTS  OF  OZONE  AND  OTHER  PHOTOCHEMICAL OXIOANTS  IN  POPULATION  STUDIES
       Lowest
  ;   estimated
  ieffect level,
       ppm
   Average maximum
hourly concentration
 range during study,
         ppm
Observed effect(s)
Subjects
                                                                           Reference
  jOXIDANTS
ro
  I 0.10-0.
                         0.03-0.15
                         <0.04-0.50
                        Daily asthma attack rates increased on days
                        with high oxidant and particulate levels and
                        on cool  days during a 34-week period in Los
                        Angeles.
                                        Juvenile and adult
                                        asthmatics
                        Symptoms  of eye irritation,  cough,  chest
                        discomfort, and headache related to oxidant
                        concentration but not carbon monoxide,
                        nitrogen  dioxide, or daily minimum
                        temperature.
                                                                                                  Young  adults
                      Whittemore and Korn,  1980
0.10

0.02-0.21 Eye irritation incidence rates increased with
oxidant concentration.
<0.23 Symptoms of eye irritation, sore throat,
headache, and cough related to oxidant
concentration and temperature but not
S02, N02, or NO.
Adolescents
Children and
adolescents
Okawada et al . , 1979
Makino and Mizoguchi, 1975
                                                                  Hammer et al.,  1974
                         0.06-0.37
                        Impaired athletic performance related to
                        oxidant concentration but not nitrogen
                        oxide,  carbon monoxide,  or particulate
                        levels  1 hr before cross-country track
                        meets in Los Angeles.
                                                                                                  Adolescents
                                                                  Wayne et al. , 1967
                                                                  Herman, 1972

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                TABLE 12-8.   SUMMARY TABLE:  ACUTE EFFECTS OF OZONE AND OTHER PHOTOCHEMICAL OXIDANTS IN POPULATION STUDIES  (continued)
h— >
1
rv>
Lowest Average maximum
estimated hourly concentration
effect level, range during study,
ppm ppm
OZONE
0.08 0.004-0.235
0.08 0.01-0.12
0.08 0.01-0.12
0.15 0.01-0.30
0.166 0.16-0.17
Observed effect(s)

Increased daily prevalence rates for cough,
eye, and nose irritation in smokers and
patients with predisposing illnesses; pH of
parti cul ate was associated with eye, nose, and
throat irritation while suspended sulfates were
not associated with any symptoms.
Daily peak flows decreased 12.2 to 14.8% with
ozone and total suspended parti cul ate matter.
Decreased daily peak flows and increased pre-
valence rate for acute symptoms associated
with ozone, low temperature, and high total
suspended parti cul ate matter.
Increased airway resistance associated with
ozone, sulfur dioxide, and temperature.
Small decrement in forced expiratory function
and increased symptoms with exercise in both
normals and asthmatics.
Subjects

Asthma and allergy
patients; normal
adults
Children and
young adults
Adult asthmatics
Adolescents
Normal and
asthmatic adults
Reference

Zagraniski et al., 1979
Lebowitz et al., 1982a, 1983
Lebowitz, 1984
Lebowitz et al . , 1982a, 1983
Lebowitz, 1984
Kagawa and Toyoma, 1975
Kagawa et al. , 1976;
Kagawa, 1983
Linn et al. , 1980, 1983
 Ranked by lowest estimated effect level for oxidant or ozone.
 Not determined.
 U.S.  Environmental Protection Agency, 1978.
dHasselblad et al., 1976.
eDaily mean concentration of ozone was monitored by ultraviolet photometry inside a mobile laboratory;  Linn et al.,  1980, report concentrations
 multiplied by 1.25 that correspond to the neutral buffered potassium iodide (KI) method.

-------
asthma and allergies.   Discomfort caused by irritative symptoms may be respon-
sible for  the impairment  of  athletic performance reported  in  high school
students during cross-country track meets  in Los Angeles (Wayne et  al., 1967;
Herman,  1972).   Although several additional studies  have  shown respiratory
irritation apparently related to ambient exposure in community populations,
none of these studies provide satisfactory quantitative data on acute respira-
tory illnesses.
     Acute epidemiological studies in children and young adults have suggested
that decreased peak flow and increased airway resistance occur  over the range
of Oo concentrations  from 157 to 294 ug/m  (0.08  to 0.15 ppm) (Kagawa and
Toyoma,  1975; Kagawa et al., 1976; Kagawa, 1983; Lebowitz et al.,  1982a,  1983;
Lebowitz,  1984).   Qualitative studies  support this finding (McMillan et al.,
1969; Lebowitz et al. , 1974; Fabbri et al.,  1979).   No controlled  human expo-
sure studies  in  children  are presently  available for comparison,  although
                                                            3
studies in  adults  appear  to  show no effect below 235 ug/m  (0.12 ppm)  0-
(Chapter 11).
     In studies of exacerbation  of asthma and chronic lung diseases, the major
problems  in  most of the  studies  have  been the lack  of  information on the
possible effects of medications,  the absence of records  for all days  on which
symptoms  could  have occurred, and  the  possible concurrence of symptomatic
attacks.  Investigators  who have  been able to control some  of  these variables
have found consistent effects of 0_ on  asthma  (TabTe 12-8).  Their findings
have been  in  accordance  with those of some of  the earlier, more qualitative
studies.  Whittemore and Korn (1980) found small  increases  in  the  probability
of asthma  attacks associated  with increases of 0.10  ppm  in oxidant levels.
Zagraniski et al.  (1979) reported an increased prevalence rate for  respiratory
                                     3
symptoms with approximately  157  ug/m   (0.08 ppm)  0,,  in patients with asthma.
Linn et al.  (1980,  1983)  found  decreased pulmonary  function and  increased
                                                                     3
symptoms  in  lightly  exercising  asthmatics exposed to 314 to 333 ug/m  (0.016
to 0.17 ppm)  0~  or  greater,  regardless  of  other pollutants.  With  increased
                                                      3
exercise levels,  small effects were found at 235 ug/m  (0.12 ppm)  0.,.  Lebowitz
et al.  (1982a, 1983) and Lebowitz (1984) showed effects in asthmatics, related
also to temperature,  at  03 levels of 102  to 235  ug/m  (0.052 to  0.12 ppm).
There have been  no  consistent findings  of  symptom aggravation  or  changes in
lung function in patients with  other chronic lung  diseases besides asthma.
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     Apparent adaptations have been observed under controlled conditions with
humans, but this effect would be  difficult to demonstrate  in  community popula-
tions.   Recent  work with animals  suggests that the processes  involved  in
adaptation may lead to other, perhaps  adverse effects,  but no implications  for
human health can yet be drawn.
     Although animal  studies indicate that ()„ impairs defenses against infec-
tion (Chapter 10), this impairment has not been examined in clinical studies.
No positive  studies  of  0,  effects on acute  respiratory illnesses  have been
reported in  human populations.   In addition, most studies have yet to address
the hypothesis  that  years  or decades  of air pollution  exposures beginning  in
childhood, especially among the sensitive, may increase the risk of developing
chronic illness (U.S. Environmental  Protection Agency,  1978).
     The lack of quantitative measures of oxidant levels limits the usefulness
of many studies  of  pollution exposure and mortality.  In addition, properly
designed studies have not been conducted to address  the effects of oxidants on
the growth and development of the lung or on the progression  of chronic diseases,
although the available evidence is consistent with toxicological data indicating
that 0, is not a strong mutagen or a demonstrable carcinogen  at ambient concen-
      «D
trations.   Most  long-term studies have employed average annual  levels or have
involved broad ranges of pollution;  others have used a  simple high-oxidant/low-
oxidant dichotomy and compared mortality results.   Failure to relate mortality
to  specific  levels (and types)  of  oxidant pollutants  makes  formulation of
exposure-response relationships impossible.  Epidemiological  identification of
chronic effects  of  air  pollution generally requires well-conducted  replicated
studies of  large,  well-defined populations over long periods  of time, which
are not available at this time for 0_ or other photochemical  oxidants.
     Studies  using  quantitative  measures find that "ozone alerts" occur fre-
quently in  association  with  high temperature.   The  latter may  mask  0,  effects
or  oy  itself produce excess mortality in susceptible elderly cardiopulmonary
patients.   When  attempts  have  been made to distinguish the effects of CL,  no
positive relationship has been found with mortality; rather,  the effect corre-
lates most closely with elevated temperature.
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12.6  REFERENCES


Adachi, T. ;  Hasegawa,  K. ;  Miyamoto, T. ;  Inone,  H. ;  Kamitsuji,  H.;  Kawa,  K.;
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Renzetti,  N. A.; Gobran, V.  (1957) Studies of eye irritation due to Los  Angeles
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     29.

Richardson,  N.  A. ; Middleton, W.  C.  (1957)  Evaluation of  filters for removing
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Richardson,  N.  A.; Middleton, W.  C.  (1958)  Evaluation of  filters for removing
     irritants  from  polluted air.   Heat.   Piping Air Cond.   30:  147-154.

Rokaw, S.  N.; Massey,  F.  (1962) Air pollution and chronic respiratory disease.
     Am. Rev. Respir.  Dis. 86:  703-704.

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Sarto,  F. ;  Carmignotto,  F. ;  Fabbri, L.  (1979a)  Osmotic resistance,  alkaline
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019DC/A                              12-52                        6/18/84

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     43:  99-105.

Schoettlin, C. E. (1962) The health effects of air pollution on elderly males.
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               13.   EVALUATION OF INTEGRATED HEALTH EFFECTS DATA
                  FOR OZONE AND OTHER PHOTOCHEMICAL OXIDANTS
13.1  INTRODUCTION
     The preceding chapters  (chapters  10,  11,  and 12) have documented a wide
array of toxicological  responses elicited jjn vivo and j_n vitro by exposures to
ozone at concentrations of 1 ppm and below and  to other photochemical  oxidants
at various concentrations.  The extensive body  of data on the effects  of ozone
on the  respiratory system was reported and discussed in particular detail  in
those chapters.   The present chapter provides  a vehicle for evaluating this
collective body of data for its significance to public health and for  assessing
the certainties and uncertainties associated with the data.  Since the purpose
of a criteria document is to provide a scientific basis for the derivation  and
promulgation of standards,  the present chapter addresses specific issues and
questions that are important in standard-setting.
     Paramount among the issues considered in standard-setting is the  identifi-
cation  of the  population or subpopulation to be protected by the regulation,
that  is,  one that is  at particular risk from  exposure  to  ozone and  other
photochemical oxidants.  The identification of  such a population or subpopula-
tion presupposes  the identification of one  or more effects  that  are in  and of
themselves adverse, or that are indicators of  other effects that are  adverse
but that are not measurable in man because of ethical constraints.
     The existing health effects data indicate  that the responses to ozone  and
other photochemical oxidants  that are most clearly  linked to  the potential
impairment of public health are those changes in pulmonary function and related
respiratory  system  variables  that  have  been observed in  human  controlled-
exposure  studies  and  in  a limited  number  of  epidemiological  studies.   As
discussed in the 1978 criteria  document  for ozone and  other  photochemical
oxidants (U.S. Environmental Protection Agency, 1978), changes in lung function
associated with exposure to ozone  and  other photochemical  oxidants are  viewed
as signalling  impairment of public  health  for  several  reasons.   Decrements in
the mechanical functions of the lung can interfere with normal activity in the
general  population  and  in  susceptible subpopulations,  depending upon the
activity and the  population.   Even  in the general population, ozone exposure
during  exercise can produce significant decrements in lung function (chapter 11).
In certain  individuals in the general  population,  not yet  characterized medi-
cally except for their responses to  ozone, significant decrements, larger than
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those seen  in the rest of the general population, are elicited by exposure to
ozone during  either continuous or  intermittent  exercise (chapter 11).  In
individuals who have respiratory diseases such as asthma or chronic obstructive
lung disease,  even small  decrements in lung function may interfere with normal
activity and may be deemed clinically significant.   Symptoms usually accompany
the observed decrements in lung function and  impairments in other respiratory
indicators  (chapters 11 and  12).   Discomfort produced by  the  symptoms that
ozone exposure produces have  been  reported as interfering with experimental
protocols, especially those employing exercise.

     Thus,  at least when associated with ozone exposure, changes  in lung
     function  often  represent a level  of  discomfort that, even  among
     healthy people, may  restrict  normal  activity or impair the perfor-
     mance of  tasks (U.S.  Environmental  Protection Agency,  1978).

     To evaluate the health effects documented and described in the preceding
chapters,  relevant effects and the  identification of potentially-at-risk popu-
lations are discussed at  length in this chapter.  In addition, inherent bio-
logical  characteristics or personal  habits and activities  that may attenuate
or potentiate typical responses  to ozone and other  oxidants  are  discussed.
The environmental factors that determine potential or real exposures of popu-
lations or  subpopulations are presented, as well, including known ambient air
concentrations of ozone,  of other related photochemical  oxidants,  and of these
combined oxidants.
        The issues  discussed in subsequent  sections are enumerated below:

     1.    Concentrations  and patterns of ozone and other photochemical  oxidants,
          including indoor-outdoor  gradients, relevant for exposure assessment.
     2.    Symptomatic effects  of  ozone  and  other  photochemical  oxidants.
     3.    Effects of ozone on pulmonary function and related airway parameters
          in the  general  population, at rest and with  exercise  and other
          stresses.
     4.    Influence on the effects  of  ozone of age, sex,  smoking status,
          nutritional  status, and red blood cell  enzyme  deficiencies.
     5.    Effects of repeated exposure to ozone.
     6.    Effects of  ozone on  lung  structure and the relationship between
          acute and chronic ozone effects.

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     7.    Effects of ozone  related  to resistance to infections,  i.e.,  host
          defense mechanisms.
     8.    Effects of ozone  on extrapulmonary tissues, organs,  and  systems.
     9.    Effects of ozone on potentially susceptible individuals.
     10.   Extrapolation to human populations of ozone-oxidant effects observed
          in animals.
     11.   Effects of other  photochemical oxidants  and  the interactions of
          ozone and other pollutants.
     12.   Identification of potentially-at-risk populations or subpopulations.
     13.   Demographic  information  on  potentially at-risk  subpopulations.

13.2  EXPOSURE ASPECTS
     Certain information about the occurrence of ozone and other photochemical
oxidants is important for assessing both the potential  and the actual exposures
of  individuals  and of  populations.   In  this  section,  both qualitative and
quantitative  information  is summarized as  background for  understanding the
relevance for public health of the concentrations at which effects have been
observed in health studies and as background for estimating exposures.

13.2.1  Exposures to Ozone
     Ozone concentrations exhibit  fairly strong diurnal and seasonal cycles.
In most  urban areas,  single or multiple peaks of ozone occur during daylight
hours, usually  during  midday  (e.g., about noon  until 3:00  or 4:00 p.m.).  The
formation of  ozone  and other photochemical  oxidants is  limited to daylight
hours since  the chemical  reactions in the atmosphere are driven by sunlight.
Because  of  the  intensity of sunlight  necessary  and  the  other meteorological
and  climatic conditions  required,  the highest concentrations of ozone and
other photochemical oxidants occur during the second and third quarters of the
year, i.e., April through September.  The months of highest ozone concentrations
depend upon  local  or regional  weather patterns  to a  considerable  degree, such
that  the time of occurrence of  maximum  1-hour, 1-month, or seasonal  ozone
concentrations  is  location-dependent.   In California, for  example,  October  is
usually  a  month of higher ozone concentrations than April, and therefore the
6-month period  of highest average ozone concentrations appears to be May through
October  in many  California cities and conurbations.
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     In nonurban areas,  most peaks in ozone concentrations occur during daylight
hours, but peak  concentrations  at night are not uncommon.   The occurrence of
nighttime peaks appears  to be the result of combined induction time and trans-
port time for urban plumes, coupled with the lack of nitric oxide (NO) sources
to provide NO for chemical scavenging of ozone in the evening and early morning
hours.  In nonurban areas,  ozone concentrations are generally lower than in
urban areas, but  it  is  not unusual to  encounter  concentrations  higher than
those found  in urban-core  source areas  or even in the suburbs of urban areas.
     In urban areas,  early morning ozone concentrations  (around 2:00 or 3:00 a.m.
until about 6:00 a.m.) are near zero (<0.02 ppm),  largely because of scavenging
by NO.  Early  morning ozone concentrations in nonurban  areas are higher than
in urban areas and are near background  levels (e.g., 0.02 to 0.04 ppm), since
surface scavenging  rather than chemical scavenging  by  NO  is the principal
removal mechanism in nonurban areas.
     Concentrations of ozone and the patterns of its occurrence are documented
in chapter 6.  Major  points  pertinent to exposure assessment  have  been  de-
scribed qualitatively above.  Quantitative  data are briefly summarized here.
Figure 13-1 shows the frequency distribution of the  three highest ozone concen-
trations for  each of 3 years  averaged together (1979  through  1981)  (U.S.
Environmental  Protection  Agency,  SAROAD data  file).  The present national
ambient air quality standard for ozone  is expressed  as a concentration not to
De exceeded on more  than  one day per year.  Thus, the second-highest 1-hour
ozone concentration, rather  than  the  highest,  is regarded as a concentration
of potential significance  for public  health.  As demonstrated by this figure,
50 percent of the monitoring stations reported second-highest ozone concentra-
tions, averaged  over  3 years,  of  0.12 ppm; 25 percent  had 3-year-average
second-highest ozone concentrations of  0.15 ppm;  and 10 percent had 3-year-
average second-highest ozone  concentrations of 0.20 ppm.   Since most of the
ozone  monitoring  stations are located  in  urban  areas  (centers of greatest
population density), the  data  cited above  reflect the potential  exposures to
ozone of urban populations.
     As data  in  chapter 11  and in section  13.3.4  show,  human controlled-
exposure studies  have demonstrated that attenuation of responses to ozone
during repeated,  consecutive-day  exposures  of at least  3 to 4 days can occur
in most, though  not all,  of  the  individuals  studied.  Thus,  the potential for
019JSA/A                           13-4                            6/26/84

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UD
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 I
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en

00
-p.
a

Z
O
oc

z
UJ
o
z
o
o
UJ
Z
o
N
O
                    99.99

                  0.45
                  0.40
                  0.35
                  0.30
                  0.25
                  0.20
                  0.15
                  0.10
                  0.05
                            99.9 99.8
                                     99  98
                               95   90
             80  70 60 50 40  30   20
10
1  0.5 0.2 0.1 0.05  0.01
               I  I
    I    I     I    I   I   I   I
HIGHEST

2nd-HIGHEST


3rdHIGHEST
                          J_L1_L_U	I    I    .I
                                                            J_J	I	L_L
       0.01  0.05 0.1 0.2  0.5  1   2     5   10    20  30 40 50 60  70  80   90   95   98  99    99.8 99.9     99.99


                 STATIONS WITH PEAK 1 hour CONCENTRATIONS < SELECTED VALUE, percent



        Figure 13-1. Collective distributions of the three highest 1-hour ozone concentrations for

        3 years (1979, 1980, and 1981) at valid  sites {906 station-years).


        Source:  U.S. Environmental Protection Agency, SAROAD data files  for 1979,1980,1981.

-------
repeated,  consecutive-day exposures of that duration to ambient air concentra-
tions of ozone is of interest.   Data records from four cities were examined in
chapter 6 for  exposures  to three  different concentrations  persisting for
3 consecutive days  or longer (see Figures  6-23  through 6-26).   Those data
indicate the probabilities of exposures lasting rr-days  or longer, as shown in
Table 13-1.   As  needed  for exposure assessment,  the consecutive days between
multiple-day occurrences of these concentrations  can be estimated from Figures
6-23 through 6-26 (chapter 6).   Probabilities given in Table 13-1 are descrip-
tive statistics  based on aerometric  data from the respective localities for
1979, 1980,   and  1981.   The data cannot be used to predict concentrations but
indicate only the probable duration  once a concentration has  been reached.
     Potential  exposures of nonurban populations,  while not easily ascertained
in  the  absence of  a  suitable  aerometric  data base, can  be  estimated from
aerometric data  for selected sites known to represent agriculturally oriented
areas and from aerometric data obtained from special-purpose monitoring networks.
Data from three  National  Forest (NF) monitoring stations of the National Air
Pollution Background  Network  (NAPBN)  show 2-year averages of mean concentra-
tions (1979  and  1980)  of 0.028 ppm at Kisatchie NF, LA;  0.070 ppm at  Custer >
NF, MT; and  0.110 ppm at Green Mt. NF, VT  (Evans et al. , 1982).   (These are
considered "nonurban" rather  than  remote  or rural  sites largely because they
are thought  to  be  subject to transport from urban areas at least some of the
time.  A documented case of transport for an NF site in Missouri is given in
chapter 6.)
     Data from Sulfate Regional Experiment (SURE) sites showed mean concentra-
tions of ozone for August through December 1977 at four "rural" sites of 0.021,
0.029, 0.026,  and 0.035  ppm at Montague,  MA, Duncan Falls,  OH, Giles County,
JH, and Lewisburg, WV, respectively.   At five "suburban" SURE sites (Scranton,
PA; Indian River, DE; Rockport, IN; Ft. Wayne, IN; and Research Triangle Park,
NC), mean concentrations for the study period were 0.023, 0.030, 0.025, 0.020,
and G.025 ppm, respectively.  Maximum 1-hour ozone concentrations for the nine
stations ranged  from  0.077 ppm at Scranton, PA,  to 0.153 ppm at Montague, MA
(Martinez and Singh, 1979).
     Concentrations of ozone  indoors,  since most people  spend most  of their
time  indoors,  are of value in estimating total exposures.  The estimation of
total exposures,  in turn,  is of value for  optimal  interpretation  and  use  of
epidemiological studies.  Data on concentrations of ozone indoors are few.  It
is  known, however,  that  ozone  decays  fairly rapidly  indoors  through  reactions
019JSA/A                           13-6                            6/26/84

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        TABLE  13-1.   PROBABILITY THAT SPECIFIED  CONCENTRATIONS  OF  OZONE
              WILL PERSIST FOR STATED CONSECUTIVE  DAYS OR LONGER
                           (probability in percent)
                  Persistence for stated no.  of
                   % Probability for
                   S concentration of:
Location
Pasadena, CA





Pomona, CA







Washington, DC





Dallas, TX





consecutive days or longer
2
3
4
5
6
7
2
3
4
5
6
7


2
3
4
5
6
7
2
3
4
5
6
7
0.12 ppm
72
56
42
35
28
23
66
50
38
30
24
19
0.06 ppm

49
33
23
16
12
9
77
62
50
40
32
24
0.18 ppm
59
40
29
20
16
12
51
34
22
15
10
7
0.12 ppm
b

—
—
—
—
—
22
7
•v4
~2
<1
<0.05
 Cumulative frequency distribution of concentrations by number of consecutive
 days of occurrence.   Calculated from aerometric data for 1979 through 1981;
 not predictive of concentrations but only of probable duration.
 Few multiple-day occurrences in Washington and Dallas for higher
 concentrations; not plotted.

Source:   Figures 6-23 through 6-26, Chapter 6, compiled from SAROAD data
         files for 1979 through 1981.
019JSA/A
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6/26/84

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with surfaces of such materials as wall  board, carpeting, and draperies (chap-
ter 6).  Ozone concentrations indoors depend also on those factors that affect
both reactive and nonreactive pollutants:   concentrations outdoors, air exchange
rates, presence  or  absence  of air conditioning, and mode of air conditioning
(e.g., 100 percent  fresh-air  intake  versus recirculation of air).  Estimates
in  the literature on indoor-outdoor ratios  (I/O,  expressed as percent) of
ozone  concentrations range from 10 percent (Berk et al.,  1981), for a residence,
to 80  ± 10 percent (Sabersky et al. ,  1973), for an office building.  Variations
in estimates in the literature are attributable to the diversity of structures
monitored, of  their  locations,  and of their  heating, ventilating, and air-
conditioning systems.
     Along with  small-scale  spatial  variations in ozone concentrations, such
as  indoor-outdoor gradients,  large-scale  variations  exist,  such as those that
occur  with  latitude.   Latitudinal  variations have little effect on potential
exposures within  the  contiguous United States, however,  since the contiguous
states  all  fall within  latitudes  where  photochemical oxidant formation is
favored  (Logan et al. ,  1981;  U.S.  Environmental Protection Agency,  1978).
     Ozone concentrations are known  to increase with altitude  (Viezee et al. ,
1979;  Seiler and Fishman, 1981).  These gradients have no physiological signi-
ficance  for  the general  population,  however,  since  concentrations are highest
in  the free  troposphere, well above inhabited  elevations.  Data presented in
chapter 6 (Table  6-6)  for Denver show, in fact, that ozone  concentrations  are
lower  there than  in many metropolitan areas of  comparable size.  These altitu-
dinal  gradients  are of possible  consequence,  however, for certain  high-altitude
flights,  as  reported in the  field studies documented in chapter  12.   (Since
pressure  and other changes with  altitude  affect measurements and  calibrations,
care  must be taken to ensure  that ozone  concentrations  reported  to  produce
health effects  at real or simulated  high  altitudes are correct).
      Despite  the commonly accepted maxim  that  ozone is  a regional  pollutant,
intermediate-scale  spatial  variations in concentrations occur that  are  of
potential consequence  for designing  and  interpreting epidemiological  studies.
For example, a study of  ozone  formation and  transport in the northeast corridor
(Smith,  1981)  resulted in data  showing that in New York City an  appreciable
gradient  existed,  at least  for the study  period (summer, 1980),  between ozone
concentrations in Brooklyn  and  those  in  the  Bronx.   The maximum  1-hour ozone
concentration  measured at the  Brooklyn monitoring  site  was 0.174 ppm, while
that  measured  at the Bronx  monitoring  site was  0.080 ppm.
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13.2.2  Potential Exposures to Other Photochemical Oxidants
13.2.2.1  Concentrations.  In chapter 6 of this document the ranges of concen-
trations of  four photochemical  oxidants other than  ozone  were presented  for
urban and, where possible,  for nonurban atmospheres.   The data presented in
sections 6.6  and 6.7 are drawn upon here to examine possible ranges of these
pollutants that might be encountered in the United States, including "worst-case"
situations, in order to determine both the minimum and maximum additive concen-
trations of  these  pollutants  with ozone likely to occur  in  ambient air.  The
four photochemical  oxidants  for which concentrations were  given  in sections
6.6 and 6.7 are peroxyacetyl nitrate, peroxypropionyl nitrate, hydrogen peroxide,
and formic acid.
     Although they  co-occur  to varying degrees with ozone, aldehydes are not
photochemical oxidants.  The  concentrations of the low-molecular-weight alde-
hydes in ambient air are given  in chapter  3 because  these  aldehydes are rela-
tively potent precursors to ozone and other photochemical  oxidants.  Aldehydes
are both primary and secondary pollutants, inasmuch as they are emitted direct-
ly to the atmosphere from certain sources and are also produced by atmospheric
photochemical reactions.  Since they  are not oxidants and  are not  measured by
methods that measure oxidants, their role relative to public health and welfare
is not reported in this document.  The reader is referred to a recent comprehen-
sive  review  by  Altshuller  (1983)  for a treatment of the  relationships  in
ambient air between ozone and aldehyde concentrations.
     Neither health effects data nor sufficient aerometric data on formic acid
exist.  Those ambient  air  concentrations that are given  in the  literature,
however, indicate  that  formic  acid  occurs at trace concentrations,  i.e.,
<0.015 ppm,  even in high-oxidant areas such as the  South  Coast Air Basin of
California (Tuazon et al.,  1981).  No data are available for other urban areas
or for  nonurban  areas.   Given  the known atmospheric  chemistry of  formic acid,
concentrations in  the  South Coast Air  Basin are expected to  be higher than in
other urban  areas  of the country (chapter 4).   More abundant aerometric data
exist for  the  other three  compounds and will be  summarized  in this section.
     The measurement methods  (IR and GC-ECD) for  PAN and PPN are  specific and
highly sensitive,  and  have  been in use in air pollution research  for nearly
two decades.  Thus,  the more recent literature on the  concentrations of  PAN
and PPN confirm  and extend,  but do not contradict, earlier findings reported
in the  two previous  criteria documents for ozone and  other photochemical

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oxidants  (U.S.  Department of  Health,  Education, and  Welfare,  1970; U.S.
Environmental Protection Agency, 1978).
     Concentrations of  PAN are reported in the  literature from 1960 through
the present.  The  highest concentrations reported over this extended period
were those found in the 1960s in the Los Angeles area:   70 ppb (1960),  214 ppb
(1965); and  68 ppb (1968) (Renzetti and  Bryan,  1961;  Mayrsohn and Brooks,
1965; Lonneman et al. ,  1976).
     The  highest  concentrations of  PAN measured and  reported  in  the  past
5 years were 42 ppb at Riverside, California,  in 1980 (Temple and Taylor,
1983), and 47 ppb  at  Claremont, California, also in 1980 (Grosjean,  1983).
These are clearly  the  maximum concentrations of  PAN reported for  California
and for the  entire country in this period.  Other recently measured PAN concen-
trations  in  the  Los Angeles  Basin were  in  the range of 10 to 20 ppb.  Average
concentrations of PAN in the Los Angeles Basin in the past 5 years ranged from
4  to  13 ppb  (Tuazon et  al.,  1981; Grosjean,  1983).  The only published  report
covering  PAN concentrations  outside  California  in the  past 5 years is that  of
Lewis et al. (1983) for New Brunswick, New Jersey.  The average PAN concentra-
tion was 0.5 ppb and the maximum was 11 ppb during a study done from September
1978 through May 1980.   Studies outside California from the early  1970s through
1978 showed  average PAN concentrations ranging from 0.4 ppb in Houston, Texas,
in  1976 (Westberg  et  al. , 1978) to  6.3  ppb  in  St.  Louis, Missouri, in 1973
(Lonneman et al.,  1976).   Maximum PAN concentrations  outside California  for
the  same  period ranged from 10 ppb  in  Dayton,  Ohio, in 1974  (Spicer et al. ,
1976) to  25  ppb in St.  Louis (Lonneman et  al., 1976).
     In Chapter  6,  data on  PPN concentrations  from  1963  through  the present
were presented.   The  highest PPN concentration  reported  in these  studies was
6  ppb in  Riverside, California  (Darley et  al. , 1963).  The next highest reported
PPN  concentration  was  5 ppb  at St.  Louis,  Missouri,  in 1973  (Lonneman  et  al.,
1976).  Among more recent data, maximum  PPN  concentrations at respective  sites
ranged from  0.07 ppb in Pittsburgh,  Pennsylvania, in 1981 (Singh et al.,  1982)
to 3.1 ppb at Staten Island, New York (Singh et  al., 1982).  California concen-
trations  fell within this range.  Average  PPN concentrations at the respective
sites  for the  more recent data ranged  from  0.05  ppb at Denver and Pittsburgh
to 0.7 ppb at Los Angeles in 1979 (Singh  et  al. ,  1981).
     Altshuller  (1983)  has  succinctly summarized the  nonurban concentrations
of PAN and PPN  by pointing out that  they overlap the lower end of  the range of

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urban concentrations at  sites  outside  California.   At remote locations, PAN
and PPN concentrations are lower than even the lowest of the urban concentra-
tions (by a factor of 3 to 4).
     In urban areas, hydrogen peroxide  (hLO_) concentrations have been reported
to range from < 0.5 ppb in Boulder, Colorado (Heikes et al., 1982) to £ 180 ppb
in Riverside, California (Bufalini  et al.,  1972).   In nonurban areas, reported
concentrations ranged  from 0.2 ppb near Boulder,  Colorado,  in 1S78  (Kelly
et al., 1979) to £ 7 ppb 54 km southeast of Tucson, Arizona (Farmer and Dawson,
1982).   These  nonurban  data  were obtained by the  1umino!  chemiluminescence
technique  (see  chapter 5).   The urban  data were obtained by a variety of
methods, including  the  luminol  chemiluminescence,  the titanium  (IV)  sulfate
8-quinol inol, and other wet chemical methods (see chapter 5).
     The higher  concentrations of H_0_ reported  in  the  literature must be
regarded as  especially  problematic, since FTIR measurements of ambient air
have not demonstrated  unequivocally the  presence of f-LCL even  in the high-
oxidant atmosphere  of  the Los  Angeles  area.  The  limit  of  detection for a
1-km-pathlength FTIR system is around 0.04 ppm (chapter 5);  FTIR is capable of
measuring concentrations of H_0? if it  is present above the limit of detection.
13.2.2.2   Patterns.  The  patterns  of formic acid (HCOOH),  PAN,  PPN,  and H^
may be  summarized  fairly  succinctly.  They bear qualitative but  not  quantita-
tive resemblance to the patterns already summarized  for ozone concentrations.
Qualitatively, diurnal patterns are similar, with peak concentrations of each
of these occurring in  close  proximity  to the time  of the  ozone  peak.  The
correspondence in  time  of day  is not exact,  but  is close.   As  the  work of
Tuazon et  al.  (1981) at Claremont,  California, demonstrates (see  Figures 6-37
and  6-43),  ozone concentrations return to  baseline  levels  faster than the
concentrations of  PAN,  HCOOH,  or H~02  (PPN  was  not  measured).   The diurnal
patterns of  PAN were  reported in earlier criteria  documents.   Newer data
merely confirm those patterns.
     Seasonally, winter concentrations (third and  fourth quarters) of PAN are
lower  than summer  concentrations  (second  and third quarters).   The winter
concentrations of  PAN are proportionally  higher,  however,  than the winter
concentrations of  ozone;  i.e.,  the PAN-to-ozone ratios are higher in winter
than in summer.   Data  are not readily available on  the seasonal  patterns of
the other non-ozone oxidants.
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     Indoor-outdoor data on  PAN  are  limited to one report (Thompson et al.  ,
1973),  which confirms the  pattern  to be expected from the known chemistry of
PAN; that is, it persists longer indoors than ozone.   Data are lacking for the
other non-ozone oxidants.

13.2.3  Potential Combined Exposures  and Relationship of Ozone and Other
        Photochemical  Oxidants
     Data on concentrations  of  PAN,  PPN, and H?0  summarized in this section
indicate that  in "worst-case" situations these  non-ozone oxidants together
could add as much  as about 0.15 ppm  of  oxidant to the ozone burden in ambient
air.  The  highest second-high  ozone concentration measured  in the  United
States in 1982 was 0.32 ppm,  in the Los Angeles area.   In the presence of that
concentration of  ozone,  the  addition of non-ozone oxidants (0.15  ppm total)
would bring  the  total  oxidant concentration to around 0.47 ppm, provided the
maximum concentrations of  ozone  and  non-ozone oxidants were  reached at the
same time.
     Data also  indicate  that at their average concentrations in recent years
in the Los Angeles Basin, PAN and PPN together would add an additional oxidant
burden of 14 ppb (0.014  ppm) (4 to 13 ppb average PAN:   Tuazon et al. ,  1981;
Grosjean, 1983,  respectively; and 0.7 ppb PPN:  Singh et al., 1981).
     The significance for  public health of the  imposition of an additional
oxidant burden  from  non-ozone oxidants rests, however, on the  answers  to at
least three basic  questions:

     1.    Do PAN,  PPN,  or H?0?, singly  or  in combination, elicit  adverse or
          potentially adverse responses  in human populations?
     2.    Do any or all  of these non-ozone oxidants act additively or synergis-
          tically  in  combination with ozone  to elicit adverse  or potentially
          adverse  responses  in human populations?  Do any or  all act antagonis-
          tically  with ozone?
     3.    Do  the  time course and  magnitude  of the concentrations of these
          non-ozone oxidants parallel  the time course and magnitude of ozone
          concentrations in  the ambient  air?

     The first  two questions are addressed by health effects  data  presented in
chapters 10  through 12 and in section 13.7 of the present chapter.
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     Altshuller (1983) has reviewed data pertinent to the third question.   His
conclusion is that  "the  ambient air measurements indicate that CL may serve
directionally, but  cannot  be  expected to serve quantitatively as  a surrogate
for the other  products"  (Altshuller,  1983).   It must be emphasized here  that
Altshuller examined the issue of whether 03 could serve as an abatement surro-
gate for  all  photochemical  products,  including those not relevant to effects
data examined in this document.   For example, the products be reviewed relative
to  ozone  included  aldehydes,  aerosols, and  nitric  acid.   Nevertheless,  his
conclusions appear to apply to the subset of photochemical products of concern
here:   PAN, PPN, and H^.
     The most straightforward evidence of the lack of a quantitative, monotonic
relationship between  ozone  and  the other photochemical oxidants is the range
of  PAN-to-03  and,  indirectly, of  PAN-to-PPN  ratios  presented  in the  review  by
Altshuller (1983) and summarized in Table 13-2 and in chapter 6.
     Certain other  information  presented  in  chapter 6  bears out the  lack of a
strict quantitative  relationship  between  ozone and  PAN,  in particular.  Not
only are ozone-PAN relationships not consistent between different urban areas,
but they  are  not consistent in urban versus nonurban areas, in summer versus
winter,  in indoor  versus outdoor  environments,  or  even,  as the ratio data
show,  in  location,  timing,  or magnitude of  diurnal  peak concentrations within
the same city.  Data obtained in Houston by Jorgen et al. (1978) show variations
in  peak  concentrations  of  concurrently measured  PAN  among three separate
monitoring sites.  Temple and Taylor (1983) have shown that PAN concentrations
are a greater percentage of ozone  concentrations in winter than in the remainder
of  the year in California  (see  chapter 6). Lonneman et al. (1976) demonstrated
that PAN-to-0~  ratios are considerably lower in nonurban  than in  urban areas.
Thompson  et  al.  (1973) showed  that PAN  persists longer than ozone  indoors.
(This  is  to be expected  from its  lower reactivity with  surfaces and  its enhanced
stability  at cooler-than-ambient  temperatures such  as  found in air-conditioned
buildings.)   Tuazon et al. (1981) demonstrated  that PAN persists  in ambient
air longer than ozone, its persistence paralleling  that  of HN03, at  least  in
some localities.   Reactivity data presented in the 1978 criteria  document  for
ozone  and other photochemical oxidants indicate that all  precursors  that give
rise to PAN also give  rise  to ozone.   Not all are equally reactive toward both
products,  however,  and therefore some precursors preferentially give rise,  on
the basis of units of product  per unit of reactant,  to  more of one  product
than the  other  (U.S.  Environmental Protection Agency,  1978).
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   TABLE 13-2.  RELATIONSHIP OF OZONE AND PEROXYACETYL NITRATE AT URBAN AND
    SUBURBAN SITES IN THE UNITED STATES IN REPORTS PUBLISHED 1978 OR LATER
Site/year
of study
West Los Angeles, CA, 1978
Claremont,
Claremont,
Riverside,
Riverside,
Riverside,
Riverside,
Houston, TX
New Brunswi
CA
CA
CA
CA
CA
CA
>
ck
, 1978
, 1979
, 1975-1976
, 1976
, 1977
, 1977
1976
, NJ, 1978-1980
PAN/OS, %
Avg. At 03 peak

9
7
4
9
5
4
4
3
4

6
6
4
5
4
4
NA3
3
2

Hanst
Tuazon
1981b)
Tuazon
Pitts
Tuazon
Tuazon
Singh
Reference
et
et
et
and
et
et
et
Westberg
al.
al
al
(1982)
. (1981a,
. (1981a)
Grosjean (1979)
al
al
al.
et
. (1978)
. (1980)
(1979)
al. (1978)
Brennan (1980)
 Not available.
Source:   Derived from Altshuller (1983).
         chapter 6.
       For primary references, see
     It must be  emphasized  that information presented in  chapter  5 clearly
shows that no  one  method can quantitatively and reliably measure ozone, PAN,
PPN, and hydrogen  peroxide,  either one at a time or in ambient air mixtures.
This point was  not clearly  presented in the 1978  criteria document but is
given substantial discussion in chapter 5 of this document.
13.3  HEALTH EFFECTS IN THE GENERAL HUMAN POPULATION
13.3.1  Clinical Symptoms
     A close association has been observed between the occurrence of respira-
tory symptoms and changes  in pulmonary function in response to acute exposure
to 0-  (Chapter  11).   This  association  holds for both the  time-course and
magnitude of effects.   In  studies  of repeated exposure to 0.,, symptoms have
                                                            *3
generally increased while  pulmonary  function has  diminished on the second to
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third day  of exposure,  followed  by partial or complete  reversal  of  these
findings on  the fourth or fifth  day.   Insofar as cough  and  chest pain  or
irritation may  interfere  with  the maximal  inspiratory or expiratory efforts
required to  perform spirometric maneuvers,  such associations  between symptoms
and  function might be  expected.   To date, epidemiological  studies of the
health effects  of  photochemical air pollution  have not been designed specifi-
cally to test  the  comparative  frequency or magnitude of response of symptoms
versus  functional  changes.   Which  type of effect is more  likely  to  occur
within the polluted community is uncertain.
     The symptoms  found in association  with clinical exposure to 0^ alone  and
with exposure  to photochemical  air pollution  are similar but not  identical.
Eye  irritation, one of  the commonest complaints associated with photochemical
pollution, is  not  characteristic  of clinical exposures to 0,., even at  concen-
trations of  the gas several  times  higher  than  any likely  to be encountered in
ambient air.   Other components of photochemical air pollution, such as aldehydes
and  PAN, are held  to  be  chiefly  responsible (National Air Pollution Control
Association,   1970;  Altshuller, 1977; National  Research Council,  1977; U.S.
Environmental Protection Agency, 1978; Okawada et al., 1979).
     There is  also evidence  to suggest that for a specified concentration of
0- other symptoms,  as well, are more likely to occur in populations exposed to
ambient air  pollution  than in  subjects  exposed in chamber studies, especially
if 0_ is the sole pollutant administered  in the chamber studies.   The symptoms
    •j
may  be  indicative  of  either upper or lower respiratory tract irritation.  In
epidemiological studies,  cough has been  reported at 0.08 ppm 0,. (Zagraniski
et al., 1979) and at 0.10 ppm oxidants  (Hammer et al., 1974; Makino and Mizoguchi,
1975).   Some subjects  have  experienced  cough  during  clinical  exposure to
0.12 ppm 03  (McDonnell  et al. , 1983).  Nose and  throat irritation have  been
reported in  community  studies  in association  with 0.10 ppm oxidants (Okawada
et al. ,  1979;  Makino and Mizoguchi,  1975), but not at  or  below 0.15 ppm  0» in
laboratory studies.
     Between  0.15  and  0.30 ppm 0-, a  variety  of  both respiratory and  non-
respiratory  symptoms have been reported in  controlled exposures.    They include
throat  dryness, difficulty  or  pain in  inspiring deeply, chest tightness,
substernal soreness or  pain, wheezing,  lassitude, malaise, and nausea (DeLucia
and  Adams,  1977;   Kagawa and Tsuru, 1979b; McDonnell  etal., 1983).   Most
"symptom scores" have been positive at  concentrations of  0.2  ppm 0, and above;
only  two  studies  reported finding no  symptoms at 0.3  ppm 0-  (Bennett,  1962;
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von Nieding et al.,  1977).   Symptoms tend to remit within hours after exposure
is ended.   Relatively few  subjects  have reported persistence  of symptoms
beyond 24 hours.
     There are several possible  explanations for the apparent differences in
symptomatic effects  between epidemiological  and  controlled human studies.
They include  differences in subject populations (e.g., children were  subjects
in two of  the epidemiological  studies but have not been studied clinically);
factors affecting the perception of symptoms  in one type of study compared to
the other; or differences in the methods used to assess symptoms.   Alternative-
ly, the presence of  highly reactive chemical species in polluted ambient air
might  be  chiefly responsible for the  symptoms  or might interact synergis-
tically with CL to initiate the symptoms.
     Symptoms  have  commonly been assessed  by the use  of  recording sheets
combined with  reliance on  the  subject's recall, usually right after exposure
but sometimes  several hours or days after exposure (e.g.,  community  studies).
While  it  is difficult to score the  intensity  of symptoms with  confidence,  the
results obtained immediately  after  exposure  have been  noteworthy for their
general consistency  across  studies.  Moreover,  as noted  earlier,  the  associa-
tion between  changes in  symptoms  and objective  functional  tests has been
impressive.  Symptoms are therefore considered as useful adjuncts in assessing
the effects of 0.,  and photochemical pollution, particularly if combined with
objective measurements.
                      *
13.3.2  Pulmonary Function at Rest and with Exercise and Other Stresses
13.3.2.1  At-Rest Exposures.  The great  majority  of  short-term ozone exposure
studies on resting subjects were published almost a decade ago and were reviewed
extensively in the previous ozone-oxidants criteria document (U.S. Environmen-
tal  Protection Agency,  1978).   Briefly, resting  subjects  inhaling ozone at
concentrations up to 0.75 ppm  for 2 hours  showed  no  decrements  or  only very
small  (<  10 percent) decrements in  FVC (Silverman et al. , 1976;  Folinsbee
et al.,  1975; Bates  et al., 1972), vital capacity  (Silverman et al., 1976;
Folinsbee et  al., 1975), FEV^ and FRC (Silverman et al.,  1976).  More discri-
minating  flow-derived variables, such as the  maximal expiratory flow  at 50 per-
cent VC  (FEF  50%)  and the maximal expiratory flow at 25 percent VC  (FEF25%),
were affected to a  greater degree,  showing  decreases  of up to 30 percent from
control in sensitive individuals at 0.75 ppm  0- (Bates  et  al. , 1972;  Silverman

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et al.,  1976).   Specific  tests  for bronchoconstriction did  not appear to be
more sensitive  in detecting ozone-induced changes than the spirometric tests.
Airway resistance (R  ) and pulmonary resistance (R. ) increased only minimally
                    cLW                             L
following 2-hr  exposures  to  0.6 to 0.75 ppm 0~ (Golden et al. , 1978 and 0.75
ppm 03 (Silverman et al. , 1976).  More specific measures of pulmonary mechanics
exhibited a similar lack of response.  Static compliance (C .) remained virtual-
                                                           S v
ly unchanged, whereas dynamic compliance (C .  ) and the maximum static elastic
recoil  pressure  of  the lung  (P.     ) showed  some borderline effects (Bates
                               *cp max
et al. ,  1972).   No  consistent  effects  of ozone were observed  in  the most
sensitive region of the respiratory system, the gas-exchange zone of the lung.
Breathing 0.6  to 0.8  ppm  0»  for 2 hr reduced  markedly  diffusion  capacity
(D.   ) across the alveolo-capillary membrane (Young et al. , 1964);  however,
the  mean  fractional  CO uptake, also an  index  of diffusion, decreased only
marginally under similar exposure  conditions (Bates et al. ,  1972).   The slope
of phase III of the single-breath nitrogen closing volume curves, which in-
creases as the inhomogeneity in the distribution of ventilation increases,  was
not significantly altered by 0~ inhalation (Silverman et al., 1976).
     More recent studies  of  at-rest exposures to 0_  lasting 2 to 4 hr have
demonstrated decrements  (< 11  percent)  in forced expiratory volume  and flow
occurring at and above 0.5 ppm  of  0- (Folinsbee  et al., 1978; Horvath et al.,
1979).   Airway resistance was not changed at these 0- concentrations.  Breath-
                                                    O
ing 0^ at  rest  at  concentrations < 0.5 ppm did not significantly impair pul-
monary function  (Folinsbee et al. ,  1978),  although  the  occurrence  of some
Og-related pulmonary symptoms has been suggested (Konig et al., 1980), indica-
ting that there may be selective sensitivity in some subjects.
13.3.2.2  Exposures With Exercise.   Minute ventilation (VV) during exposure is
considered to be one  of the principal  modifiers of the magnitude of response
to 0_.   The  most convenient  physiological procedure for  increasing  Vp is to
exercise exposed individuals  either on  a treadmill  or  bicycle ergometer.
Adjustment by the respiratory system to an increased work load is characterized
by increased frequency and depth of breathing.   Consequent increases in VF  not
only increase the overall  volume of inhaled pollutant, but  such ventilatory
patterns also promote  a  deeper penetration of ozone into the peripheral  lung
structures, which  are most sensitive  to injury and which  favor  a greater
absorption of ozone.  These processes are further enhanced at higher workloads
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(Vp > 35 L/min), since  the  mode of breathing will  most  likely change from
nasal to oronasal  or oral  only (Niinimaa et a!.,  1980).   Such a redistribution
of the  respiratory airflow, with an increasingly greater portion of the total
minute  volume  being  inhaled orally as  the ventilation increases (Niinimaa
et al.,  1981),  may proportionally  augment the ozone burden  of  the  airways.
The  overall  amount  of  inhaled  ozone  depends on minute  ventilation,  ozone
concentration, and duration of exposure.   The effective dose of Q~.,  which is a
composite index of these three determinants (Silverman et al.,  1976; Folinsbee
et al.,  1978; Adams  et al.,  1981) can  be used to  predict group mean  decrements
in pulmonary  function  following 0- exposure.  However, considering  the great
variability  in  individual responses to 03  exposure, prediction  equations that
use some form of effective dose may not be adequate for predicting differences
in responsiveness to 0_ among individuals.
     Even in  well-controlled  experiments  on a homogenous group of  subjects,
physiological responses to  the  same work  and pollutant loads will vary widely
among individuals (Chapter 11).   The nature of the primary mechanisms inducing
such a  spectrum of  responses is unclear.   Despite such large interindividual
variability,  the  magnitude  of (individual)  responses, assessed in  terms of
decrements in pulmonary function, correlates reasonably well with the severity
and  frequency of  subjective symptoms;  but the positive association with both
GO concentration and exercise stress is much stronger (Folinsbee et al., 1978;
McDonnell et al., 1983; Haak  et al.,  1984).  Generally, within-individual
variations  in  response, both  subjective and objective, appear  to be almost  an
order of  magnitude  smaller  than the  variations  observed between subjects.
     The post  hoc categorization of subjects into  "responders/sensitives"  and
"nonresponders/nonsensitives" is  based  on arbitrary criteria  that  vary  from
study to study  (Bell et al., 1977; Gliner  et al., 1983; Haak et  al., 1984) and
is clearly open to criticism.  Using this  approach, up to 20 percent of subjects
in the  studies  cited were classified as more reactive to ozone  than the rest
                                                                  »
of the  cohorts.   Even under very  strenuous  exposure  conditions (Vr - 45-57
L/min at  0.4 ppm),  when lung function  in the most responsive  yet apparently
healthy  individuals  was severely impaired  (FEV =40 percent of control),  the
least responsive  subjects  showed decrements of  less than 10 percent; and the
average  decrement was 26  percent (Haak  et al., 1984;  Silverman et al.,  1976).
                    *
Moderate  exercise  (VV = 34 L/min)  in  an  atmosphere containing 0.4  ppm ozone
may  reduce  the  average  FEV-, of  healthy subjects  by  17 percent  (3 to 50 percent).

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The same  level  of exercise in 0.24 ppm  ozone  elicits  mean  decreases  in  FVC,
FEV.., and  FEF?c-_7c  of  H»  14,  and  12 percent,  respectively.   Even  very low 0,
concentrations  (0.12 ppm)  will induce  measurable changes in lung function of
more responsive individuals; reported decrements in FVC, FEV  and FEF?I- 75 did
not exceed 20 percent of control  (McDonnell et al., 1983).
     The maximum response can be observed within 5 to 10 min following the end
of  each exercise  period  (Folinsbee et  al.,  1977b; Haak et al.,  1984).  During
subsequent rest periods, however, the augmented response is not maintained and
partial improvement, but not a return to the preexercise level, in lung function
can be observed even though the subject still inhales ozone (Folinsbee et al.,
1977b).  Continuous exercise equivalent in duration to the sum of intermittent
exercise  periods  at comparable ozone  concentrations  (0.20  to 0.40 ppm)  and
minute ventilations  (approximately 60  to 80 L/min) seems to elicit about the
same changes  in pulmonary  function (Adams et al.,  1981; Adams and Schelegle,
1983).   Functional  recovery,  at  least  from a  single  exposure with exercise,
appears to progress  in two phases:  during the  initial  rapid phase,  lasting
between 1 and 3 hours,  pulmonary function improves more than 50 percent (Bates
and Hazucha,  1973); this is followed by a much slower recovery that is usually
completed within  24  hours.   There  is  some indication, however, that recovery
from sequential  exposures  may take longer  than  24  hours (Folinsbee  et al.,
1980).   In  some  individuals,  despite  apparent  functional  recovery,  other
regulatory systems may still exhibit abnormal responses when stimulated;  e.g.,
airway hyperreactivity might  persist  for days (Golden et al., 1978;  Kulle et
al., 1982b).
     In evaluating group response,  the magnitude of lung functional changes is
positively associated  with the  level  of exercise  and ozone  concentration.
Heavy intermittent  exercise  (V£  >  44 L/min) at high ozone concentrations  (0.4
to  0.6 ppm)  significantly  reduces  FVC  by more  than 10  percent,  FEV  by almost
20 percent, and FEF_  ?5 by nearly 30 percent, on the average.  The comparable
exercise stress at  lower ozone concentrations (0.12  to  0.20)  decreases  the
above lung function  variables  between  3 and 7 percent, with these decrements
bordering on  statistical significance.
     The effects of intermittent exercise and 0  concentration on the magnitude
                                               *5
of  average pulmonary function  response (e.g.,  FEV-) during  2-hr exposures are
best illustrated in Figures 13-2 through 13-6.   The data base for these concen-
tration-response  curves  comprises  studies  published  between 1973 and 1983

019JSA/A                           13-19                                6/26/84

-------
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         LIGHT EXERCISE

         K25 Umin)

         r = 0.87
                                 0.1
                       0.2
0.3
0.4
0.5
0.6
0.7
0.8
                                                  OZONE CONCENTRATION, ppm
Figure 13-2. The effects of ozone concentration on 1-sec forced expiratory volume dur-
ing 2-hr exposures with light intermittent exercise. Quadratic fit of group mean data,
weighted by sample size, was used to plot a concentration-response curve with 95 per-
cent confidence limits.  Individual means (± standard error) are given in  Table 13-3
along with specific references.

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          MODERATE EXERCISE

          (26-43 L/min)

          r = 0.85
                                0.1
                        0.2
0.3
0.4
0.5
0.6
0.7
0.8
                                                   OZONE CONCENTRATION, ppm
Figure 13-3. The effects of ozone concentration on 1-sec forced expiratory volume

during 2-hr exposures with moderate intermittent exercise.  Quadratic fit of group

mean data, weighted by sample size, was used to plot a concentration-response curve

with 95 percent confidence limits. Individual means (+  standard error) are given in

Table 13-3 along with specific references.

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                            r = 0.94
                                0.1
                      0.2
0.3
0.4
0.5
0.6
0.7
0.8
                                                 OZONE CONCENTRATION, ppm
Figure 13-5. The effects of ozone concentration on 1-sec forced expiratory volume
during 2-hr exposures with very heavy intermittent exercise. Quadratic fit of group
mean data, weighted by sample size, was used to plot a concentration-response curve
with 95 percent confidence limits. Individual means (±standard errorjare given in Table
13-3 along with specific references.

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                                                                 VERY HEAVY
                                                                 EXERCISE
                                                                                        LIGHT
                                                                                        EXERCISE
                                                                   MODERATE
                                                                   EXERCISE
                                                            ' HEAVY   \.
                                                             EXERCISE    \
                                                                                               \

                             0.1
                    0.2
0.3
0.4
0.5
0.6
0.7
0.8
                                               OZONE CONCENTRATION, ppm
Figure 13-6. Group mean decrements in 1-sec forced expiratory volume during 2-hr
ozone exposures with different levels of intermittent exercise: light (VE <  25 L/min);
moderate (Vg -26 43 L/min); heavy (Vg = 44-63 L/min); and very heavy (Vg ^ 64 L/min).
Concentration-response curves are taken from Figures 13-2 through 13-5.

-------
(Table 13-3).  In order to compile as complete a data base as possible, comple-
mentary data were obtained from published technical reports and from conference
proceedings.  The  original  articles  often  reported  data  that were either
incomplete  or that were presented only  in graphical  form.  Only those  studies
that  reported  or for  which  it was possible  to  calculate,  from additional
sources, all five  critical  variables (minute ventilation, 0.,  concentration,
exposure duration (90 to 150 min), cohort size, and at least FEV,) were included
in the  data base.   Calibration methods for ozone measurements differed among
the  studies from which these data were obtained,  but the curve  parameters
proved  insensitive to  corrections  for biases between methods.  Thus,  the  0-
concentrations as  reported  in the original  articles  were  used.   To minimize
inhomogeneity of data, studies  that  did not utilize  the  intermittent exercise
protocol were not included in the calculations.
     Despite methodological and protocol differences among various studies, it
was  possible to  group  the  reported averaged data by  workloads  into  four cate-
gories  of  exercise:   light (V_ < 25  L/min),  moderate (Vp = 26 to 43 L/min),
heavy  (V£  = 44 to  63 L/min),  and  very  heavy  (V^  >  64 L/min).  Subsequent
curve-fitting by means of a quadratic regression equation, weighted by sample
size, produced clearly differentiated response curves (Figures 13-2 through
13-5) with  high  correlation  coefficients (r = 0.85 to 0.97).   The 95 percent
confidence  limits for any of the curves did not exceed +5 percent of response.
At 0.6  ppm 03,  the expected average  decrement in  FEV, of  lightly exercising
subjects is  12 percent (Figure 13-2), while  heavy exercise under comparable
conditions  may lower  the  FEV, by 27  percent  (Figure 13-4).  Other  pulmonary
function variables analyzed in the same manner, although not illustrated here,
showed the same trend as the FEV • but as expected, changes differed in magni-
tude.   For  example,  the  decrements in  FVC were  smaller, while decrements  in
FEF25-75 were Skater, for a  given Og concentration,  than  decrements in FEV .
The Raw shows a similar concentration-dependent,  positively correlated response
(r = 0.540).
     A  comparison of  the  respective  combinations of  minute ventilation (V )
and  ozone  concentration  that induce  the  same amount of functional change,
e.g., a 10  percent decrease  in FEV^ further illustrates the interdependence
of these two determinants.   From the  curves  in Figure 13-6 it can be seen  that
very heavy exercise at 0.24 ppm, heavy exercise at 0.43 ppm,  moderate exercise
at 0.48 ppm, or  light exercise at 0.56 ppm 03 can all be expected to  reduce

019JSA/A                           13-25                                6/26/84

-------
               TABLE  13-3.   EFFECTS  OF  INTERMITTENT  EXERCISE  AND  OZONE  CONCENTRATION ON 1-SEC FORCED EXPIRATORY VOLUME
VjJ
 I
Ozone
concentration
ug/m3
LIGHT
1470
1470
1470
1470
1470
0
196
588
980
0
392
823
0
784
490
725
980
784
784
0
0
725
725
1470
1470
ppm
EXERCISE
0.75
0.75
0.75
0.75
0.75
0.0
0.1
0.3
0.5
0.00
0.20
0.466
0.0
0.4
0.25
0.37
0.50
0.4
0.4
0.00
0.00
0.37
0.37
0.75
0.75
Measurement,
method

MAST, NBKI



CHEM, NBKI
CHEM, NBKI



UV, UV


CHEM, GPT

CHEM, NBKI


CHEM, NBKI

MAST, NBKI





Exposure
duration,
min

90
90
120
120
120
120
120
120
120
125
125
125
120
120
120
120
120
135
135
120
120
120
120
120
120
Number of
subjects

10
10
10
10
11
10
10
10
10
21
21
21
15
15
6
5
7
6
9
6
6
6
6
6
6
Minute
ventilation,
L/m i n

22.5
22.5
22.5
22.5
20.0
11.2
11.2
9.6
11.8
22.6
22.6
22.6
10.0
10.0
20.0
20.0
20.0
20-0
20.0
22.0
22.0
22.0
22.0
22.0
22.0
FEVt.0,d
%

84.6 ±1.8
81.6 ± 2.2
79.3 ± 2.7
76.6 ± 2.7
77.2 ± 4.4
99.0 ± 15.1
98.4 ± 15.7
99.0 ± 16.1
92.6 ± 17.1
100.3 ±0.8
96.9 ± 1.3
81.6 ±2.7
99.4 ± 5.0
100.0 ±5.3
100.3
97.7
95.3
99.5
95.5
101.4 ±1.7
100.5 ±3.3
92.6 ± 2.3
96.1 ±0.7
73.3 ± 6.8
72.4 ± 4.7
Reference

(2) Bates and Hazucha, 1973



(3) Folinsbee et al . , 1977b
(4) Folinsbee et al . , 1978



(6) Gliner et al. , 1983


(7) Haak et al . , 1984

(8) Hackney et al . , 1975c


(9) Hackney et al. , 1976

(11) Hazucha et al. , 1973






-------
TABLE 13-3. EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC FORCED EXPIRATORY VOLUME (continued)
Ozone3
concentration Measurement >c
ug/m3
431
451
470
784
784
784
1215
1235
0
0
490
490
980
980
1470
1470
0
0
392
392
784
941
1509
ppm method
0.22 MAST, NBKI
0.23
0.24
0.40
0.40
0.40
0.62
0.63
0.00 CHEM, NBKI
0.00
0.25
0.25
0.50
0.50
0.75
0.75
0.0 UV, NBKI
0.0
0.2
0.2
0.40
0.48
0.77
Exposure
duration,
min
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
140
140
140
140
120
120
120
Number of
subjects
4
4
4
4
4
4
4
4
8
7
8
7
8
7
8
7
12
12
12
12
5
5
5
Minute
ventilation, FEV^Q,
L/min % Reference
22.5
22.5
22.5
22.5
22.5
22.5
22.5
22.5
8.4
8.4
8.2
8.2
7.8
7.8
7.7
7.7
20.0
20.0
20.0
20.0
11.0
11.0
11.0
101.5 (12) Hazucha et al . , 1977
93.7 ± 1.4
96.0 ± 3.1
93.9 ± 2.5
91.9 ± 5.9
89.5
88.0
86.0
101.0 (14) Horvath et al., 1979
102.3
101.6
98.3
96.9
91.4
89.2
81.0
101.2 (17) Linn et al . , 1979
99.8
101.5
99.5
101.7 + 2.8 (20) Silverman et al . , 1976
101.4 ±8.3
90.4 ± 4.0

-------
TABLE 13-3. EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON I- SEC FORCED EXPIRATORY VOLUME (continued)
Ozone3
concentration Measurement >c

ug/m3
ppm method
Exposure
duration,
min
Number of
subjects
Minute .
ventilation, FEVn.A,
L/min
% Reference
MODERATE EXERCISE



UJ
i
NJ
oo












0
1470
0
0
0
0
0
0
980
980
980
980
980
980
0
196
588
980
0.00 MAST, NBKI
0.75
0.0 CHEM, NBKI
0.0
0.0
0.0
0.0
0.0
0.5
0.5
0.5
0.5
0.5
0.5
0.0 CHEM, NBKI
0.1
0.3
0.5
120
120
100
100
118
118
125
125
100
100
118
118
125
125
120
120
120
120
3
3
8
6
8
6
8
6
8
6
8
6
8
6
10
10
10
10
25.0
25.0
36.0
35.0
36.0
35.0
36.0
35.0
33.3
39.2
33.3
39.2
33.3
39.2
32.6
32.3
31.0
32.1
104.9 (1) Bates et al., 1972
69.7
96.5 ± 4.3 (3) Folinsbee et al . , 197/b
98.7 -•- 6.6
99.4 + 2.7
96.4 ± 5.5
98.6 ±6.5
100.7 ±5.5
89.9 ± 5.9 j
81.1 ± 6.8 |
87.8 ± 6.4
81.9 ± 5.6
92.0 ± 6.6
92.3 ± 5.8
99.4 ± 13.1 (4) Folinsbee et al., 1978
101.9 ± 13.8
95.4 ± 16.0
87.3 ± 16.6

-------
TABLE 13-3. EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC FORCED EXPIRATORY VOLUME (continued)
Ozone3
concentration Measurement 'c
ug/m3
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
392
392
392
392
392
666
666
666
666
666
902
902
902
902
902
ppm method
0.00 CHEM, NBKI
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.20
0.20
0.20
0.20
0.20
0.34
0.34
0.34
0.34
0.34
0.46
0.46
0.46
0.46
0.46
Exposure
duration,
min
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
135
Number of
subjects
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
Minute .
ventilation, FEVj.Q,
L/min % Reference3
32.0
32.0
32.0
32.0
32.0
32.0
30.0
30.0
30.0
30.0
31.0
31.0
31.0
31.0
31.0
31.0
31.0
31.0
31.0
31.0
32.0
32.0
32.0
32.0
32.0
30.0
30.0
30.0
30.0
30.0
99.2 ±4.9 (5) Folinsbee et al . , 1980
99.7 ±4.5
101.3 ±4.4
101.1 ±4.4
99.6 ± 4.3
100.7 ± 4.8
101.0 ±4.9
100.3 ±4.5
99.8 ± 4.7
100.6 ±4.7
101.4 ± 4.5
101.9 ±5.1
101.9 ±5.3
100.9 ±5.4
100.2 ±5.1
101.8 ±4.8
102.5 ± 4.8
102.8 ± 4.7
102.2 ±4.8
101.3 ±4.8
101.3 ±4.6
100.6 ±4.3
99.7 ±4.6
96.9 ± 4.8
95.5 ± 4.3
99.8 ± 5.1
95.0 ± 4.8
93.3 ± 6.0
87.0 ± 6.0
91.3 ± 5.0

-------
TABLE 13-3. EFFECTS OF INTI
Ozone3
concentration Measurement >c
ug/ms ppm method
0
0
784
725
725
0
0
1176
1176
0
1058
0
921
921
921
921
921
921
784
941
1509
0.0 CHEM, GPT
0.0
0.4
0.37 CHEM, NBKI
0.37
0.0 CHEM, NBKI
0.0
0.6
0.6
0.00 UV, UV
0.54
0.00 UV, NBKI
0.47
0.47
0.47
0.47
0.47
0.47
0.40 MAST, NBKI
0.48
0.77
EFFECTS OF INTERMITTENT EXERCISE AND  OZONE CONCENTRATION ON 1-SEC FORCED EXPIRATORY VOLUME (continued)
                    Exposure
                   duration,
                      min

                      120
                      120
                      120

                      120
                      120

                      120
                      120
                      120
                      120

                      125
                      125

                      120
                      120
                      120
                      120
                      120
                      120
                      120

                      120
                      120
                      120
Number of
 subjects

    29
    15
    15

     4
     4

    14
    14
    14
    14

    24
    24

    11
    11
    11
    11
    11
    11
    11

     5
     5
     5
   Minute
ventilation,
   I/min

   35.0
   35.0
   35.0

   25.0
   25.0

   35.0
   35.0
   35.0
   35.0

   30.0
   30.0

   30.0
   30.0
   30.0
   30.0
   30.0
   30.0
   30.0
   27.
   27.
   27.5
101.5 ±2.6
 99.7 ± 4.3
 96.9 ± 5.5

 91.7 ± 27.4
 99.7 ± 18.1

 97.9 ± 5.1
 96.0 ± 6.7
 78.8 ± 6.1
 73.1 ± 6.5

 99.7 ±1.0
 78.9 ±3.0

100.8
 88.7
 91.4
 84.8
 87.4
 86.6
 86.5

 94.6 ± 3.5
 95.1 ± 1.9
 79.8 ± 6.4
                          Reference
 (7) Haak et al. , 1984
(10) Hackney et al., 1977b
(13) Hazucha, 1981
(15) Horvath et al. ,  1981
(18) Linn et al.,  1982
(20) Silverman et al.,  1976

-------
TABLE 13-3. EFFECTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC FORCED EXPIRATORY VOLUME (continued)
Ozone
concentration Measurement >c
ug/m3
HEAVY
0
196
588
980
0
0
784
784
0
1176
784
784
941
941
0
784
ppm method
EXERCISE
0.0 CHEM, NBKI
0.1
0.3
0.5
0.0 CHEM, GPT
0.0
0.4
0.4
0.0 CHEM, NBKI
0.6
0.40 MAST, NBKI
0.40
0.48
0.48
0.0 CHEM, NBKI
0.4
Exposure
duration,
min

120
120
120
120
120
120
120
120
120
120
90
120
90
120
120
120
Number of
subjects

10
10
10
10
15
15
15
15
20
20
5
5
5
5
10
12
Minute
ventilation, FEVX
L/min %

50.4
49.8
56.3
51.4
57.0
57.0
57.0
57.0
45.0
45.0
46.5
46.5
44.7
44.7
55.3
55.3

100.8 ±
100.5 ±
93.7 ±
85.8 ±
98.7 ±
101.9 ±
90.6 ±
95.6 ±
102.5
71.6
96.0
94.3
89.3
84.4
98.8 ±
92.3 ±
d
• o»

16.3
16.2
17.5
19.5
4.1
4.3
4.9
5.4


5.6
4.8
Reference

(4) Folinsbee et al., 1978
(7) Haak et al . , 1984
(16) Ketcham et al . , 1977
(20) Silverman et al., 1976
(21) Stacy et al . , 1983

-------
     TABLE 13-3.  EFFFCTS OF INTERMITTENT EXERCISE AND OZONE CONCENTRATION ON 1-SEC FORCED EXPIRATORY VOLUME (continued)
Ozone
concentration
ug/m3 ppm
VERY
0
196
588
980
^ 0
£ 235
353
470
588
784
b Exposure
Measurement ' duration, Number of
method min subjects
Mi nute
ventilation, PLV1.0,
L/mi n %
d

HEAVY EXERCISE
0
0
0
0
0
0
0
0
0
0
.0
.1
.3
.5
.00
.12
.18
.24
.30
.40
CHEM, NBKI 120
120
120
120
CHEM, UV 150
150
150
150
150
150
10
10
10
10
22
22
20
21
21
29
66.
71.
68.
67.
66.
68.
64.
64.
65.
64.
8
2
4
3
?
0
6
9
4
3
99.
97.
92.
76.
98.
95.
93.
85.
83.
83.
7
4
3
1
9
7
6
6
2
0
± 13
± 17
± 12
± 11
•*: ?.
± 3.
± 3.
± 3.
± 3.
± 3.



•
4
2
4
4
8
7
7
6
7
9






                                                                                                         Reference
                                                                                                 (4) Folinsbee et al., 1978
                                                                                                (19) McDonnell  et al.,  1983
 References are listed alphabetically within each exercise category;  reference number refers to data points on
 Figures 13-2 through 13-5.
 Measurement method:   MAST = Kl-coulometric (Mast meter);  CHFM = gas-phase chemi1uminescence;  UV = ultraviolet photometry.
"Calibration method:   NBKI = neutral  buffered potassium iodide; GPT = gas phase titration;  UV  = ultraviolet photometry.
 Data reported as  mean ± standard error of the mean;  not all  references provided  standard errors.
3
"Subjects exposed  to  0.42 and 0.50 ppm ozone were treated  as  the same subject group (Gliner et al.,  1983).

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FEV  by 10 percent, on the average.   The curves also indicate that there is no
threshold concentration;  i.e.,  the concentration below which  no measurable
effects are  induced as  assessed  by a mean response.   Furthermore,  the 95
percent confidence limits show that even very low 0_ copcentrations (<0.2 ppm)
will induce  some  functional  decrements.   For example, as  Figure  13-4  shows,
one may be  95  percent confident that very  heavy exercise  during  exposure  to
0.2 ppm ozone  will  decrease FEV  by  5 to 12 percent;  and  during  exposure  to
0.1 ppm,  by  1  to  7  percent,  on  the  average.  Thus,  at  any  ozone  concentration
there  will  presumably be healthy individuals who will show effects of  the
exposure.
     Exercise not only stresses the respiratory system but other physiological
systems, as well, particularly the cardiovascular and musculoskeletal systems.
Various compensatory mechanisms activated within these systems during physical
activity  might facilitate,  suppress, or otherwise  modify  the  magnitude and
persistence  of  the reaction to ozone.  Unfortunately,  to  date only  a  few  of
the  studies  were  specifically  designed  to  examine nonpulmonary  effects of
exercise in  ozone atmospheres (Gliner et al., 1979).   In one study, very heavy
exercise  (V_ > 64  L/min) at a  high ozone  concentration (0.75 ppm)  reduced
post-exposure maximal exercise capacity by  limiting maximal oxygen consumption
(Folinsbee et al. ,  1977a); submaximal oxygen consumption changes were  inconsis-
tent (Folinsbee et  al.,  1975).  The extent  of ventilatory  (VT, fR) and respira-
tory metabolic changes (V0?) observed during or following  the  exposure appears
to  have been  related to the  magnitude  of pulmonary  function impairment.
Whether such (metabolic) changes are consequent to respiratory discomfort or
are the result of  changes in lung mechanics or both is still unclear and needs
to be  elucidated.
13.3.2.3   Environmental  Stresses.   Environmental  conditions such  as heat  and
relative  humidity  (rh)  may  enhance  subjective  symptoms   and  physiological
impairment following  0   exposure.   A  hot (31 to 40°C)  and/or humid (85 percent
                      <3
rh)  environment,  combined with exercise in the 0_  atmosphere,  has been  shown
                                                 O
to  reduce forced expiratory volume more than  similar exposures at normal room
temperature  and  humidity  (25°C,  50 percent rh)  (Folinsbee  et al. ,  1977b;
Gibbons and  Adams,  1984).  Modification of  the effects of  03 by  heat or  humidi-
ty  stress may be attributed to  increased  ventilation which,  like exercise,
increases the  overall volume of  inhaled pollutant and  promotes greater penetra-
tion into the  peripheral  areas  of the lung.

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13.3.3  Other Factors Affecting Pulmonary Response to Ozone
13.3.3.1  Age.  Although  changes  in growth and development of the lung with
age have been  postulated  as one of many factors capable of modifying respon-
siveness to 0.>, studies have not been designed to test adequately for effects
of CL  in different  age groups.  An enhanced  responsiveness  of the young to
ozone exposure has been suggested from field and epidemiology studies in which
decreases in  lung function  were reported at 0,, concentrations of 0.08 to 0.15
                                              O
ppm (Kagawa and Toyoma,  1975;  Kagawa et al. ,  1976;  Kagawa, 1983;  Lebowitz et
al., 1982,  1983; Lebowitz, 1984).   Symptoms have also been observed in children
exposed to 0.10 ppm oxidant and above (Okawada et al, 1979; Makino and Mizoguchi,
1975).  No  comparable data are  available, however,  from controlled human
studies, since possible age differences in response to 0_ have not been explored
                                                        O
systematically in controlled studies.
     The influence  of age on  responsiveness  to  ozone is also difficult to
assess from animal  studies.  Very  few age  comparisons have been made within  a
single  study.   Raub  et al.  (1983),  Barry (1983), and Barry  et  al.  (1983)
studied pulmonary function  and morphometry of the proximal alveolar  region  in
neonatal (1-day-old)  and  adult (6-week-old)  rats exposed  to  0.08,  0.12,  or
0.25 ppm ozone  for  12 hr/day,  7 days/week for 6 weeks.   A few different re-
sponses were  observed in  the  neonates and adults,  but  they were not major.
Generally,  neonates and adults  were about equally responsive.
     The stage  of  development  at initiation  of  exposure may  be an important
determinant of  age  responsiveness.  A rat  is  generally considered to be adult
(e.g., sexually mature) at  about 60 days of age, while alveolarization of  the
lungs  is complete  at roughly 40 days of age.   Stephens et al. (1978) exposed
rats of various ages  (1 to  40  days  old) to 0.85  ppm  ozone continuously for  1,
2, or  3  days.   Rats  exposed prior  to weaning (20 days  old)  had  few or no
effects on  lung structure.  For rats older than  20  days,  centriacinar  lesions
increased progressively,  reached  a plateau at 35 days of age, and persisted.
Biochemical  studies (antioxidant metabolism  and oxygen consumption in the
lung)  of similar  design  have  been conducted by Lunan et al.  (1977),  Tyson et
al. (1982),  and  Elsayed  et al. (1982).   In  the  first two studies,  animals
were exposed  to  0.9 ppm ozone for  96 hr;  in  the  latter  study, subjects were
exposed to  0.8 ppm ozone  for  92  hr.   Generally, in  rats exposed prior to
weaning (about  20 days old), activities of enzymes  decreased;  in  those around
weaning age  there was no  change; and in more  mature  young rats (35 to  90 days

019JSA/A                           13-34                                6/26/84

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old), enzyme activities increased.   Numerous other studies of adult rats using
similar methods  show increases  in  these activities.  Lunan  et  al.  (1977)
observed a peak in the response at 35 days of age, similar to that of Stephens
et al.  (1978).   In the studies of Elsayed et al.  (1982),  the 7- and 12-day-old
rats had  60 percent  mortality; the older  rats  had no mortality.   Lunan  et  al.
(1977) used an additional exposure regimen  in  which  rats  aged 10, 15, 25,  and
32 days were exposed up to 32 to 34 days of age.   Thus, the animals had differ-
ent  lengths of exposure.   Effects were observed  only  in  the animals 25 and
32 days old.  The  greatest magnitude  of the effect was observed  at 32 days of
age, regardless of the absolute length of exposure.
     Interpretation  of these  animal  studies may be confounded by the exposure
techniques used.    In some studies, neonates and mothers were  exposed together
and  the possibility  exists  that the ozone  concentration was  different  in  the
breathing zone of  the neonates.   In  the  Raub  et  al.  (1983)  and  Barry et al.
(1983) studies,  this potentially confounding  factor was minimized.  In other
studies,  neonates were exposed without mothers.  It is not known whether their
breathing parameters may have  been  influenced from the  consequent  stress.
Even without these factors, the dosimetry of ozone in the different age groups
is unknown.  From  the reported studies it  appears that rats  about 35 days of
age  respond equivalently to  adult  animals when exposed to ozone.   Responsive-
ness of rats prior to weaning (about 20 days old) is confounded.
13.3.3.2  Sex.   Sex  differences  in   responsiveness  to ozone have not  been
adequately studied.   A small  number of female subjects  have been exposed  in
mixed  cohorts  in many human controlled studies,  but only three  reports gave
enough information for a limited comparative evaluation (Horvath  et al., 1979;
Gliner et al., 1983;  DeLucia et al.,  1983).  Lung function of women, as assessed
by  changes  in FEV,  „, appears  to be affected more  than  that of men under
similar exercise and exposure conditions,  but the  differences have  not been
analyzed  systematically.   Further research is needed to  determine  whether
differences in lung  volumes or differences  in  exercise capacity  during  exposure
may  lead  to sex  differences in responses  to 0,.
     The  majority  of animal  studies  have been conducted with male animals.
Generally, when  females  have been used they have  not been  compared to males  in
the  same  study.    This  makes comparisons of sex  sensitivity to  ozone  from
animal data virtually impossible.  The only exception  is  a study of effects  of
ozone  in  increasing  pentobarbital-induced sleeping time  (Graham  et al., 1981).

019JSA/A                           13-35                                6/26/84

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Since waking  from pentobarbital anesthesia  is  brought about by xenobiotic
metabolism in the liver, this effect is considered to be extrapulmonary.   Both
sexes of  mice,  rats, and  hamsters  were exposed to 1  ppm  ozone for 5 hr.
Increased sleeping time was  observed in all  females, but not in male mice or
male  rats.   Male hamsters were affected, but  significantly  less  than the
females.   The reasons for  this sex difference  are unknown.   Rats  have major
sex differences  in xenobiotic metabolism, but the other species do not.
13.3.3.3  Smoking Status.   Differences between  smokers  and  nonsmokers have
been studied often,  but the data are not documented well and are often confus-
ing.  Published  results  indicate  a discrepancy  in findings.  Hazucha  et  al.
(1S73) and Bates and Hazucha (1973) appear to have demonstrated greater responses
(FVC, MMFR)  in  nonsmokers  at 0.37 ppm 0   but the responses were reversed at
                                        O
0.75 ppm (RV, FEVI}  Vmax50,  and MMFR).  Kerr et al. (1975) observed greater
responses (FRC,  SG   , R, ,  FEV, and symptoms) in nonsmokers at 0.5 ppm C_ for
                  dw    L,                                                O
6 hr.  DeLucia  et al. (1983) observed  similar results  for  VC, FEV.. , MMFR,  fD,
                                                                 1         D
and VT at 0.3 ppm 0_ (1 hr,  CE).   Kagawa  and  Tsuru  (1979a) stated that the
      I              J
effects of ozone among nonsmokers were greater for the 0.5 than for the 0.3 ppm
0- exposure levels (2 hr); a later study (Kagawa, 1983) showed that nonsmokers
 O
had a greater response  (SG   )  to 0.15  ppm  (2 hr, IE).   Shephard et al. (1983)
                           QW
found a  slower  and  smaller change in spirometric variables in smokers at 0.5
and 0.75 ppm  (2 hr,  IE).   None of these controlled studies have examined the
effects of different amounts of smoking.  Epidemiological studies have detected
an  increase  of  symptoms (cough, nose,  and eye  irritation) in heavy smokers
compared to  others  at 0.08 ppm 0«  and  above (Zagraniski et al. , 1979).   The
general  trend,  however, is  to imply that smokers are less  sensitive than
nonsmokers.
13.3.3.4  Nutritional Status.   Posin et al. (1979) found that human volunteers
receiving 800 (about 4 times the recommended daily units) or 1,600  (a very high
supplement)  IU  vitamin  E  for 9 weeks  as a supplement showed no  differences in
blood biochemistry from unsupplemented volunteers when exposed to 0.5 ppm  ozone
for 2 hours.  The biochemical  parameters  studied included  red cell  fragility,
hematocrit,  hemoglobin,  glutathione  concentration,   acetylcholinesterase,
glucose-6-phosphate  dehydrogenase,  and lactic  acid dehydrogenase  activities.
Hamburger and Goldstein (1979) studied the agglutination of  rat red cells by
the  lectin  concanavalin A  after jji vivo  exposure  to  0.5 to 2 ppm  ozone  for
2 hours  or  incubation i_n vitro with 1 ppm ozone for 2 hours.   Agglutination

019JSA/A                           13-36                                6/26/84

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was decreased  by  ozone exposure, but the  number  of concanavalin A  binding
sites on red  cells  was not decreased.  Hamburger et  al.  (1979)  also studied
the effects of ozone  exposure on the agglutination of  human  erythrocytes by
concanavalin A.  As with  rat  erythrocytes, pre-incubation with malonaldehyde,
an oxidation  product  of polyunsaturated fatty  acids,  decreased concanavalin A
agglutination of red cells exposed i_n vitro to ozone.   Red cells obtained from
29 subjects receiving  800 IU  vitamin E  (a high supplement) or a placebo were
exposed  to  0.5 ppm ozone  for  2  hours.   Following  ozone  exposure, a slight
decrease in agglutination occurred  in cells  from subjects who did  not receive
vitamin E supplementation, but the results were not statistically significant.
     Increased activity of the glutathione peroxidase system may be  one of the
most sensitive  indices of exposure to < 1 ppm of  0,  measured biochemically
because it is  involved in  antioxidant metabolism.   Increases  in the  glutathione
peroxidase  system  have been  reported after exposure of  rats on a  vitamin
E-deficient diet to levels as low as 0.1 ppm 0_ for 7 days (Chow et  al., 1981;
Mustafa, 1975;  Mustafa and Lee,  1976).  The  dietary vitamin  E fed  to the  rats
influenced the  ozone-induced  increase of this system.  For example, when the
diet of rats had 66 ppm of vitamin E, increased glutathione peroxidase activity
was observed at 0.2 ppm of 0_; with 11 ppm of  vitamin E,  increases occurred at
                            *5
0.1 ppm  (Mustafa  and  Lee, 1976).   Several  other investigators have shown  that
vitamin E deficiency in rats makes them more susceptible  to these ozone-induced
enzymatic changes  (Chow et al. ,  1981; Plopper et al., 1979;  Chow and  Tappel,
1972).
     Morphological studies of ozone-exposed vitamin E-deficient or supplemented
rats have been undertaken  to correlate the biochemical findings with morpholog-
ical alterations  (Plopper et al. ,  1979; Chow  et al. ,  1981;  Schwartz et  al. ,
1976;  Sato  et al. , 1976,  1978,  1980).   Scanning and transmission  electron
microscopy were clearly shown to be better than light microscopy for visualiza-
tion  of the  ozone  lesions.   Lesions were worse  in vitamin E-deficient or
marginally  supplemented  rats  than  in highly  supplemented  rats,  supporting the
finding  from  mortality (Donovan et al. , 1977) and  biochemical  studies that
vitamin E is  protective.   Despite  the presence of  vitamin  E in  the  diets  of
these  animals, the morphological  lesion  resulting from  ozone exposure  was
unchanged.  Vitamin E  thus alters the rate and extent of  toxicity, but not the
lesion  itself.
019JSA/A                           13-37                                6/26/84

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     The difference in  response  between  animals and man with  regard to the
protective effects of vitamin E against ozone toxicity may  lie in the pharmaco-
kinetics of vitamin E distribution  in the body.  Redistribution of vitamin E
from extrapulmonary stores to the lung is slow.  Short exposures to  ozone may
not allow adequate time for  redistribution and for a protective effect to be
observed.   Animal  exposures  in which the  striking  effects  of vitamin E on
ozone toxicity were observed were generally conducted over long times.  Human
subjects were exposed for  shorter  times  and lower concentrations because of
ethical  considerations.   Thus,  the  protective  effects of  vitamin  E might
likewise be demonstrated in  man,  but might require  longer  times  and higher
ozone exposures.    In  addition,  animal studies are generally conducted with a
deficient diet (0  ppm vitamin  E) group  for comparison.   The respective human
group would very  likely not have had a  substantial  deficiency.   Thus, the
antioxidant properties of vitamin E in preventing ozone-initiated peroxidation
j_n vitro are well  demonstrated and the protective effects j_n vivo are  clearly
demonstrated in rats  and mice.   No  evidence indicates, however, that man would
benefit from increased  vitamin  E intake  relative to ambient ozone exposures.
Further, vitamin  E protection is not absolute and can be overcome by continued
ozone exposure.  The  vitamin E  effects  do support the general  idea, however,
that lipid peroxidation  is  involved in ozone intoxication.
13.3.3.5  Red Blood Cell Enzyme Deficiencies.   The enzyme glucose-6-phosphate
dehydrogenase  (G-6-PD) is essential  for the function of the glutathione peroxi-
dase system in the red  blood cell (RBC), the enzyme  system proposed  as  having
an integral part  in  the decomposition of  fatty acid peroxides or  hydrogen
peroxide formed by 0\-initiated  polyunsaturated fatty acid peroxidation (see
Section 13.5.1).    Therefore,  Calabrese et al.  (1977) has  postulated that
individuals with a hereditary deficiency of G-6-PD may be at-risk to signifi-
cant hematological effects  from CL  exposure.   However, there have been too few
studies performed  to  reliably  document this possibility.   Most ozone studies
have been with red blood cells from rodents, even though differences may exist
between rodent and human RBCs.   Calabrese and  Moore  (1980) and Moore  et al.
(1981) have pointed out  the lack of ascorbic acid synthesis and the relatively
low  level  of  glucose-6-phosphate dehydrogenase (G-6-PD) in man  compared to
active ascorbic acid  synthesis  and high levels of  G-6-PD  in  mice and rats.
Although this species comparison  is  based on a very limited  data base, the
authors point out the importance of developing animal models that can accurate-
ly predict the response of G-6-PD-deficient humans to oxidant  stressor agents
019JSA/A                           13-38                                6/26/84

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such as 0,.   This group has suggested the use of the C57L/J strain of mice and
         O
the Dorset sheep as better animal models for hematological studies since these
species have  levels of G-6-PD closer to  those  in man, especially  those  levels
found in G-6-PD-deficient patients.   The RBCs of Dorset sheep, however, appear
to be no more sensitive to ozone than normal human RBCs even though the G-6-PD
levels are very  low.   Further i_n vitro  studies  (Calabrese et  al. ,  1982, 1983;
Williams et al.  ,  1983a,b,c)  have demonstrated  that  the  responses  of  sheep and
normal  human  erythrocytes were  very similar when  separately  incubated with
potentially toxic CL intermediates,  but that G-6-PD-deficient human erythrocytes
were  considerably more susceptible.   Even  if 0- or  a  reactive product of
00-tissue interaction  were to penetrate  the  RBC after in  vivo exposure, it  is
 o
unlikely  that decrements in reduced  glutathione  levels  leading  to  chronic
hemolytic anemia would be of functional significance for  the affected individ-
ual.  More research may therefore be needed to determine  the susceptibility of
these  individuals to 0-.-induced  hemolysis  from near-ambient CL  exposures.

13.3.4  Effects of Repeated Exposure to Ozone
13.3.4.1  Introduction.   Ozone  toxicity  may be mitigated through altered
responses that  are functional,  biochemical, or morphological  in type.   For
example,  in  response  to  03 there may  be an increase in  tissue  or cellular
levels  of antioxidants,  which  act to quench  free  radicals and reduce lipid
peroxidation.   At present the  underlying mechanisms for  this  response are
unclear  and  the  effectiveness  of such  mitigating  forces  in  protecting the
long-term health  of the individual against 0, is still  uncertain  (Bromberg and
Hazucha, 1982).
      Reduction of responses associated with repeated exposure to  0.,  is generally
referred  to  as  "adaptation."  Earlier work in animals  that focused primarily
on  reductions in pulmonary edema and mortality  rate to  assess this process
employed  the  term "tolerance"  (Chapter 10, Section 10.3.5).    Other  terms,
including "tachyphylaxis," have also been used to  describe this  phenomenon.
The  distinction,  if  any,  among  these  terms  with respect to 0., and its  effects
has  never been established in a clear, consistent manner.
13.3.4.2   Development of Altered Responsiveness to Ozone.  Successive  daily
brief exposures to 0_  (<  0.7 ppm for ~ 2  hrs)  induce a  typical temporal pattern
of  response (Chapter 11,  Section 11.3).   Maximum functional changes that occur
after  the first exposure day (airway resistance, bronchial reactivity tests)

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(Parrel! et al. , 1979; Dimeo et al., 1981) or the second exposure day  (spiro-
metric tests) become  progressively  attenuated  on each of the subsequent days
(Horvath et al., 1981; Kulle et al., 1982b; Linn et al.,  1982).   By the fourth
day of  exposure, the  effects  are, on the  average,  not  different from those
observed following control  (air)  exposure.   Individuals  need between 3 and 7
days to develop full  attenuation, with more sensitive subjects requiring more
time (Horvath  et  al., 1981; Haak et al.,  1984).  The magnitude  of  a peak
response appears to be directly related to 0-  concentration (Folinsbee et al.,
1980; Haak  et  al. ,  1984).   Whether varying the  length or  the frequency of
exposure will modify  the  time  course of this altered responsiveness  has not
been explored.  Full  attenuation,  even  in ozone-sensitive  subjects,  does not
persist for more than 3  to 7 days in most individuals (Horvath et al., 1981;
Kulle et al.,  1982b;  Linn  et  al. ,  1982),  while partial attenuation might
persist for up to  2 weeks (Horvath et al.,  1981).  Although symptomatic response
is  generally  related  to  the magnitude of  the  functional  response, partial
symptomatic attenuation appears to  persist longer,  for up  to  4  weeks (Linn
et al.,  1982).  Ozone concentrations inducing only minimal  functional effects
(< 0.2 ppm) have not elicited altered responsiveness to  03  in either pulmonary
function or  airway responsiveness  (Folinsbee  etal., 1980;  Dimeo  et al. ,
1981).   The last findings are  consistent with the proposition that functional
attenuation may not occur in the airways of individuals living in communities
where the ambient  ozone levels  do not exceed 0.2 ppm.   The  difficulty, however,
of drawing such inferences on the basis  of narrowly defined laboratory studies
is  that  under ambient conditions  a number of  uncontrollable  factors will
modify the  response.  Most  notably,  other pollutants may interact with ozone
to modify changes  in  the  host  at lower concentrations during generally more
protracted  exposures.  The  evidence  suggesting that Los Angeles residents
exhibit functional attenuation of the response to 0, is sparse and  requires
confirmation (Hackney et  al.,  1976,  1977a,b;  Linn et al.,  1983).
13.3.4.3   Mechanisms  of Altered Responsiveness  to Ozone.   The time  course,
type, and consistency of  changes  of such  indices as  symptoms, lung  volumes,
flows,  resistances, and bronchial reactivity strongly implicate vagal  sensory
receptors (cholinergic post-ganglionic pathways) in substantially modifying
the development of altered  responsiveness  to  0- (Dimeo  et al., 1981).  Post-
exposure inhalation of atropine (a bronchodilator) blocked  completely, though
only transiently,   the  increase in bronchial  reactivity  (Golden et al., 1978;

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Holtzman et al., 1979).  Similarly,  inhalation of  isoproterenol  (a  bronchodila-
tor)  relieved  all  symptoms and normalized functional  changes induced by ozone
(Golden  et al. ,  1978).   Since afferent vagal  activity is one of the principal
modifiers  of  bronchomotor  tone, any attenuated  changes  will be reflected in
airway  smooth  muscle response and thus in altered airway resistance, which is
used  as a  convenient  index of  bronchoconstriction.  Besides  the  vagal component,
numerous other mechanisms  might play  an  important role  in the  development of
altered  responsiveness  to  0~; e.g., release of  mediators (Linn  et  al., 1982)
or  increased  airway mucosa permeability  (Davis  et al.,  1980).   The relative
importance  and the overall contribution  of any  of these mechanisms is  still
unclear.
      Whether  laboratory  animals develop  functional attenuation  of  responses
similar  to that observed in human subjects, as  measured by  airway  resistance
or  forced  expiratory  flow rates, is  unreported.  In this regard, recent experi-
ments  by Gertner  et  al. (1983a,b,c) are  noteworthy,  since  they offer  some
clues on possible  mechanisms.  They  demonstrated that even a brief  exposure  of
the peripheral  airways  of  dogs to ozone  triggered functional  response that
appeared to be mediated through both reflex and  humoral pathways.   The reflex-
mediated response  was subject to  attenuation  after repeated  exposure, whereas
the response mediated humorally was  not.
      As  noted  previously,  functional and  symptomatic  attenuation of responses
to 03 in human subjects is typically preceded by a limited period during which
effects  are slightly exaggerated.   The latter period  corresponds roughly in
time  to  the period  of  heightened  responsiveness to  a provocative  aerosol,
response also caused by QS (Dimeo et al., 1981).   Recent experimental evidence
in  laboratory  animals points  to an  intimate relationship between the cellular
response to 03~induced injury, as measured by the appearance of neutrophils  in
the airway  epithelium of dogs exposed  to 03,  and airway hyperresponsiveness,
as  determined  with a provocative aerosol  (Holtzman et al. ,  1983a,b; Fabbri
et al., 1984;  Sielczak  et  al., 1983).   When mobilization of the neutrophils
was prevented  by prior  treatment  with  hydroxyurea (O'Byrne et al.,  1983), or
the neutrophilic infiltration found after ozone exposure was depressed (Fabbri
et al., 1983), no  increase  was seen in  airway responsiveness.
     Since many proposed mechanisms  of altered responsiveness to CL in humans
                                                                  O
are difficult if not impossible to investigate, animal studies become essential
in providing necessary confirmatory evidence.   Numerous basic metabolic proces-
ses in humans  and animals appear to be  very similar (Mustafa and Tierney,  1978;
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Boushey  et  al. ,  1980).   Some mechanisms  underlying  these processes at the
cellular and  subcellular level studied extensively in animals do provide some
clues on possible  mechanisms  in  humans.   It has  been  shown that human and
animal leukocytes, pulmonary  macrophages,  and  neutrophils produce superoxide
radicals not  only  as  a  product of a vital biological reduction of molecular
oxygen but  also  as a  result of stressful  stimuli  (Pick and Kersari,  1981).
Excessive production of  radicals  without adequate scavenging will  injure the
supporting  tissues, while  the attenuation of response  to successive stimuli
suppresses  the release of  free  oxygen radicals and depresses the chemotactic
responsiveness of  the  cells  (Mustafa and Tierney,  1978; Bhatnagar et al.,
1983).  Accumulation of inflammatory cells at the site of injury and subsequent
release  of  proteases  capable of degrading connective  tissue may upset the
protease-antiprotease  balance critical  for controlling the extent of inflamma-
tion and injury.   Reported ozone  inactivation of human a-.-proteinase inhibitor
(Johnson, 1980) observed HI vitro and perturbation of lung collagen metabolism
seen  i_n  vivo in  animals  (Hussain et al.,  1976;  Mustafa and Tierney,  1978)
could be factors  potentially  affecting  inflammatory response.  Furthermore,
the metabolic  attenuation  of propyl hydroxylase  (a  key enzyme  in collagen
synthesis)  activity (Hussain  et al., 1976a,b),  and concurrent  changes  in
superoxide dismutase activity, which catalyzes  the dismutation of the  superoxide
free radical  (Bhatnagar  et al. ,  1983),  could be another important pathway to
the development  of altered responsiveness to 0~.   The glutathione peroxidase
system, which provides another line of defense by protecting cells from lipid
peroxides,  also  exhibits metabolic attenuation  (Chow,   1976; Chow et al. ,
1976).
     With time,  there is a  reduction in  intensity and a  change in composition
of  the  inflammatory response.   Partial  remission occurs  with continuous  or
intermittent exposure.   There are no data showing how important  the timing and
duration of the 03 pulsations may be in  influencing the induction and  remission
of the inflammatory reaction.   The latter issue has potential significance for
public health, since exposure to  ambient air  pollution at levels of concern is
essentially  intermittent.   The timing  and intensity of  exposure  within  the
community,  and consequently its potential for inducing  altered responses,  are
likely to be  highly variable.   Differences within the population in patterns
of activity and biological  status may be expected to contribute  to this varia-
bility.

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13.3.4.4  Conclusions Relative to Attenuation with Repeated Exposures.   Insofar
as different effects  of 0» share the same mechanism(s), they may be expected
to follow approximately similar  time courses in their development of altered
responsiveness to CL.  As a corollary, effects that are not linked mechanisti-
                   O
cally should  follow  independent  although not  necessarily  dissimilar  time
courses, assuming that they are involved in this process.
     The attenuation  of acute effects of 0- after repeated exposure, such as
changes  in  respiratory mechanical  behavior,  have been well  documented in
controlled  exposure  studies.   In contrast, there  is  no practical means at
present of assessing the role of altered responsiveness to 0, in human popula-
tions chronically exposed to ozone.   There have been no epidemiological studies
designed to  test whether  the modification of changes involving  irritative
symptoms, pulmonary function, or morbidity occur in association with photochem-
ical air pollution.  It might be added that the proposition would be difficult
to test epidemiologically.  Thus, scientists, as well as regulators, must rely
mainly on inferences and extrapolations from animal experimentation.
     Altered responsiveness to 0- may be viewed as a process exhibiting concen-
tration/response characteristics.  Concentrations of 0, that have no detectable
effect  appear  not  to invoke changes  in  response  to  subsequent exposures at
higher 0, concentrations.  Insofar as this generalization is valid, it suggests
that photochemical air pollution may induce altered responses only in individ-
uals who previously  responded to exposure.  Over  some  higher range (0.4 to
0.8 ppm) of exposure, changes occurring after repeated exposure may be optimal
so that  recovery (assessed by pulmonary function tests) after initial  damage
is virtually  complete.   Above this optimal range, persistent or  progressive
damage  is  most  likely  to accompany protracted exposure.   The  attenuation,
however, of pulmonary function (and the  time  course  of  attenuation)  following
repeated exposure  to 0-  does not  necessarily  follow the morphological or
biochemical pattern of  responses.
     Responses to  0_, whether functional,  biochemical,  or morphological, have
the potential  for  altering responses during repeated or continuous exposure.
There is an interplay between tissue inflammation, hyperresponsiveness, ensuing
injury  (damage), and changes  in response.  The hyperresponsiveness followed by
attenuation of  responses caused by 0_ may be viewed as obverse or sequential
states  in a continuing process.
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13.3.5  Relationship Between Acute and Chronic Ozone Effects
     Understanding the  relationship  between  acute  effects that  follow (L
exposure of man or animals and the effects that follow long-term exposures of
man or  animals  is  crucial  to the evaluation of possible  human health effects
of oxidant pollutants.   Most of the acute responses  to 0- described in animals
and man tend  to  return  to control (filtered  air) values with time after the
exposure ends.  While effects of longer periods of exposure have been documen-
ted in  laboratory  animals  (Chapter 10),  long-term exposures of human beings
have not been  done  because of possible  health  hazards.   In fact, little is
known about the  long-term  implications of acute damage or  about the chronic
effects of prolonged exposure to 0_ in man.
     With newer techniques, pulmonary functions of experimental  animals can be
more completely evaluated  and  correlated with biochemical  and morphological
parameters.   Long-term exposure  of rats  to less than  1.0  ppm 0.,  results in
increased lung volume, especially  at high transpulmonary pressures (Bartlett
et al., 1974;  Moore and Schwartz,  1981; Raub et al., 1983;  Costa et al. ,
1983).   Costa et al. (1983)  also observed increased pulmonary resistance and,
at low lung volumes, decreased maximum expiratory flows in rats  exposed to 0.2
or 0.8 ppm 03  6  hr/day,  5  days/week for 62 exposures.   The latter change was
related to decreased airway  stiffness or to  narrowing of  the  airway lumen.
Raub et al. (1983), in neonatal  rats  exposed  to 0.12 or 0.25 ppm 0, 12  hr/day
for 42 days,  observed significantly  lower peak inspiratory  flows during  spon-
taneous respiration, in  addition to the increased lung volumes noted above.
While Yokoyama and Ichikawa (1974) did not find changes in lung  static pressure-
volume curves of rats exposed to 0.45  ppm 0,  6 hr/day, 6 days/week for  6 to 7
weeks, Martin et al. (1983) reported increased maximum extensibility of alveolar
walls and increased fixed lung volumes following exposure of rabbits to 0.4 ppm
0,, 7 hr/day, 5 days/week for 6 weeks.
     Wegner (1982)  studied  pulmonary functions in bonnet  monkeys  exposed  to
0.64 ppm DO 8 hr/day, 7 days/week for up to 1 year.   After 6 months of exposure,
significant increases in pulmonary resistance and in the frequency dependence
of pulmonary  compliance were reported.   In the monkeys exposed 1 year,  Wegner
(1982) reported significantly increased pulmonary resistance and inertance and
decreased flows during  forced  expiratory maneuvers at low lung  volumes and
decreased volume expired in  1 second (FEV,).   These findings were  interpreted
as indicating narrowing of the peripheral airways.   Following a 3-month postex-
posure period,  static  lung compliance tended to decrease in both exposed and
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control monkeys, but the decrease in exposed monkeys was significantly greater
than that  for  control  monkeys.   Although values for other parameters studied
in control  and  exposed monkeys were  not  significantly different at the end of
the postexposure period,  they tended to be  substantially different.  Wegner
(1982) interpreted  these  differences as an  indication  that recovery was not
complete  following  the 3-month  postexposure period.   This  interpretation
appears  reasonable,  as  fewer monkeys were available  for pulmonary function
testing at  the  end  of the postexposure period because monkeys were terminated
for biochemical and morphological  evaluation at the end of each experimental
period.  To find the same level of statistical  significance with fewer animals,
the difference of the means would have to be greater at the end of the postexpo-
sure period than at the end of the exposure.
     Morphological   alterations in both rats  and monkeys  tend to decrease with
increasing  duration of exposure to  0~,  but  significant alterations in the
centriacinar region  have  been reported at the end  of long-term exposures of
rats (Boorman et al.,  1980;  Moore and Schwartz, 1981;  Barry  et a!.,  1983),
monkeys (Eustis et al., 1981), and dogs (Freeman et al., 1973).   While repair,
as indicated by DNA synthesis by  repair  cells, starts as early as 18 hours of
exposure (Castleman  et al. ,  1980; Evans  et al., 1976a,b,c; Lum et al., 1978),
damage continues throughout long-term exposures,  but at a lower rate.
     Morphological   damage  reported   in the  centriacinar region  of rats and
monkeys exposed to  less  than 1.0 ppm 03 for 42 to 90 days includes damage to
ciliated and alveolar type 1 cells;  hyperplasia of nonciliated bronchiolar and
alveolar type 2 cells,  with extension of nonciliated bronchiolar cells into
more distal structures than in unexposed controls;  accumulation of intraluminal
inflammatory cells;  and  in  rats,  but not reported  in monkeys, thickening of
interalveolar septa  (Boorman  et al.,  1980;  Moore and Schwartz, 1981; Eustis
et al., 1981; Barry et al.,  1983).   Freeman  et al.  (1973) exposed dogs to 1.0
to 3.0 ppm 03 8 to 24 hr/day for 18 months.   Dogs exposed to 1.0 ppm 0~ 8 hr/day
had the mildest changes,  including  minimal   fibrosis of  terminal airways and
adjacent alveoli with  a  few "extra" macrophages in these areas.  Epithelial
hyperplasia and metaplasia and increased fibrosis were seen in dogs exposed to
higher concentrations or more hours  per day.   These investigators also observed
that bronchiolar walls  were  thickened  by both epithelial  hyperplasia  and
intramural   fibrosis, which  reduced  the caliber of small airways.   Lungs  from
the bonnet monkeys studied by Wegner (1982)  were evaluated morphologically and
morphometrically by  Fujinaka  (1984).   At the end of  the 1-year exposure to
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0.64 ppm 0^ for 8 hr/day,  a significant increase was found in the total  volume
of  respiratory  bronchioles in the  lung,  but their lumens were  smaller in
diameter because  of thickened epithelium  and other wall  components.   The
reduction  in  diameter  of  the first generation  respiratory bronchioles  cor-
relates with  the  results  of the  pulmonary function tests performed by Wegner
(1982).  Cuboidal broncniolar epithelial  cells in respiratory bronchioles were
hyperplastic.   Walls of respiratory  bronchioles contained significantly more
macrophages,  lymphocytes,   plasma cells, and neutrophils.  Neither the numbers
of  fibroblasts  nor  amount  of stainable collagen was increased significantly,
but there  was more  amorphous intercellular material.  There was also a  signi-
ficant increase in arteriolar media and intima.
     Lung  collagen  content was  increased after short-term exposure  to  less
than 1.0 ppm 0., (Last et al., 1979;  Last et al. , 1981).   This change continued
during  long-term  exposure (Last and  Greenberg, 1980;  Last  et al. ,  1984).
Exposure to less  than  1.0 ppm  0~ resulted in increased lung  collagen content
in  both weanling  and adult rats exposed for 6 and 13 weeks, respectively, and
in young monkeys exposed for I year (Last et al.,  1984).  Some of tne weanling
rats and  their controls  were  examined after a 6-week  postexposure  period
following  the 6-week 0^ exposure during which all rats  breathed filtered air.
During this postexposure period, the differences in lung collagen content be-
tween  exposed and pair fed controls increased rather than decreased.   Thus,
with respect  to  this  biochemical  alteration,  the postexposure period was one
of continued damage rather than recovery.
     A similar  observation of  continued  damage during  a postexposure period
was reported  by Gillespie  (1980) in pulmonary function  studies of beagle dogs
exposed for 5 years to a  variety of pollutants  (see Chapter 10, Section 5.2).
Similar pulmonary function tests were  performed during and at the end of the
5-year exposure  in  a  Cincinnati,  Ohio, laboratory and  repeated  in  a Davis,
California, laboratory after a  2-year  postexposure period.   The postexposure
values of  the control  group were similar to values at the end  of the exposure
and to  values for other healthy beagle dogs at Davis.   All exposed groups had
more functional  abnormalities at the end of  the 2-year postexposure period
than at the end of  the exposure.  Thus,  the  postexposure period was one of
continued damage, as evaluated by pulmonary function tests.
     Continuation of the centriacinar inflammatory process during long-term 03
exposures  is especially important,  as it appears to be correlated with remodel-
ing of  the centriacinar airways  (Boorman et al., 1980;  Moore  and Schwartz,
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1981; Fujinaka, 1984).   There  is  morphometric (Fujinaka, 1984), morphologic
(Freeman et al., 1973),  and  functional  evidence (Costa et al.,  1983;  Wegner,
1982) of  distal  airway  narrowing.   Continuation of the  inflammation also
appears to be correlated with increased lung collagen content (Boorman et al. ,
1980; Last et al.,  1979; Last et al., 1984).
     The distal airway  and  arteriolar changes described in the  above studies
of ozone-exposed animals  have  many similarities to those  reported  in lungs
from cigarette  smokers  (Niewoehner  et al.,  1974;  Cosio et al., 1980; Hale
et al. , 1980; Wright  et al.,  1983).   Even though cigarette  smoking has been
linked with emphysema in humans, however, there is no evidence of emphysema in
the  lungs  of  animals  exposed to 0_.  The  previous  criteria document for 0,
(U.S. Environmental  Protection Agency, 1978) cited  three  studies  reporting
emphysema  in  laboratory animals after exposure  to  <1  ppm 0- for prolonged
periods (P'an et al. , 1972;  Freeman  et al.,  1974; Stephens et al., 1976); but
a reevaluation of these findings based on the currently accepted definition of
emphysema  does  not  find any  evidence  for  such  claims (see Chapter 10;
Section 3.1.4.2).   Since  then,  no  similar exposures (i.e.,  same species, 0~
concentration, and  times) have been documented to  confirm observations of
emphysematous changes in the lungs of animals exposed to 03.

13.3.6  Resistance to Infection
     Normally the mammalian respiratory system is protected from bacterial  and
viral infections by  the integrated activity of  the mucociliary, phagocytic,
and immunological  defense systems.   Animal models and isolated cells have been
used to assess the effects of oxidants on the various components of these pul-
monary defenses and to  measure  the  ability of these  systems  to  function as an
integrated unit in suppressing pulmonary disease.  In these studies, short-term
(3 hr) exposure to  0~ at concentrations of 0.08 to 0.10 ppm can increase the
incidence  of  mortality  from  lower respiratory bacterial infection (Coffin et
al., 1968; Ehrlich et al. , 1977; Miller et al. , 1978).   Subchronic exposure to
0.1 ppm caused  similar  effects (Aranyi et al. ,  1983).  Following short-term
exposures  to  0^, a  number of alterations  in vital defenses  have been shown,
such as (1)  impairment  in the ability of the lung to inactivate bacteria and
viruses (Coffin  et  al., 1968; Coffin  and  Gardner,  1972;  Goldstein et al.,
1974, 1977;  Ibrahim et  al. ,  1976;  Nakajima et al. , 1972;  Ehrlich  et al. ,
1979);  (2) reduced  effectiveness  of  mucociliary clearance (Phalen et al. ,

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1980; Frager et  al. ,  1979;  Kenoyer et al.  , 1981; Abraham et al.  , 1980); (3)
immunosuppression (Campbell  and Hilsenroth, 1976; Thomas et al.,  1981b); (4) a
significant reduction in  number  of pulmonary defense cells  (Coffin  et  al. ,
1968; Alpert et al., 1971);  and (5) macrophages with less phagocytic  activity,
less mobility, more fragility and membrane alterations, and  reduced  lysosomal
enzymatic activity (Dowell et al.,  1970;  Hurst et al.,  1970;  Hurst and Coffin,
1971; Goldstein et al.,  1971, 1974, 1977; Hadley et al., 1977;  Ehrlich et a1.,
1979; McAllen et al. , 1981;  Witz et al.  ,  1983; Amoruso et al. ,  1981).  Such
effects have been reported in a variety of  species of animals following either
short-term and subchronic exposure  to  0- alone or  in combination with  other
airborne chemicals  (Gardner  et al.  , 1977;  Aranyi et al., 1983; Ehrlich, 1980,
1983; Grose et al. , 1980, 1982; Phalen et  al. , 1980; Goldstein et al.,  1974).
Studies have also indicated  that the activity  level of the test  subject is  an
important variable that  can influence the determination of the  lowest effective
concentration of the pollutant (Tiling et al., 1980).
     The major problem  remaining is the  assessment of the relevance  of these
animal  data to humans.   If animal models  are to be used to reflect the toxicol-
ogical  response occurring in humans, then the end point for comparison of such
studies should not  be mortality, since today few individuals die of  bacterial
pneumonias.  A better comparison in humans would be the increased prevalence
of respiratory illness  in the community.  Such a comparison is  proper  since
both mortality (animals)  and morbidity (humans) result from a loss  in pul-
monary defenses.   Ideally,  studies  of  pulmonary host defenses  should be per-
formed in  man  using epidemiological or volunteer methods of study.   Unfortu-
nately, such studies have not yet been reported.   Therefore,  attention must, be
paid to experiments conducted with  animals.
     Our present knowledge of the physiology, metabolism, and function of host
defense  systems  has come primarily from various  animal  systems, but it is
generally  accepted  that  the  basic mechanisms of  action  of these  defense cells
and  systems are  similar  in both animals  and man.  The effects seen in animals
represent  alterations in  basic  biological  systems.   One would not expect to
see an equivalent response (e.g., mortality) in man, but one could assume that
similar alterations in  basic defense mechanisms could  occur in  humans, who
possess equivalent pulmonary defense systems.  It is understood,  however, that
different  exposure  levels may be  required to produce similar responses in
humans.  The  concentrations of  0_  at which effects become  evident  can be

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influenced by a number of factors, such as preexisting disease, dietary factors,
combinations with other pollutants, and/or the presence of other environmental
stresses.   Thus, one could hypothesize that humans exposed to 03 could experi-
ence decrements  in  host  defenses, but at the present time one cannot predict
the exact concentration  at  which effects may occur in man or the severity of
the effect.

13.3.7  Extrapulmonary Effects of Ozone
     Because of the reactivity of 0  with biological tissue, it was not intui-
                                   O
tively obvious  that 0. would ever  reach the circulation.  Several  studies
discussed in Chapters  10 and 11 are indicative, however, of either direct or
indirect extrapulmonary  effects  of ozone exposure.  For example, alterations
in red blood cell  morphology, deformity, and enzymatic  activity,  as well as
chromosomal  effects  in circulating  lymphocytes,  have been  reported in man and
laboratory animals.  Other  organ systems of the  body  may also be involved.
Exposure to high concentrations of 0_ may have central nervous system effects,
                                    O
since decrements in performance  of  exercise  and vigilance tasks  have been
observed  in  man and laboratory  animals.   Cardiovascular,  reproductive,  and
teratological effects  of 0_ have also been  reported  in  laboratory animals,
                           J
along with changes in endocrine function; but the implications of these findings
for human health are difficult to judge  at  the present time.  More recent
studies in laboratory animals have shown that hepatic metabolism of xenobiotic
compounds may be impaired by 0_ inhalation.  While some systemic effects, such
as those  associated with exercise performance, may be secondary to pulmonary
damage, the  others  are more difficult to  conceptualize.   These effects  may
result from  direct  contact  with  0_  or from contact with  a reactive product of
0_ that penetrates to the blood and is transported to the other organs.
     Chromosomal and mutational  effects  of ozone are  controversial.  In  cells
in  culture,  a  significant  increase  in  the  frequency of  sister  chromatid
exchanges has been reported to occur after exposure to concentrations of ozone
as low as  0.25 ppm for  1  hr (Guerrero et al. , 1979).  Lymphocytes isolated
from animals were found to  have significant increases in the numbers of chromo-
somal (Zelac et al. ,  1971a,b) and chromatid (Tice et al., 1978) aberrations,
after 4-  to  5-hr exposures to 0.2  and 0.43  ppm ozone ozone,  respectively.
Single-strand breaks  in  DNA of mouse peritoneal  exudate  cells  were measurable
after a 24-hr  exposure to  I  ppm  ozone (Chaney, 1981).   Gooch et al. (1976)

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analyzed the bone marrow samples from Chinese hamsters exposed to 0.23 ppm of
0~ for  5 hr  and  the leukocytes and spermatocytes from mice exposed for up to
2 weeks to 0.21 ppm  of  0~.   No effect was  found on  either the frequency of
chromatid or chromosome aberrations, nor were there any reciprocal transloca-
tions in the primary spermatocytes.   An increase (although not significant)
was observed in chromatid lesions in peripheral  blood lymphocytes  from 6 human
subjects exposed to 0.5 ppm ozone for 6 or 10 hr (Merz et al.,  1975).   Subsequent
investigations, however, with more human subjects exposed  to ozone at various
concentrations  and  for various  times  have failed to  show any cytogenetic
effect  considered to  be  the result of ozone exposure (McKenzie et al.,  1977;
McKenzie, 1982; Guerrero et al., 1979).  In addition, epidemiological studies
have not shown  any evidence of chromosome changes in peripheral lymphocytes of
humans  exposed  to the ambient  environment  (Scott and Burkart, 1978; Magie
et al., 1982).   Clearly, additional evaluation of the human mutagenic potential
of ozone is needed.   Evidence now available, however, fails to demonstrate any
mutagenic effect  of  ozone  in humans when exposure schedules are used that are
representative  of exposures that the population at large might actually experi-
ence.
     With the exception of peripheral blood lymphocytes, the genotoxic effects
of ozone for all  of the other body tissues is unknown.  It is somewhat puzzling
that  in spite  of the experimental difficulties  that  may be encountered  no
cytogenetic  investigations  have been conducted  in the respiratory tissues of
animals exposed to ozone.   These tissues are exposed to the highest concentra-
tions and are  also  the target  of  most  of the toxic manifestations of ozone.
Clearly, one cannot extrapolate ozone-induced genotoxicity  data  from peri-
pheral  blood lymphocytes to other organs, such as the lungs.
     Ozone exposure  produces  a number of hematological  and  serum chemistry
changes  both in  rodents and man, but the physiological significance of these
studies  is  unknown.   Most of the  hematological  changes appear linked to  a
decrease in  RBC  GSH  content (Menzel  et  al., 1975; Buckley  et al., 1975;  Posin
et al., 1979; Linn et al., 1978) at concentrations of 0.2 ppm for 30 to 60 min
in man, or 0.5 ppm for 2.75 hr  in sheep, or 0.5  ppm continuously for 5 days in
mice  and rats.   Heinz bodies,   disulfide cross-linked methemoglobin complexes
attached to  the  inner RBC membrane, were detected  in mice exposed to ozone
(Menzel  et al.,  1975).   Inhibition of RBC  acetylcholinesterase was  found in
mouse  (Goldstein  et al.,  1968), human  (Buckley  et al.,  1975), and squirrel

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monkey  RBCs  (Clark et al., 1978) at  concentrations  of 0.4 to 0.75 ppm  and
times as  short  as  2.75 hr in man or 4 hr/day for 4 days in monkeys.  Loss of
RBC acety1cholinesterase  could  either be  mediated  by  membrane  peroxidation or
by  loss of acetylcholinesterase  thiol groups at  the active site.   Dorsey
et al.   (1983) observed that the deformability of CD-I mouse  RBCs  decreased on
exposure  to 0.7  and  1 ppm for 4 hr.   Deformability also  decreased at  0.3 ppm,
but was not statistically significant.  These data also support the concept of
membrane  damage  to circulating  RBCs.   While  it  is  theoretically possible that
species differences  in ozone  sensitivity may exist because of differences in
G-6-PD  (see Section 13.3.3.5), most experiments have  reported a close similari-
ty in the responses of animal  and normal  human RBCs to ozone exposure.

13.4  HEALTH EFFECTS  IN POTENTIALLY SUSCEPTIBLE INDIVIDUALS
13.4.1  Patients with Chronic Obstructive Lung Disease (COLD)
     Patients with mild  COLD  have not shown increased sensitivity  to 0- in
                                                                        O
controlled human exposure studies, and the epidemiological findings are incon-
sistent.  Linn et  al. (1982, 1983) and Hackney et al.  (1983) showed no changes
in symptoms or  function  at 0.12, 0.18, or 0.25 ppm 03 (1 hr, IE).  Likewise,
Solic et  al.  (1982)  and  Kehrl  et al.  (1983) found no significant changes in
symptoms or function  at 0.2 or 0.3 ppm 0- (2 hr, IE).  At higher concentrations,
however, Kulle et  al. (1984) found decreased function  in a group of 20 smoking
chronic bronchitics at 0.4 ppm (3 hr,  IE) on day 1 of  exposure and upon reexpo-
sure at day 6.   In an epidemiological  study, Balchum  (1973)  found aggravation
of symptoms and decreased function in COLD patients at an oxidant concentration
of 0.11 ppm.
     There is suggestive  evidence that bronchial   reactivity is increased in
some subjects with COLD (two of three) following exposure to 0.1 ppm 0, (Kb'nig
                                                                      •3
et al., 1980), and that  arterial 02  saturation is reduced slightly in these
subjects  during  exposure  to  0.12 ppm 03  combined with exercise (Linn et al. ,
1982; Hackney et al., 1983).   The latter observation  is  consistent with  the
occurrence of  unequally  distributed  defects  in  mechanical  function in  the
lung.
     One difficulty in attempting to characterize the  responsiveness of patients
with COLD is that they may exhibit a wide diversity of clinical and functional
states.   These range  from a history  of smoking, cough, and minimal  functional
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defects to chronic disability that is usually combined with severe defects in
blood gases or respiratory mechanical  behavior.   The chief locus of damage may
also vary:  either the bronchi (chronic bronchitis) or parenchyma  (emphysema)
may dominate  the clinical picture.  Finally, the mixture of acute  and chronic
inflammatory processes may  vary  considerably among patients.   There has been
no attempt to  sort  out these manifestations of COLD  in  the design of these
studies.

13.4.2  Asthmatics
     There is yet no laboratory evidence that mild asthmatics are functionally
more sensitive than  healthy individuals to 0~.   Linn et al. (1978) found no
significant changes in lung function,  as indicated by forced expiratory spiro-
metry  or  the nitrogen washout  test,  when asthmatic subjects with mild to
moderate  bronchial  obstruction  were  exposed to 0.20 ppm 0, for  2 hr with
                                                            *5
intermittent  light  exercise;  increased symptom scores were noted, however.
Silverman (1979)  found minimal  changes in forced expiratory spirometry following
2-hr exposures of  asthmatic subjects  to 0.25 ppm 0_ while at rest.  Although
                                                   O
group mean changes were not statistically significant,  one third of the subjects
who rested for 2  hr  while inhaling 0.25 ppm 0_ demonstrated  a  greater than
10 percent decrement  in  lung  function,  and it is doubtful  if this would have
been true  for  normal  subjects.   Finally, in ambient air exposures containing
0.17 ppm  0_,  Linn et al. (1980)  found  small but statistically significant
decrements in forced expiratory measures in both normal  and asthmatic subjects,
following 2-hr exposures  with  intermittent light exercise.   The magnitude of
functional responses in both groups was practically the same.
     The  studies  reported  above  are  not considered definitive since major
limitations  leave  open the  question  of whether the pulmonary  function of
asthmatics is more affected by 03 than  that  of  normals.  Intake of medication
was not controlled  in several  of the studies, and some subjects continued to
use oral  medication  when  being tested.   Some of  the  subjects  in  one study
(Linn  et  al., 1978)  showed  evidence of chronic obstructive lung  disease in
addition  to  asthma.   Most of the normal subjects  in  the Linn et al.  (1980)
study, in  which asthmatics  were  compared to  normals, had a  history of allergy
and appeared atypically reactive to the 0_ exposure.  In addition, the subjects
in these  studies either performed light exercise or rested  while  exposed.  In
view  of  the  recognized  importance  of  minute ventilation,  which  increases

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proportionately with the intensity of exercise, in determining the response to
0_, additional  testing at higher  levels  of exercise should be undertaken.
     Finally, it may  be  that the specific measurements of pulmonary function
and the exposure protocols  employed in the  above  studies were  inappropriate
for ascertaining pulmonary effects in asthmatic subjects.   Asthma is essential-
ly characterized by bronchoconstriction.  Compared to  airway resistance,  some
measures of forced expiratory spirometry are less sensitive to bronchoconstric-
tion,  since  fairly  severe  bronchoconstriction must occur in order  to affect
decrements in these measures.   McDonnell  et al.  (1983), reporting  on normal
subjects exposed to levels  of CL as low  as  0.12 ppm with heavy intermittent
exercise,   attributed  small  decrements  in forced expiratory spirometry and
increased symptoms to a reduced inspiratory capacity resulting from stimulation
or sensitization of airway receptors by 0_.   They also observed that there was
                                         o
no correlation  between changes  in  airway resistance and forced expiratory
spirometry for  individual  subjects, which  prompted them to  postulate  two
different mechanisms of action.   It may be that the sensitivity of the mechanism
affecting  inspiratory  capacity  is  the  same  in asthmatics and normals, while
the mechanism affecting airway resistance is different.
     Epidemiological findings stand  somewhat in contrast to clinical findings
in that they provide some evidence of exacerbation of asthma at ambient concen-
trations of  0»  below  those generally associated with  symptoms or functional
changes in healthy adults.   For  example,  Zagraniski et al. (1979) reported an
increased prevalence of symptoms among clinic asthmatic patients in association
with a  mean  ambient 0_ concentration of 0.08 ppm;  Whittemore and Korn (1980)
reported an increasing risk of asthmatic attack with increasing ambient oxidant
concentrations  between 0.04  and 0.15 ppm; and Lebowitz et al.  (1982,  1983)
found similar results  when  0_ concentrations were above 0.056 ppm (there was
an interaction  between 0., and  ambient  temperature),   Lebowitz (1984) also
reported finding a reduction  in  expiratory  peak flow rate in asthmatics at 0,
                                                                            O
concentrations  above  0.056 ppm.   The  inconsistency  of the epidemiological
findings and the controlled  human  exposure  studies with bronchoconstriction
could be the  result of several  factors:  (1)  insensitivity of the pulmonary
function tests employed,  (2) insufficient clinical  information in these studies;
or (3) interactions of the pollutants inducing responses in  the epidemiological
studies.
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13.4.3  Subjects with Allergy, Atopy,  and Hyperreactive Airways
     These  diagnostic  categories have  generally  been  established  through
hi story-taking in clinical exposures and through skin-testing  and other diag-
nostic procedures in epidemiological  studies.   The information available on
the responsiveness of these individuals, i.e.,  whether they differ from normal
non-allergic, non-atopic individuals,  is sparse.
     Hackney  et al.  (1977a)  found  decreases  in  spirometric function among
atopic individuals exposed to  0.5 ppm 0,. at rest.  Neither Folinsbee et al.
(1978),  in  a controlled laboratory exposure, nor  Linn et al.  (1980), in a
field study  in  the  Los  Angeles area,  distinguished between the responses of
normal subjects and  allergic non-asthmatic subjects.    In  the  latter study,
spirometric  function was  reduced  and  symptoms were increased  in association
with an average ambient 0, concentration of 0.12 ppm.   As with asthmatics (see
13.4.2.2), Zagraniski et al.  (1979) found that non-asthmatic allergic subjects
experienced an increased prevalence of symptoms in association with ambient CL,
                                                                             O
concentrations above 0.08 ppm:   cough  and hay fever were exacerbated.  Similar-
ly, Lebowitz  et al.  (1982,  1983)  also reported an  increase  in eye symptoms
among non-asthmatic  allergic  subjects  in association  with CL  concentrations
                                                            O
above 0.056  ppm.  The association was independent of other air pollutants and
weather.
     Some normal  subjects  with no prior history of respiratory  symptoms or
allergy demonstrate increased nonspecific airway sensitivity resulting from 0^
                                                                             O
exposure  (Golden  et al. ,  1978; Holtzman  et  al. ,  1979; Konig  et al.  , 1S80;
Dimeo et al. ,  1981;  Kulle  et  al. , 1982b).  Airway responsiveness  is  typically
defined by  changes  in  specific airway resistance produced  by  a  provocative
bronchial challenge  to  drugs  like acetylcholine,  methacholine, or nistamine,
administered  after  0-  exposure.  In one  study  (holtzman et al. , 1979), in
which subjects were classified as atopic or nonatopic  based on medical history
and allergen skin testing, the induction and time course of increased bronchial
reactivity  after  exposure  to 0~ were  unrelated to the presence of atopy.  An
association  of G--induced increases  in airway responsiveness with  airway
inflammation  has  been reported in dogs  at  high 0., concentrations  (1  to 3 ppm)
(Holtzman et al., 1983a,b;  Fabbri  et  al.,  1984);  and  in  sheep at  0.5 ppm G,
(Sielczak et al. ,  1983).  Little is known, however, about this relationship in
animals at  lower  CL  concentrations (<0.5 ppm), and the possible  association
between 0.,-induced inflammation and airway hyperresponsiveness in human subjects
has not been explored systematically.
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13.5  EXTRAPOLATION OF EFFECTS OBSERVED IN ANIMALS TO HUMAN POPULATIONS
13.5.1  Species Comparisons
     Comparisons of the  effects  of  ozone on different animal  species  is of
interest  in  attempting to understand  whether  man might  experience similar
effects.  For  example,  if  only one  of several tested  species  experienced a
given effect of ozone, this effect might  be species  specific and not occur in
man.  Conversely,  if  several  animal  species,  with all  their inherent differ-
ences,  shared  a given  effect of ozone, it is likely  that some element present
in all mammalian species, including  man,  was susceptible  to ozone.   A commonal-
ity  of  effects across  species would be   expected, provided the  effect was
related to a mechanism which is shared across  species.  In the case of ozone,
the proposed major molecular mechanisms of action are the oxidation of polyun-
saturated fatty acids  and  the  oxidation   of thiols or  amino  acids  in tissue
proteins or small-molecular-weight peptides.   Thus,  if the affected molecules
are identical  across all species,  then any differences in the  observed responses
between species would  be a function of species differences in delivered doses
or of subsequent processes of toxicity.  For example, a likely target site for
0, toxicity is the  cellular membrane,  particularly the membrane of cells  like
the Type 1 and ciliated  cell which cover  a  large  surface area of the respira-
tory tract.   Since there are no major interspecies differences in cell  membranes
and membranes are composed of proteins and lipids, then both proposed molecular
mechanisms of  0- toxicity could occur  at  the cellular membrane.  In fact, the
two  proposed  hypotheses most  likely  occur  simultaneously.   The consequent
toxic impact on the membrane, the cell, and surrounding tissue would be influ-
enced by  species  differences in antioxidant defenses  or  repair  mechanisms.
Some of the products of ozone oxidation are water-soluble and can diffuse from
the  site  of oxidation  in the membrane into cytosol  or the circulation.   The
extrapulmonary effects of ozone exposure  may be due to such circulating products.
Inflammatory cells  appear  in  the  lung after ozone exposure.   Peroxides  are
active  in the  inflammatory  process  as intermediates  in the prostaglandin and
leukotriene cascades.   Some of the peroxides formed  from ozonized arachidonic
acid are active as prostaglandin agonists, but apparently can  not be converted
to more complex prostanoids,  at least by  human platelets.   Fatty acid ozonides
could release  histamine  and  cause  both local   and  pulmonary edema.   Many of
these substances (histamine, prostaglandins,  etc.) will  not only enter addi-
tional  metabolic reactions,  but  will  also act as local or, if distributed by

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the pulmonary  circulation,  as  systemic mediators.   Depending on  the  target
site and the amount  released,  they may be vasoactive, modulate bronchomotor
tone,  stimulate receptors, or trigger reflex reactions and thus  influence lung
or other organ  function.   Such functional  changes might be transient or become
more permanent  if tissue structure was altered as well.   The extent of interde-
pendence among biochemical,  morphological,  immunological,  and  functional
changes induced by CL  remains  to be determined.  Since current knowledge is
not sufficiently advanced to assess such events quantitatively,  only qualitative
hypotheses  can be made, based on the available evidence.  A  commonly accepted
hypothesis  is that if ozone causes an effect in several  animal  species, it can
cause a similar effect in man.   It is important to note that this  is a qualita-
tive probability;  it does not permit assessment of the concentrations at which
man might experience the common effect.
     The health data base for ozone consists of hundreds of studies with about
7 species,  and even more  strains, of animals.  Generally, for a given  effect,
whether it be  on  lung morphology, physiology, biochemistry,  or host defenses,
all species  tested were  responsive to ozone, albeit  sometimes  at different
concentrations.  The few studies of several  species having at least two points
of identity for comparison will  be discussed.
     Morphological examinations of the lungs of several  mammalian  species have
been conducted after ozone  exposure.   Of the groups studied, there  are signi-
ficant differences in  lung structure.   Man, nonhuman primates,  and dogs have
both nonrespiratory and respiratory bronchioles, while respiratory bronchioles
are either absent  or  poorly developed in mice, rats,  and guinea pigs.   Addi-
tional differences exist.   Nonetheless,  a characteristic ozone lesion occurs
at the  junction  of  the conducting airways  and  the gaseous  exchange tissues,
whatever the species  specifics  of the structure are.  The  typical  effect in
all the species examined  is damage to ciliated and Type 1 cells and hyperplas-
ia of nonciliated bronchiolar cells and Type 2 cells.   An increase in  inflamma-
tory cells is  also observed.  Such changes  were  observed  after a  7-day inter-
mittent  exposure  of  monkeys to 0.2  ppm  (Dungworth et al. ,  1975;  Castleman
et al., 1977)  and of  rats to 0.2  ppm (Schwartz  et  al., 1976).  With different
exposure regimens, similar effects occur in cats (0.26 ppm,  endotracheal tube,
about 6 hr, Boatman et al., 1974), mice (0.5 ppm, 35 days, Zitnik et al., 1978),
and guinea pigs  (0.5  ppm, 6 mo,  Cavender et al.,  1978).   For these studies,
lower concentrations  of  ozone  were not tested.  Unfortunately, quantitative

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comparisons between monkey and rat studies is not possible because of inadequate
data.   Nonetheless, a rough equivalency of responses was observed under similar
exposure conditions between species having major structural differences.   Since
the monkey  lung  may be the most  representative model of  the human  lung, the
possibility is enhanced that man would experience similar effects.
     Pulmonary function of  eight  species of animals  has  been  studied after
exposure to ozone.   Short-term exposure for 2 hr to 03 concentrations as low
as 0.22 ppm produces rapid, shallow breathing.   Similar changes in respiration
have been  observed  in  man during  comparable  ozone exposure,  as shown  in
Table 13-7.  The  onset  of  these effects  is  rapid  and  appears to  be  related  to
the ozone concentration.  In a recent review, Mauderly (1984) compared changes
in breathing patterns of humans and guinea pigs during and after a 2-hr exposure
to 0.7 ppm 0-.  The respiratory frequency decreased and tidal volume increased
with similar  patterns  during  exposure  and  returned  toward normal  in the  first
3 hr after exposure.
     Enhanced airway reactivity to  inhaled bronchoconstrictive agents has also
been observed  in animals  and man after 0- exposure (Table 13-8).  Short-term
exposure to 0.,  concentrations as low as 0.32 ppm increases airway resistance
following  inhalation of the drugs  acetylcholine, carbachol, methacholine, or
histamine  in  sheep, dogs,  and humans.   However,  the time course  of  this
response differs.   A maximum response is obtained  immediately after exposure
in man but appears  to be delayed by 24 hr in sheep  and dogs.
     Mauderly  (1984) has  also compared  the  effect  of 2-hr 0~ exposures  on
airway  constriction in humans,  guinea pigs,  and cats.   Although measured
indices of airflow  limitation are similarly depressed in  both animals and man,
there are too many  differences in the experimental  methods and too  few species
studied to provide  an adequate comparison.
     Qualitative  comparisons  of  changes  in breathing  patterns  and airway
reactivity  indicate that  many similarities occur during  exposure of animals
and humans to ozone.  However, quantitative extrapolation of these  effects may
be limited by the small number of studies having  similar  experimental procedures
and  similar exposure levels.  Other  effects of short- and  long-term  ozone
exposure on lung  function  have been observed (Chapter 10)  but there  are  insuf-
ficient points  of identity in the  experiments  to permit direct  comparisons
among animal species or between animals and man.
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                                TABLE  13-4.   COMPARISON OF THE ACUTE  EFFECTS OF OZONE ON BREATHING PATTERNS  IN ANIMALS AND MAN
Ozone3
concentration
MQ/m-3
392
686
431
804
1568
470
588
784
588
OJ 588
i
<_n
666
1333
2117
2646
725
980
1470
980
1100
ppm
0.20
0.35
0.22
0.41
0.8
0.24
0.30
0.40
0.3
0.3
0.34
0.68
1.08
1.35
0.37
0.50
0.75
0.5
0.56
Measurement Exposure
method duration
UV 1 hr
(mouthpiece)
CHEM 2 hr
CHEM 2.5 hr
MAST 1 hr
(mouthpiece)
UV 1 hr
(mouthpiece)
NBKI 2 hr
MAST 2 hr
NBKI 2 hr
CHEM 2 hr
Activity0
level (VE)
CE(77.5)
R
IE(65)
CE(34.7, 51)
CE(66)
R
IE(29)
R
R
Observed effects(s)
Increased fp and decreased V,.
Concentration-dependent increase in f_ for
all exposure levels.
Increased fR and decreased V,..
Increased fR and decreased V-,.
Increased fR and decreased VT.
Increased fR and decreased V-, during
exposure to all 03 concentrations.
Dose-dependent increase in fD and decrease
in VT. K
Increased fD.
K
Abnormal, rapid, shallow breathing while
exercising on a treadmill after exposure.
Species Reference
Human Adams and Schelegle, 1983
Guinea pig Amdur et at., 1978
Human McDonnell et al., 1983
Human DeLucia et al., 1983
Human DeLucia and Adams, 1977
Guinea pig Murphy et al., 1964
Human Folinsbee et al., 1975
Guinea pig Yokoyama, 1969
Dog Lee et al . , 1979
Ranked by lowest observed effect level.

Measurement method:  MAST = Kl-Coulometric (Mast meter); CHEM = gas phase cheroiluminescence;  UV = ultraviolet photometry;  NBKI  = neutral  buffered
potassium iodide.

Minute ventilation reported in L/min or as a multiple of resting ventilation.   R = rest;  IE = intermittent exercise;  CE  =  continuous  exercise.

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                                TABLE 13-5.   COMPARISON OF THE ACUTE EFFECTS OF OZONE ON AIRWAY REACTIVITY IN ANIMALS AND MAN
Ozone3
concentration
i — >
GO
i
en
UD
Mg/mJ
627
784
784
980
1176
1176
1372
1960
ppm
0.32
0.4
0.4
0.5
0.6
0.6
0.7
1.0
Measurement
method
MAST
CHEM
UV
CHEM
UV
CHEM
CHEM
UV
Exposure
duration
2 hr
3 hr
2 hr
2 hr
2 hr
2 hr
2 hr
2 hr
Activityc
level (V£)
R
IE(4-5xR)
IE(2xR)
R
IE(2xR)
R
R
R
Observed effects(s)
SR increased with ACh challenge.
aw
SG decreased with methacholine;
attenuation develops with repeated
exposures.
SR increased with histamine challenge;
attenuation develops with repeated expo-
sure. No effect on bronchial reactivity
at 0.2 ppm.
R. increased with carbachol 24 hr but not
immediately after exposure.
SR increased with histamine and
metfiacholine in atopic and non-atopic
subjects.
Bronchoreactivity to histamine; may persist
for up to 3 weeks.
R. increased with histamine 24 hr but not
1 hr after 03 exposure.
R. increased with ACh and histamine 1 hr
and 24 hr after exposure.
Species Reference
Human Konig et al. , 1980
Human Kulle et al. , 1982b
Human Dimeo et al., 1981
Sheep Abraham et al., 1980
Human Holtzman et al., 1979
Human Golden et al., 1978
Dog Lee et al. , 1977
Dog Holtzman et al . , 1983a,b
Ranked by lowest observed effect level.
Measurement method:   MAST = Kl-Coulometric (Mast meter); CHEM = gas phase chemiluminescence; UV = ultraviolet photometry.
Minute ventilation reported in L/min or as a multiple of resting ventilation.   R = rest; IE = intermittent exercise.

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     Species comparisons of host  defense  against Infection are possible for
alveolar macrophages.  After an intermittent (8 hr/day) 7-day exposure to 0.2
ppm ozone,  an  increased  number of alveolar macrophages was  observed in the
lungs of  both  rats  and  monkeys  (Castleman et al., 1977;  Dungworth, 1976;
Stephens et al., 1976).  Although numerous other macrophage studies  have been
conducted,  there are  insufficient  points  of identity for species comparison.
     Rats and  monkeys have been examined  for  changes in lung biochemistry
following ozone exposure.   In  these  animals exposed for 7 days (8 hr/day)  to
0.8  ppm ozone (DeLucia  et al.,  1975),  glucose-6-phosphate dehydrogenase
activity was elevated  to a roughly equivalent degree.  Glutathione reductase
activity was increased  in  rats,  but not monkeys.   Chow et al.  (1975) also
compared these species  after  exposure  to 0.5 ppm ozone for 8 hr/day for 7
days.   Antioxidant enzymes  were  increased in the rats, but not the  monkeys.
The  authors referred to "relatively large  variations"  in the monkey data.
Oxygen  consumption was  measured  in rats and monkeys after a 7-day (8 hr/day)
exposure to several  levels of ozone (Mustafa and Lee, 1976).   Rhesus monkeys
may  have  been  slightly  less responsive than rats.   However, at 0.5 ppm ozone,
bonnet  monkeys and  rats  had roughly equivalent  increases.   In  all  of these
reports, there was no mention of statistical comparisons between species or of
power calculations that  would indicate whether under the experimental condi-
tions of  data  variability,  there was equivalent  power to  statistically detect
effects in  both  species.  In a few of the reports,  the number of animals was
not  given.  Mustafa  et al. (1982) compared mice to 3 strains of rats exposed
to 0.45 ppm ozone  continuously for 5 days.  Antioxidant metabolism and  oxygen
consumption were  measured.  Generally, increases in  enzyme activities were
observed in both species;  in several cases the increase in the mice was statis-
tically greater than the increase in the rats.
     For  extrapulmonary  effects,  the  only species comparison using  identical
methods was made by Graham et al. (1981).  Female mice, rats, and hamsters had
an increase in pentobarbital-induced sleeping  time  after  a 5-hour exposure  to
1 ppm ozone.   Under the  experimental conditions used, relative species respon-
sivity  cannot  be assessed.
     An overview of the  animal toxicological data for ozone indicates that rats
are  the most prevalent species tested.   Other species often used  include mice,
rabbits,  guinea pigs, and  monkeys.  A few  dog and hamster  studies exist.  As has
been noted  above, very few species comparisons can  be made  due to differences  in

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exposure regimens and measurement techniques.  Even when direct comparisons are
possible, interpretation is difficult.  Statements regarding responsiveness can
be made.   Statements about  sensitivity (e.g.,  responses  to an equivalent
delivered dose) cannot be made until more dosimetry and other types of data are
available.   Nonetheless, it is remarkable that even with the wide variation in
techniques and  experimental  designs,  acute  and subchronic  exposures  to  levels
of ozone less  than 0.5  ppm produce  similar  types  of  responses  in many species
of animals.  Thus,  it may be hypothesized that man may experience more types
of effects than have been established  in human  clinical  studies.   Types of
effects  for which substantial animal  data bases  exist  include  changes in  lung
structure,  biochemistry,  and host defenses.  However, the actual risk to man
breathing ambient levels  of  ozone cannot be determined until the animal data
can be quantitatively extrapolated to man.

13.5.2  Dosimetry Modeling
     The discussion  of species  comparisons in  response  to  ozone  exposure
presented above  (Section  13.5.1)  assesses  the net effects of species differ-
ences in sensitivity and  dosimetry.   An uncoupling  of these two elements  is
required to be able to make quantitative interspecies comparisons of toxicolog-
ical  results from different experiments.  In this context, dosimetry refers to
determination of the amount  of  ozone which reaches specific sites in animals
and man, while sensitivity relates to the likelihood of equivalency of biologi-
cal  response given that the same dose of ozone is delivered to a target site in
different species.
     Although additional research is needed on dosimetry and on species sensi-
tivity before quantitative extrapolations of effective 0., concentrations can be
                                                        «j
made between species,  only  dosimetry is sufficiently advanced for discussion
here.   Because  the  factors  affecting the transport  and absorption of 0_  are
                                                                        O
general  to animals  and to man,  dosimetry models  can be  formulated that use
appropriate species anatomical and ventilatory parameters to describe 0^ absorp-
                                                                       O
tion.   Thus far, theoretical  modeling efforts (McJilton et al., 1972; Miller
et al., 1978) have focused on the lower respiratory tract.
     Largely due to  the technical ease  of measuring  ozone  uptake in  the head,
nasopharyngeal   removal  of ozone  has been experimentally  studied  in  the dog
(Vaughan et al., 1969; Yokoyama  and Frank,  1972;  Moorman et al., 1973),  rabbit
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(Miller et al., 1979), and guinea pig (Miller et al., 1979).  To date, infor-
mation on nasopharyngeal  removal  of 0~  in man is not available.   Since naso-
pharyngeal removal  of  03 serves to lessen  the  insult to lower respiratory
tract tissue which  is  thought to be more sensitive, an assessment of species
differences in this area is critical to  interspecies comparisons of dosimetry.
     Damage to all  respiratory  tract regions occurs  in animals exposed to CL,
with location and  intensity  dependent  upon concentration.  When comparisons
are made  at the analogous anatomical site,  the morphological effects of 03 on
the  lungs of a  number of animal species are remarkably similar.   Despite
inherent  differences in  anatomy between  various  experimental animals and man,
the junction between the conducting airways and the  gas exchange region is
most affected by  CL exposure in animals (See 10.3.1) and most likely will  be
                   •3
the  principal  site affected  in man.   Dosimetry model  simulations (Miller
et al. , 1978) predict  that  the maximal   tissue dose  occurs  at the region of
predominant morphological damage in animals.   The overall  similarity of the
predicted 0~  dose  patterns  in animal  lungs studied  thus  far  (rabbits and
guinea pigs) extends to  the  simulation of CL  uptake  in humans (see 10.2.3.1).
     The  consistency and similarity of the  human and  animal lower  respiratory
tract dose curves  lend strong  support to the feasibility of extrapolating to
man the results obtained on animals exposed to 0«.   In the past, extrapolations
have  usually been  qualitative in nature.   With  additional  research  in areas
which are basic to  the formulation of dosimetry models, quantitative dosimetric
differences among species can be determined.  If in addition, more information
is obtained  on  species sensitivity to a given dose,  significant advances can
be made  in  quantitatively extrapolating animal  toxicological results to man.
Since animal  studies  are the only  available  approach for investigating the
full array of potential  disease  states induced by exposure to 0,, quantitative
use  of  animal  data is in the interest  of better establishing 03  levels to
which man can safely be  exposed.
 13.6   HEALTH  EFFECTS OF OTHER PHOTOCHEMICAL OXIDANTS  AND POLLUTANT MIXTURES
     Ozone  is  considered to be chiefly responsible for the adverse effects of
 photochemical  air pollutants  largely,  if not  exclusively,  because of  its
 relative  abundance compared with  other  photochemical  oxidants.   Still, the
 coexistence  of other  reactive oxidants (Section 13.2.2)  suggests  that the

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potential effects of these other oxidants should be examined.   Not unexpected-
ly, however, animal  and clinical  research has  centered  largely  on 03; very
limited effort has  been devoted to studies of peroxyacetyl nitrate (PAN) and
hydrogen peroxide (HJ),,).   Field  and epidemiological studies evaluate health
effects associated  with exposure to  the  ambient environment, making  it diffi-
cult to  single out  the oxidant species responsible for the observed effects.

13.6.1  Effects of  Peroxyacetyl Nitrate
     There have  been far too few controlled  toxicological  studies with  the
other oxidants to permit any sound scientific evaluation of their contribution
to the toxic action  of photochemical oxidant mixtures.  The few animal toxicol-
ogy studies  on PAN  indicate  that it  is much  less  acutely toxic than  0.,.  When
the effects seen after exposure to 0- and PAN are examined and compared,  it is
obvious  that the test animals must  be exposed  to concentrations  of  PAN  much
greater  than those  needed with 0, to produce a similar  effect on lethality,
                                 O
behavior modification, morphology, or significant alterations in  host pulmonary
defense  system (Campbell  et  al. , 1967; Dungworth  et  al. , 1969; Thomas  et al. ,
1979, 1981a).
     All of  the  available controlled human  studies  with other photochemical
oxidants have  been  limited to a series  of  reports on the effects of  PAN on
healthy young and middle-aged males during intermittent exercise  on a  treadmill
(Drinkwater  et al. , 1974; Raven et al. ,  1974a,b;  Gliner  et al.,  1975).   No
significant  effects were observed  at PAN concentrations of 0.25  to 0.27 ppm.
Two additional studies at 0.24 ppm  (Raven et al., 1976) and 0.30 ppm  (Smith,
1965)  of PAN suggested a possible limitation on  forced expiratory volume and
flow,  but  not  enough data are available to evaluate  the significance  of this
effect.
     Field and epidemiological  studies  have  found very few specific  relation-
ships  between  reported health effects and PAN  concentrations.  The  increased
prevalence of  eye irritation reported during ambient air  exposures  has  been
associated with  PAN as well  as other photochemical reaction products (National
Air Pollution  Control  Association,  1970; Altshuller, 1977; National Research
Council,  1977;  U.S. Environmental Protection Agency, 1978; Okawada et  al. ,
1979).   In  one of  these  studies (Okawada  et al., 1979), eye irritation was
produced  experimentally in  high  school  students  at. concentrations  of  PAN
>0.05 ppm.   An increased incidence  of  other health   symptoms such as  chest

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discomfort was reported  along  with  eye irritation as PAN concentrations in-
creased from 0 to 0.012  ppm (Javitz et al., 1983).  However, the significance
of these symptomatic responses is questionable since functional  changes reported
in this study  for  the subjects exposed to  total  oxidants  (CL  and PAN) were
similar to those found for CL  alone.

13.6.2  Effects of Hydrogen Peroxide
     Controlled toxicological  studies on H^O^ have been performed at concentra-
tions much  higher than those found in the  ambient air (see Section 13.2), and
the majority have  been  mechanistic  studies using various i_n vitro techniques
for exposure.   Very limited information is available on the health significance
of inhalation  exposure to  gaseous H?0»  in  laboratory animals.  No significant
effects were observed in rats  exposed for  7 days to >95  percent  hLCL gas with
a  concentration  of 0.5  ppm in the presence  of  inhalable  ammonium  sulfate
particles (Last et al. ,  1982).   Because I-LO^ is highly soluble,  it is generally
assumed that it  does  not penetrate into the alveolar regions of the lung but
is instead  deposited  on  the surface of  the upper airways (Last et al.,  1982).
Unfortunately, there  have not been studies designed to look for possible effects
in this region of the respiratory tract.
     A few j_n vitro studies have reported cytotoxic, genotoxic,  and biochemical
effects of  HpO~  when using isolated cells  or organs  (Stewart  et al. , 1981;
Bradley et  al. ,  1979; Bradley and Erickson, 1981; Speit et al. , 1982; MacRae
and Stich, 1979).  Although these studies can provide useful data for studying
possible  mechanisms  of  action, it is not  yet possible  to  extrapolate these
responses to those that  might occur in the mammalian system.

13.6.3  Interactions  with Other Pollutants
     Controlled human exposures have not consistently demonstrated any enhance-
ment of  respiratory effects for combined  exposures of  03  with  S02,  N02,  CO,
and  H?SO. or other particulate  aerosols.   Ozone  alone  is  considered  to  be
responsible for  the observed  effects of those  combinations  or  with  multiple
mixtures  of these  pollutants.   Studies reviewed  in the previous 03  criteria
document  (U.S.  Environmental  Protection Agency,  1978)  suggested that mixtures
of S09  and 0-  at a concentration of  0.37 ppm are  potentially more active  than
     L-       O
would  be  expected  from  the behavior  of the gases  acting separately  (Bates  and
Hazucha,  1973; Hazucha   and Bates, 1975).   High concentrations  of inhalable

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aerosols, particularly H?SO, or ammonium sulfate, could  have been  responsible
for the results (Bell et al. , 1977); however, subsequent studies of 0., mixtures
with SO,,, H?SO.,  or  ammonium sulfate have  not conclusively demonstrated  any
interactive effects (Bedi et al.,  1979, 1982; Kagawa and Tsuru, 1979c; Kleinman
et al., 1981; Kulle et al.  , 1982a; Stacy et al.,  1983).
     Combined  exposure  studies in  laboratory animals have produced  varied
results, depending upon  the  pollutant combination evaluated and the measured
variables.    Additive  and/or  possibly synergistic effects  of 0, exposure in
combination  with  N0? have been  described  for increased susceptibility to
bacterial infection (Ehrlich et al., 1977; Ehrlich,  1980, 1983), morphological
lesions  (Freeman  et  al. , 1974), and increased antioxidant  metabolism  (Mustafa
et al.,  1984).  Additive effects  from  combined exposures to 0.,  and H?SO.  have
also been reported for host defense mechanisms (Gardner  et al., 1977; Last and
Cross,  1978;  Grose et al.  , 1982)  but  not for morphology  (Cavender et  al. ,
1977; Moore and Schwartz, 1981).
     Early  studies  in animals exposed to  complex mixtures of  UV-irradiated
auto exhaust  containing  oxidant concentrations of 0.2  to 1.0 ppm demonstrated
a  greater  number of  effects compared to  those  reported for nonirradiated
exhaust  (Chapter  10,  Section  5.3).   No significant differences were found in
the magnitude  of  the response either with  or without  the  presence of sulfur
oxides  in the mixture.   Although  the effects described in  these studies would
be difficult to associate with any particular oxidant  species,  they are quali-
tatively similar  to  the general  effects described  for exposure to 0,. alone.
                                                                    O
     A  major limitation of  field and epidemiological studies  includes the
interference  or potential  interactions  between 0_ and  other pollutants  in the
environment.   The lack  of  quantitative measurements  of oxidant concentrations
has limited  the  usefulness of these  studies.  Nevertheless, there is still
concern  that combinations of  oxidant pollutants,  including  precursors of
oxidants, contribute  to  the  decreased function  and  exacerbation of symptoms
reported in  asthmatics  (Zagraniski et al. ,  1979; Whittemore and Korn,  1980;
Linn et  al.,  1980,  1983;  Lebowitz et al., 1982,  1983; Lebowitz, 1984) and in
children and young  adults  (Kagawa and Toyoma,  1975;  Kagawa  et al. ,  1976;
Kagawa,  1983;  Lebowitz  et  al., 1982,  1983).   Possible  interactions between 03
and total  suspended  particulate  matter have been  reported with  decreased
expiratory flow  in children  (Lebowitz  et  al., 1982,  1983;  Lebowitz, 1984) and
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adults with  symptoms  of  airway obstructive disease (Lebowitz  et  al.,  1982,
1983) and  with increased symptom  rates in asthmatics  (Zagraniski  et al. ,
1979).
     The effects of interaction between inhaled oxidant gases and  other environ-
mental pollutants on the lung  have not  been systematically studied.  In fact,
one of the major problems with the available literature on interaction studies
is the exposure design.  Most  of the controlled studies have not used concen-
trations of combined pollutants that are found in the  ambient environment.   It
may be desirable to place greater research emphasis on characterizing sequen-
tial patterns of air pollutant exposure which may have quite different effects
compared with  continuous exposure to  pollutant mixtures.   An alternative
approacn might be  to  study  the interaction of photochemical oxidant species
and/or precursors of photochemical oxidants.  However, since these issues are
complex, they  must  be addressed experimentally using  exposure regimens for
combined pollutants that  are  more representative of ambient  ratios  of peak
concentrations, frequency, duration,  and time intervals between events.
13.7   IDENTIFICATION  OF POTENTIALLY  AT-RISK POPULATIONS OR SUBPOPULATIONS
13.7.1  Introduction
     The identification  of  a population or  subpopulation as the group to be
protected by  a  national  ambient air quality  standard depends upon a  number of
factors, including  (1)  the  identification  of one or more specific biological
endpoints (effects) that individuals  within a population should be protected
from;  and (2) the  identification  of those individuals in whom those specific
endpoints are observed  (a)  at  lower concentrations  than  in  other individuals,
(b) with greater frequency  than in other individuals,  (c) with greater conse-
quences than  in other individuals, or (d)  at various combinations of "effects
levels," frequency, or  consequences.   In addition,  as  discussed in Chapter 2,
other  factors such as activity patterns and personal habits, as well  as actual
and  potential exposures to  the  pollutant in question,  must  be  taken into
account when  identifying one or more subpopulations potentially at  risk from
exposure to that pollutant.
     In the  following sections,  biological  and other  factors  that have  been
found  to predispose one  or more subpopulations to particular risk from exposure
to photochemical oxidants are discussed.   It should be noted that these factors

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are discussed in relation to ozone exposure only.   There are too few controlled
studies with the  other  oxidants  to permit a  sound  scientific  evaluation of
their contribution to the toxic action of photochemical  oxidant mixtures.   The
following sections also  include estimates  of  the number of  individuals in the
United States that fall  into certain categories of potentially at-risk subpopu-
lations.
     It must be emphasized that the final identification of those effects that
are considered "adverse" and the final identification of "at-risk" populations
are both the domain of the Administrator.

13.7.2  Potentially At-Risk Individuals
     Sensitivity to  ozone  varies  within and  among  individuals.   The  factors
suspected of altering sensitivity to ozone are numerous.  Those actually known
to alter sensitivity, however, are few, largely because few have been examined
adequately to determine definitively their effects on sensitivity.  The discus-
sion below presents  information  on the  factors that  are thought  to have the
potential for  affecting sensitivity to  ozone,  along  with  what is actually
known  from  the data regarding the  importance of  these factors.  The terms
"sensitivity" and "susceptibility" have been  used interchangeably in the Clean
Air Act and are also used interchangeably in this discussion.
     Sensitivity to  a  specified  dose of an air pollutant  may be greater or
less than normal.  Statistical analysis  is generally  relied upon  to establish
the range of  normal  responses for a  particular biological  endpoint,  and to
distinguish those  responses  that  are indicative of increased sensitivity and
those that are indicative of decreased sensitivity.
     Susceptibility may be conferred by some predisposing host factor, such as
immunologies! or biochemical factors; or by some condition, such as preexisting
disease.   Susceptibility may  also result from some aspect  of  the growth or
decline  of  lung development (e.g., greater bronchomotor tone  in childhood,
loss of lung function in the elderly), or some previous infectious or immunolog-
ical process  (e.g.,  childhood  respiratory trouble, prior  bronchiolitis or
other  lower  respiratory  tract  infections,  and prior asthma).   Sensitivity may
arise  from some  prior  exposure,  that is,  one that  entails  a response, as in
"sensitization"; or may result from cross-reactivity to chemicals.  Sensitivity
may also be  simply an unusual  response  upon exposure, possibly  resulting from
prior challenge with respiratory irritants).

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     Most human  studies  do  not  perform the complex  diagnostic  procedures
needed to classify study subjects properly, nor do they usually determine the
mechanism of response (i.e., underlying immunological, biochemical,  or structural
character).   Furthermore,  even diagnostic labels,  such as  COLD,  asthma, allergy,
and atopy, are not usually based on sufficient clinical evaluation nor standard-
ized inclusion/exclusion criteria, so that differences in  such classifications
within and  between studies  are bound to occur.   For  example,  there are few
studies in which bronchoconstrictor challenges, skin or blood antibody testing,
or other procedures were performed that characterize disease status, let alone
radiograpnic  studies.   In epidemiological  studies, often  not  even  baseline
pulmonary function is  determined.   Yet, even if these tests are performed, a
relatively  large  group of apparently healthy subjects, not previously  identi-
fied as  being susceptible or sensitive  to 0,., will respond dramatically to 0,
exposure.
     Ultimately,  a complex  set of mechanisms activated to varying degrees  and
acting differently in  different  individuals  will  determine susceptibility or
sensitivity.   For  example,  bronchoconstriction  induced by several mechanisms
may be blocked accordingly  by different agents,  such  as  £„ agonists, anti-
inflammatory agents,  methyl-xanthines,  membrane or receptor agonists, catecho-
lamine agents, and prostaglandins.  Unfortunately, little information on these
aspects  of  the study population is available so that  reliance must be placed
on  limited  work-ups,  non-standard!zed  clinical  evaluations and  definitions,
and theoretical  considerations.   Thus,  estimates  of "at-risk" populations  are
difficult if  not  impossible  to assess with any precision.
     Various  anthropomorphic  and demographic characteristics have been used to
try to characterize susceptible individuals in the general population.  Gender
differences,  especially  for children;  age differences, especially between  the
very young  and the very old;  and possibly racial  or ethnic differences, such
as  differences in nutritional status,   differences in  baseline lung function,
or  differences in  immunological status, may predispose individuals to suscepti-
bility or sensitivity  to ozone, since  all of  these factors have well-known
implications  for infectious  and  chronic  diseases and immunological states.
None  of  these factors, however, has been sufficiently studied in relation to
0-  exposure to give definitive answers.
  O
     The  most prominent modifier of response to 0~ in the general population
is  minute  ventilation, which increases proportionately  with increases in

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exercise workload.   Higher levels of exercise enhance the likelihood of increased
frequency of irritative  symptoms  and decrements in forced expiratory volume
and flow.  Unfortunately, even in a well-controlled experiment on a homogeneous
group of subjects,  physiological  responses to the same exercise levels and the
same CL concentrations will vary widely among individuals.
     Exposure history may  determine  susceptibility or sensitivity.  Smokers
may be more  or  less sensitive.  They are more susceptible to  impaired defense
against  infection, they  have  some chronic inflammation  in the airways, they
have cellular damage,  and they may have altered biochemical/cellular responses
(e.g., reduced  trypsin inhibitory capacity,  neutrophilia, impaired macrophage
activity).    Likewise,  those with  "significant" occupational  exposures  to
irritants  or sensitizers  or  allergens may  have similar predispositions.
Furthermore, both groups  show  differential  immunological status, atopy,  and,
in some  cases,  bronchomotor tone.   Despite these  inferences,  there  is some
evidence to suggest that smokers may be less sensitive to 0~, although data are
available only from a limited number of studies and are inconclusive.
     Social, cultural, and economic  factors, especially  as they  affect nutri-
tional  status  (e.g.,  vitamin  E  intake, anemia),  may  be important.   While
animal  studies  with vitamin E indicate that differential  responses may  be
related  to  nutrition,  no evidence exists to indicate  that man would benefit
from increased vitamin E intake in relation to ambient ozone exposures.
     Another determinant  of sensitivity is preexisting disease.   Asthmatics,
who  have variable  airflow obstruction  or reversible airway  reactivity,  or
both, and who  may  have altered immunological states  (e.g.,  atopy, increased
immunoglobulin-E, possibly prostaglandin  function  and/or T-cell  function) or
cellular function (e.g.,  eosinophilia), may be potentially more sensitive to
0_.   Defining  an asthmatic, however, may be difficult.   Likewise, allergic
individuals, with a predisposing  atopy, have altered  immunological responses,
similar  to  asthmatics,  and may have labile bronchomotor tone, such that they
may be considered to be potentially more sensitive.  Patients with COLD may or
may  not  be  potentially more sensitive  to 0_.   Although  currently available
                                            O
evidence indicates  that  individuals with preexisting  disease respond  to 0«
                                                                           O
exposure to  a  similar degree as normal  subjects,  appropriate inclusion  and
exclusion criteria for selection of these subjects, especially better clinical
diagnoses  validated by pulmonary function, must be  considered before their
sensitivity  to  ()„ can be  adequately determined.   Nevertheless,  one question

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that arises is whether  or not small functional changes  in  individuals with
COLD,  asthma,  or allergy  represent equivalent physiological  significance
compared to the normal  subject.

13.7.3  Potentially At-Risk Subpopulations
     As the preceding  discussion  clearly indicates, definitive data  on the
relative susceptibilities to ozone of various kinds of individual  subjects are
lacking, both  in  epidemiological  and control 1ed-exposure studies.  Notwith-
standing the uncertainties that exist in  the data,  it is possible to  identify
three major subpopulations  that may be  at particular risk  from  exposure to
ozone.
     In the Clean Air Act, the definition of a "sensitive population"  excludes
"individuals who are otherwise dependent on a controlled internal  environment"
and  includes "particularly  sensitive citizens  .  .  . who in the normal course
of daily activity  are  exposed to  the ambient  environment."   Early  research
demonstrated that the  respiratory system is affected by exposure to  certain
air  pollutants,  including  ozone,  nitrogen dioxide, and  other oxidants.  As a
consequence, Congress took note of pollutant effects on  the respiratory system
and  gave bronchial  asthmatics and emphysematics as examples of "particularly
sensitive" individuals.  With regard to research on health effects, Congress
has  noted  that attention should go beyond "normal  segments of the population
to effects on  the very young, the  aged,  the infirm,  and other susceptible
individuals."  Concern  should be  given  to the "contribution  of age,  ethnic,
social, occupational,  smoking, and  other factors  to susceptibility  to  air
pollution agents."
     Consonant with the provisions of the Clean Air Act and with its  legislative
history, the first  major subpopulation  that appears to be at particular risk
from exposure  to ozone  is that subgroup of the general population characterized
as having preexisting disease.  Available data on actual differences  in sensitiv-
ity  between these and healthy, normal members of the general population indicate
that under  the exposure regimes used to  date,  individuals  with preexisting
disease may not be more sensitive to ozone than normal individuals.    Neverthe-
less,  two  considerations place these individuals  among  subpopulations at
potential  risk from exposure to ozone.    First, it must be noted that  concern
with triggering  untoward reactions  has  necessitated the  use  of low  concentra-
tions  and  low  exercise levels in most  studies on  subjects with preexisting

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disease.   Therefore, few or no data on responses at higher concentrations and
higher exercise levels  are  available  for comparison with responses in normal
subjects.   Thus, definitive data on responses in individuals with preexisting
disease are not available and may not even become available.   Second,  however,
it must be  emphasized  that  in individuals with already compromised pulmonary
function,  the  decrements in function produced  by  exposure  to ozone,  while
similar to or even the same  as those experienced by normal subjects, represent
a  further  decline  in volumes and flows  that  are already diminished.   Such
declines may  be expected to  impair further the ability  to  perform normal
activities.   In individuals  with preexisting diseases such as asthma or allergies,
increases in symptoms  upon  exposure to ozone, above and beyond symptoms seen
in the general  population,  may also impair or further curtail the ability to
function normally.
     A second  major  subpopulation  at apparent special  risk  from  exposure to
ozone consists  of  individuals  ("responders")  in the  general  population, not
yet characterized medically except for their responses to ozone, who experience
greater decrements in lung function from exposure to ozone than those  observed
in the remainder of the general population.  As yet no means of determining in
advance those  members  of the general population  who are "responders"  has been
devised.   It is important  to note here what has been discussed previously in
this chapter and  in chapter 11;  that is, group means presented in chapter 11
and  in  Figures 13-2  through  13-5 (and Table 13-3) include  values for the
"responders" in the respective  study  cohorts of otherwise  healthy,  normal
subjects.   Although  no  means of  identifying the  number  or demographic charac-
teristics of "responders" exists,  they are clearly a subgroup of the general
population  whose  individual members  appear to  be  at particular  risk from
exposure to ozone.
     Data presented in Chapter 11 and in this chapter underscore the  importance
of exercise  in the potentiation of effects from exposure to ozone.   Thus, a
third major  subpopulation potentially  at risk from exposure to ozone is com-
posed  of  those individuals (healthy or  otherwise) whose activities  out of
doors, whether  vocational or avocational, result in increases in minute ventila-
tion.  As  stated  in section 13.7.2, "the most prominent modifier of  response
to 0_ in the general population is minute ventilation, which increases propor-
tionately with increases in exercise workload."  Although  many individuals
with preexisting disease would not  be expected  to  exercise  at the  same  levels

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one would expect in healthy individuals, any increase in activity level would
bring about a commensurate increase in minute ventilation.
     As pointed out throughout this chapter,  other biological  and nonbiological
factors are suspected of influencing responses to ozone.   Data remain inconclu-
sive at the  present,  however,  regarding the importance of  age,  gender, and
other factors in influencing response to ozone.   Thus,  at  the  present time,  no
other subpopulations are  thought  to be biologically predisposed to increased
sensitivity  to  ozone.   To the  extent that the aged, the young,  males, or
females participate in activities out of doors that raise  their minute ventila-
tions, all of  these  subgroups may be considered  to  be  potentially at risk,
depending upon  other  determinants  of total ozone dose, 0., concentration and
exposure duration.

13.7.4  Demographic Distribution of the General  Population
     The U.S. Bureau of the Census periodically provides an updated statistical
summary of the  U.S. population  by  conducting a decennial survey,  supplemented
by monthly surveys of  representative  population  samples.  The  complete  census
represents a total  count of the population since an attempt is made to account
for the social, economic,  and housing characteristics of every residence.   In
determining  residence,  the census  counts each person as  an  inhabitant of a
usual place  where  eating  and  sleeping take place  rather than  a person's legal
or voting  residence.   Each residence is, in turn,  grouped  according to the
official standaro metropolitan statistical areas (SMSA's)  and  standard consoli-
dated statistical  areas (SCSA's)  as defined by  the  Office of Management and
Budget.  Briefly,  SMSA's  represent a large population  nucleus together with
adjacent communities  which have a  high  degree of  social and economic integra-
tion; SCSA's  are large metropolitan complexes consisting  of groups  of closely
related adjacent SMSA's.   Table 13-6 gives the  geographical  distribution of
the  resident  population of the United  States for 1980  (U.S.   Bureau  of the
Census, 1982).  The entire territory  of the U.S.  is classified as metropolitan
(inside SMSA's) or nonmetropolitan (outside SMSA's).  According  to the 1980
census, the  urban population comprises  all persons living in cities,  villages,
boroughs, and towns of  2500 or more inhabitants.   Additional data on  age, sex,
and race obtained from  the 1980 census  are shown  in Table 13-7.   Evaluation of
previous  census data  indicated a  total net underenumeration  rate  of about
2.2 percent  in  1970 and 2.7 percent in  1960.  Although estimates  for  1980 have

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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,
mil lions
226.5
49.1
58.9
75.4
43.2
169.4
68.0
101.5
57.1
167.1
59.5
Population,
percent
100.0
21.7
26.0
33.3
19.0
74.8
30.0
44.8
25.2
73.7
26.3
aU.S.  Bureau of the Census (1982).
 Represented by 318 standard metropolitan statistical  areas (SMSA's).
cComprises all  persons living in cities, villages,  boroughs,  and towns of
 2500 or more inhabitants but excluding those persons  living  in the rural
 portions of extended cities.

not been published, preliminary results indicated that overall  coverage improved
in the 1980  census.   Census data presented  in Tables 13-6 and 13-7 have not
been adjusted for underenumeration.

13.7.5  Demographic Distribution of Individuals with Chronic  Respiratory
        Conditions
     Certain subpopulations  have been  identified  as  potentially-at-risk to
ozone or  photochemical  oxidant exposure by virtue of preexisting respiratory
conditions  like  chronic obstructive lung disease  (COLD),  asthma,  and upper
respiratory allergies.   Each  year  the National Health Interview Survey (HIS)
conducted by  the National Center for  Health Statistics  (NCHS) reports  the
prevalence  of  chronic  respiratory  conditions  in the  United  States.  These
conditions  are  classified by type,  according  to the  Ninth Revision of  the
International Classification  of  Diseases adopted for  use in the United States
(World Health Organization, 1977).   According to NCHS, a condition is  considered
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              TABLE 13-7.   TOTAL POPULATION OF THE UNITED STATES
                         BY AGE, SEX,  AND RACE, 1980a
Age, sex, race
Total
Under 5 years
5-17 years
18-44 years
45-64 years
65 years and over
Male
Female
Whitelj
BlacIC
h
Other
Population,
mill ions
226.5
16.3
47.1
93.3
44.4
25.5
110.0
116.5
194.8
26.6
5.1
Population,
percent
100.0
7.2
20.8
41.2
19.6
11.3
48.6
51.4
86.0
11.7
2.3
aU.S.  Bureau of the Census (1982).
 Data represent self-classification according to 15 groups listed on the 1980
 census questionnaire:   White,  Black,  American,  Indian,  Eskimo,  Aleut,
 Chinese,  Filipino, Japanese,  Asian Indian,  Korean, Vietnamese,  Hawaiian,
 Samoan, Guamanian, and Other.

to be  chronic  if it had been documented by a physician more than three months
before the  interview was  conducted.   In the HIS for 1979 (U.S.  Department of
Health and  Human Services,  1981)  COLD was not  listed as a specific medical
condition since it  is  a clinical  term and  not  generally recognized by  the
general public.  However,  this  term has been used with increasing frequency by
physicians rather  than  the more common terms chronic bronchitis and emphysema
in classifying  chronic  airways  obstruction.   As a  result,  there  may be an
underestimation by  the HIS of  the  true prevalence of this disorder.
     The estimated prevalence of chronic bronchitis, emphysema, and asthma in
the United States  is shown in  Table 13-8 for the year 1979 (U.S.  Department of
Health and  Human Services,  1981).   All three respiratory conditions combined
accounted for over  16 million  individuals in 1979,  representing 7.5 percent of
the population.  Approximately  one-third of  the  individuals  with  chronic
bronchitis and  asthma were  under  17 years of age.   An  additional  15 to 16
million persons reported having hay fever and other upper respiratory allergies.
Accounting for  an  underestimation by  the HIS, the  total  number of individuals

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                     TABLE 13-8.   PREVALENCE OF CHRONIC RESPIRATORY CONDITIONS BY SEX AND AGE FOR 1979
Number of persons, in thousands



CO
i
en
Condition
Chronic bronchitis
Emphysema
Asthma
Hay fever and
other upper
respiratory
allergies
Total0
7474
2137
6402
15,620
Male
3289
1364
3113
7027
Female
4175
770
3293
8584
years old
2458
12d
2225
3151
17-44
years old
2412
127d
2203
8278
45-64
years old
1547
1008
1482
3012
>65
years old
1060
990
488
1181
% of U.S.
population
3.5
1.0
3.0
7.2
b
f
 U.S.  Department of Health and Human Services,  1981.
 Classified by type, according to the Ninth Revision  of the International  Classific of Diseases (World Health
 Organization, 1977).
"Reported as actual number in thousands;  remaining subsets have been calculated from percentages and are rounded off.
 Does  not meet standards of reliability or precision  set by the National  Center for Health Statistics (more than 30%
 relative standard error).
'With  or without hay fever.
 Without asthma.

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with documented and  undocumented  respiratory conditions in the United States
is estimated to be  at least 47 million, which is approximately 20 percent of
the population.
13.8  SUMMARY AND CONCLUSIONS
     Controlled human studies  of  at-rest exposures to 0_  lasting  2 to 4 hr
have demonstrated decrements in forced expiratory volume and flow occurring at
and above 0.5 ppm of 0~.   Airway resistance was not changed at these 0~ concen-
trations.  Breathing 0- at rest at concentrations < 0.5 ppm did not significantly
impair pulmonary function although the occurrence of some 0--related pulmonary
symptoms has been suggested in a number of studies.
     One of  the  principal  modifiers of the magnitude  of response  to 0.,  is
minute  ventilation  (VV), which increases proportionately  with increases in
exercise work load.   Adjustment by the respiratory system to an increased work
load is characterized by increased frequency and depth of breathing.  Consequent
increases in VV not only increase the overall  volume of inhaled pollutant, but
such ventilatory patterns  also promote a  deeper  penetration  of ozone  into the
peripheral lung, which is the  region most sensitive to ozone and where a  greater
absorption of  ozone will occur.   These processes are further enhanced at high
work loads (VF > 35 L/min), since the mode of breathing will most likely  change
at that Vp from nasal to oronasal.
     Even  in wel1-controlled  experiments on a homogeneous group of subjects,
physiological  responses  to the same  work and pollutant loads will  vary widely
among individuals.   Despite such  large interindividual  variability, the  magni-
tude of group  mean  lung function changes  is  positively associated with  the
level of  exercise and  ozone concentration.  Based on reported studies of 1  to
3 hr duration,  significant pulmonary function impairment  (decrement)  occurs
when exercise  is combined with exposure to ozone:

     1.    Light exercise (VV < 25 L/min) - Effects at  > 0.37 ppm 03;
     2.   Moderate exercise (VV = 26 to  43  L/min) -  Effects  at > 0.30 ppm 03;
     3.   Heavy exercise (VV = 44 to 63  L/min) -  Effects at  >  0.24 ppm 03; and
     4.   Very heavy exercise  (VV >  64 L/min) -  Effects at :> 0.18 ppm 03, with
           suggestions of decrements  at 0.12 ppm  0~.
 019JSA/A                           13-76                                6/26/84

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For the  majority of  the  controlled studies,  15-min  intermittent exercise
alternated with  15-min  rest  was employed for  the  duration  of the exposure.
Continuous exercise equivalent in duration to the sum of intermittent exercise
periods at comparable ozone concentrations (0.2 to 0.4 ppm) and minute ventila-
tion (60  to  80  L/min) seems to elicit  about the same changes in pulmonary
function.  The maximum  response to 0., exposure  can be  observed  within 5 to
10 min following the  end  of each exercise period.  Functional  recovery,  at
least from a single exposure with exercise,  appears to progress in two phases:
during the initial  rapid phase, lasting between 1 and 3 hr, pulmonary function
improves more than 50 percent; this is followed by a much slower recovery that
is  usually  completed within  24 hr.   In some individuals, despite apparent
functional recovery,  other regulatory  systems may still  exhibit abnormal
responses when  stimulated; e.g.,  airway hyperreactivity might persist for
days.
     A close association has been observed between changes in pulmonary function
and the  occurrence  of respiratory symptoms  in  response  to acute  exposure  to
Q~.  This association holds for both the time-course and magnitude of effects.
The symptoms found  in association with  clinical  exposure  to  0,, alone  and with
exposure  to  photochemical  air pollution are similar but  not identical.  Eye
irritation,  one  of  the  most common complaints  associated with photochemical
pollution, is not characteristic of clinical exposures to 0~, even at concen-
trations  several times   higher than any likely  to be encountered in  ambient
air.  There  is  also evidence to suggest that  other  symptoms, indicative of
either upper or  lower respiratory tract irritation,  are more likely to occur
in populations exposed to ambient air pollution than in subjects exposed to 0,,
alone in  chamber studies.   For example, cough has been reported at 0.08 ppm 0~
and at 0.10 ppm oxidants in epidemiological  studies and during clinical exposure
to  0.12  ppm  03;  nose and throat irritation  have been  reported in community
studies  in association  with  0.10 ppm oxidants  but  not at  or  below 0.15 ppm 03
in  laboratory studies.  Between 0.15 and 0.30  ppm, a variety of both  respira-
tory and  nonrespiratory symptoms  have been reported in controlled exposures.
They include throat dryness, difficulty or pain during deep  inspiration,  chest
tightness, substernal  soreness or  pain, wheezing, lassitude, malaise, and
nausea.   Symptoms are therefore considered to  be useful  adjuncts  in assessing
the effects  of  0^  and photochemical pollution, particularly if combined with
objective measures of lung function.

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     Only a few  studies  have been designed to  examine  the effects of 0_ on
exercise performance.  In one study, very heavy exercise (V^ > 64  L/min) at a
high 0- concentration (0.75 ppm) reduced postexposure maximal  exercise capacity
by limiting maximal  oxygen consumption; submaximal oxygen  consumption changes
were inconsistent.   The extent of ventilatory and respiratory metabolic changes
observed during  or  following the  exposure appears to  have  been related to the
magnitude of pulmonary function impairment.   Whether such changes are consequent
to respiratory discomfort  (i.e.,  symptomatic effects) or  are  the  result of
changes in lung mechanics or both is still unclear and needs to be elucidated.
     Environmental   conditions such  as  heat  and relative humidity may enhance
subjective  symptoms and  physiological  impairment  following  03 exposure.
Modification of  the effects  of 0, by these  factors may  be attributed to in-
creased  ventilation which,   like  exercise,  increases  the overall  volume of
inhaled pollutant and  promotes  greater penetration into peripheral  areas of
the lung.
     Additional factors suspected of altering sensitivity to ozone are numerous.
For example, age differences,  especially between the very young and the very
old;  gender  differences, especially for  children;  personal habits  such as
cigarette smoking;  and possibly social, cultural, or  economic  factors  such  as
differences in nutritional  status or differences in  immunological status may
predispose individuals to  susceptibility  to ozone.    Those actually  known to
alter sensitivity,  however, are few, largely because  they  have not been examined
adequately to  determine  definitively their  effects  on sensitivity  to 0.,.  The
following briefly  summarizes what is actually  known  from  the  data regarding
the importance of these factors:

     1.   Age.   Although  changes in growth and development of the lung  with
age have been postulated as  one of many factors capable  of  modifying responsive-
ness  to  CL,  studies have not been designed to  test adequately for effects of
GO in different  age groups.
     2.   Sex.   Sex differences  in  responsiveness  to  ozone  have not been
adequately studied.  Lung function of women, as assessed by changes  in FEV, Q,
appears  to  be  affected more  than that  of  men under  similar exercise  and  expo-
sure  conditions,  but the differences have  not  been analyzed systematically.
Further  research is needed to determine whether differences in lung  volumes or
differences  in  exercise  capacity during  exposure may lead to  sex  differences
in responses to  0_.
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     3.   Smoking Status.   Differences  between smokers  and nonsmokers have
been studied often, but the data are not documented well and are often confusing.
Published results indicate a discrepancy in findings.  There is some evidence,
however, to suggest that smokers may be less sensitive to 0~.
     4.   Nutritional Status.  Antioxidant properties of vitamin E in preventing
ozone-initiated peroxidation jj\ vitro are well demonstrated and their protective
effects 2ji  vivo  are  clearly demonstrated  in  rats  and mice.   No  evidence  indi-
cates, however, that man would benefit from increased vitamin E intake relative
to ambient ozone exposures.
     5.   Red Blood Cell Enzyme Deficiencies.  There have been too few studies
performed to document  reliably that individuals with a hereditary deficiency
of glucose-6-phosphate dehydrogenase may be at-risk to significant hematological
effects from 0_ exposure.

     Successive daily brief exposures of healthy human subjects to 0,. (<0.7 ppm
for approximately 2 hr) induce a typical temporal pattern of response.  Maximum
functional changes that  occur after the first or second  exposure  day  become
progressively attenuated on each of the subsequent days.  By the fourth day of
exposure, the  effects  are, on the average, not different from those observed
following control  (air)  exposure.   Individuals need between 3  and 7  days  to
develop full attenuation,  with more sensitive subjects  requiring  more time.
The magnitude  of  a peak response to 0~ appears to be directly related to its
concentration.    In  addition,  concentrations  of  03 that have no detectable
effect appear  not  to invoke changes in response  to subsequent exposures at
higher 0^ concentrations.  Full attenuation, even in ozone-sensitive subjects,
does not  persist  for more  than 3 to 7 days  in  most individuals, while  partial
attenuation might persist  for  up to 2 weeks.  Although symptomatic response is
generally related to the magnitude of the functional response,  partial sympto-
matic attenuation appears  to persist longer, for up to 4 weeks.
     Whether populations  exposed to photochemical  air  pollution  develop at
least partial  attenuation  is unknown.   No epidemiological  studies have  been
designed to test this hypothesis.   While there is limited information obtained
from controlled  laboratory  studies to  support this hypothesis, additional
information is required.
     Responses to 0~, whether  functional, biochemical,  or morphological, have
the potential for altering responses in both man and laboratory animals during

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repeated or continuous exposure.   At  present,  the underlying mechanisms for
this response are poorly  understood  and the effectiveness of such mitigating
forces  in  protecting  the  long-term health of the  individual  against 0- is
still uncertain.  Therefore,  hyperresponsiveness  to  0^,  including changes  in
bronchial  reactivity, and the subsequent attenuation of responsiveness may be
viewed as sequential states in a continuing process.
     Several animal experiments have demonstrated  increased susceptibility to
respiratory infections following 0~ exposure.  Thus, it could be  hypothesized
that humans exposed to  03 could experience decrements in their host defenses
against  infection.  At the present time, however,  these effects have not been
described  in humans exposed  to  0-, so  that  concentrations  at which effects
might occur in  man  or the severity of such effects are unknown and difficult
to predict.
     Animal studies have also reported a number of extrapulmonary responses to
0«,  including cardiovascular, reproductive,  and teratological effects, along
 «J
with changes in endocrine function.   The  implications of these findings for
human health are difficult to judge at the present time.   In addition, central
nervous  system  effects, alterations in red blood cell morphology  and enzymatic
activity,  as well as chromosomal effects on circulating lymphocytes, have been
observed  in man and laboratory  animals following  exposure to high concentra-
tions  of 0~.    It  is  unlikely,  however, that these  changes  would have any
functional  significance  in humans  when exposure  schedules  are  used  that are
representative  of  exposures  that the  population  at large  might  actually expe-
rience.
     Currently  available  evidence  indicates that individuals with preexisting
disease  respond to  0_ exposure to a similar degree as normal subjects.  Patients
                    •J
with chronic  obstructive  lung disease  and/or asthma have not shown  increased
sensitivity  to  CL  in controlled human  exposure  studies,  but there  is some
indication from epidemiological studies that asthmatics may be symptomatically
and possibly  functionally more  sensitive  than healthy individuals to  ambient
air exposures.   Appropriate  inclusion and exclusion criteria for  selection of
these  subjects, however,  especially  better clinical diagnoses validated  by
pulmonary function, must be considered before their sensitivity  to  0^ can  be
adequately determined.   None of these  factors  has been  sufficiently studied
in  relation to  0.,  exposures  to  give  definitive answers.   Thus,  estimates  of
                 O
at-risk populations are difficult  to  assess with  any precision.
      Despite  wide  variations in  study  techniques and experimental  designs,
acute  and subchronic  exposures  of  animals  to  levels  of ozone  < 0.5 ppm produce
019JSA/A                          13-80                                6/26/84

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similar types of responses in all  species examined.   A characteristic inflamma-
tory lesion occurs  at  the junction of the conducting  airways  and the gas-
exchange regions of the lung after acute 0_ exposure.   Dosimetry model  simula-
tions predict that  the maximal tissue dose of 0- occurs in this region of the
lung.  Continuation of the  inflammatory process during longer 0_ exposures is
especially important since  it  appears  to be correlated with  increased  lung
collagen content  and  remodeling of the  centriacinar  airways.   There is no
evidence of emphysema, however,  in the lungs of animals  exposed  to 0~ for
prolonged periods of time.
     Controlled human and animal exposures have not consistently demonstrated
any  enhancement of  respiratory effects for combined exposures of 0- with SC-  ,
NOp, CO, or  HLSO.  and  other particulate aerosols.   Ozone alone is considered
to be  responsible for the observed effects of those combinations or of multi-
ple  mixtures  of  these  pollutants.   In addition, there have been far too few
controlled toxicological  studies  with other oxidants, such  as  peroxyacetyl
nitrate or hydrogen peroxide,  to  permit any sound  scientific  evaluation  of
their  contribution  to  the  toxic  action  of photochemical  oxidant mixtures.
Nevertheless, there is still some  concern  that combinations of  oxidant pollu-
tants  with  other pollutants may contribute  to  the  symptom aggravation and
decreased lung  function  described  in  epidemiological  studies on individuals
with asthma and in children and young adults.  For this reason,  the effects of
interaction between inhaled oxidant  gases and other environmental  pollutants
on the lung need to be systematically studied using exposure regimens that are
more closely  representative of ambient  air  ratios  of peak concentrations,
frequency, duration, and  time intervals between events.
     Despite  uncertainties  that may  exist in  the data,  it  is  possible  to
identify three  major subpopulations that  may be at particular risk  from expo-
sure to  ozone,  based on  known  health  effects,  activity patterns,  personal
habits, and actual or potential exposures to ozone.
     The first  major subpopulation that  appears to be  at  particular  risk from
exposure to  ozone  is that subgroup of  the  general population characterized as
having preexisting  disease.  Available  data  on actual  differences  in sensiti-
vity between  these and  healthy,  normal members of  the  general population
indicate that under the  exposure regimes  used to date individuals  with pre-
existing disease  may  not be more sensitive to ozone than normal individuals.
Nevertheless, two  considerations place  these individuals  among  subpopulations
at potential  risk from exposure to ozone.  First, it must be noted that concern
019JSA/A                           13-81                                6/26/84

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with triggering  untoward reactions has necessitated the use of low concentra-
tions and  low  exercise  levels in most studies  on  subjects  with  preexisting
disease.  Therefore, few or no data on responses at higher concentrations and
higher  exercise  levels  are  available  for comparison with responses in normal
subjects.  Thus, definitive data on responses in individuals with preexisting
disease are not available and may not ever become available.   Second, however,
it must  be  emphasized  that  in individuals with already compromised pulmonary
function,  the  decrements in  function produced  by  exposure  to ozone, while
similar to or even the same  as those experienced by normal subjects,  represent
a  further  decline  in volumes and flows  that  are already diminished.  Such
declines may  be expected to  impair  further the ability  to  perform  normal
activities.  In individuals  with preexisting diseases such as asthma  or aller-
gies, increases  in  symptoms upon exposure to ozone, above and beyond symptoms
seen in the general  population,  may also impair or further curtail  the ability
to function normally.
     A  second major  subpopulation  at  apparent special risk from exposure to
ozone consists  of individuals ("responders")  in the  general population, not
yet characterized medically  except for their responses to ozone,  who  experience
greater decrements in lung function from exposure to ozone than those observed
in the remainder of  the general  population.   As yet no means of determining  in
advance those members of the  general population who are "responders" has been
devised.
     Data presented  in  this  chapter  underscore the importance of exercise in
the  potentiation  of effects  from  exposure  to ozone.   Thus,  a third major
subpopulation potentially at  risk from exposure to ozone  is composed of those
individuals (healthy and  otherwise)  whose activities out of  doors,  whether
vocational  or avocational,  result in increases in minute ventilation.  Although
many individuals with preexisting disease would not be expected to  exercise  at
the  same  levels one would  expect  in healthy individuals, any increase  in
activity level  would bring about a commensurate increase in  minute  ventilation.
To the  extent  that  the  aged, the  young, males, or females  participate  in
activities out  of doors  that  raise their minute ventilations, all  of these
subgroups may be considered  to  be potentially at risk, depending upon other
determinants of  total  ozone  dose,  Q-3 concentration,  and  exposure  duration.
     Other biological and nonbiological  factors are suspected of influencing
responses to ozone.   Data remain inconclusive at the present,  however, regard-
ing the  importance  of  age,  gender,  and other factors in influencing  response
019JSA/A                           13-82                                6/26/84

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to ozone.  Thus,  at  the present time, no other subpopulations are thought to
be biologically predisposed  to  increased sensitivity to ozone.   It  must be
emphasized, however, that  the  final  identification of those effects that are
considered "adverse" and the final identification of "at-risk" populations are
both the domain of the Administrator.
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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 urn)  separating
     alveolus from capillary; composed of epithelial  cells lining the alveolus,
     a  thin  layer  of connective tissue, and a layer of capillary endothelial
     cells.

Alveolar carbon  dioxide  pressure (P.CO?):   Partial pressure of carbon dioxide
     in the air  contained in the lung alveoli.

Alveolar oxygen  partial  pressure  (P^Oo):   Partial pressure of oxygen in the
     air contained in the alveoli  ofHne lungs.

Alveolar septum  (pi.  septa):   A thin tissue  partition between two adjacent
     pulmonary  alveoli,  consisting of a close-meshed capillary  network and
     interstitium covered  on both  surfaces by alveolar  epithelial  cells.
*References:  Bartels, H.; Dejours, P.; Kellogg, R. H.; Mead, J. (1973) Glossary
              on respiration and gas exchange.  J.  Appl. Physiol. 34: 549-558.

              American College of Chest Physicians - American Thoracic Society
              (1975) Pulmonary terms  and symbols:   a report  of the  ACCP-ATS
              Joint Committee on  pulmonary nomenclature.   Chest 67:  583-593.
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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,, a»at):   Volume of the conducting airways down to the
     level where, duringr air Breathing ,  gas exchange with blood can occur, a
     region probably situated at the entrance of the alveolar ducts.

Arterial oxygen saturation  (SaO?):   Percent saturation of dissolved  oxygen in
     arterial blood.

Arterial  partial  pressure of carbon  dioxide  (PaCO?):   Partial  pressure of
     dissolved carbon dioxide in arterial  blood.

Arterial  partial  pressure of oxygen (PaCL):   Partial pressure  of dissolved
     oxygen in arterial  blood.

Asthma:  A disease characterized by an increased responsiveness  of the airways
     to various stimuli  and manifested by slowing of forced expiration which
     changes in severity  either spontaneously  or as a result of therapy.  The
     term asthma  may be  modified by words  or phrases indicating its  etiology,
     factors provoking attacks,  or its duration.

Atelectasis:   State  of  collapse  of air spaces with  elimination of the gas
     phase.

ATPS condition (ATPS):  Ambient temperature and pressure, saturated with water
     vapor.  These are the conditions existing in a water spirometer.
Atropine:   A poisonous white crystalline alkaloid, ci7H2.3N033 from bel
     and related plants,  used  to relieve spasms of smoorn muscles.   It is an
     antichol inergic agent.

Breathing pattern:   A general  term  designating  the  characteristics  of the
     ventilatory activity,  e.g., tidal  volume, frequency  of  breathing,  and
     shape of the volume time curve.

Breuer-Hering reflexes (Hering-Breuer reflexes):   Ventilatory reflexes originat-
     ing in the lungs.  The reflex arcs  are formed by the pulmonary mechanore-
     ceptors, the vagal  afferent fibers, the respiratory centers,  the medullo-
     spinal  pathway,  the motor neurons, and the respiratory muscles.   The af-
     ferent link informs the respiratory centers of the volume state  or of the
     rate of change  of volume of the lungs.  Three types of Breuer-Hering re-
     flexes have been described:   1)  an  inflation reflex in which  lung inflation
     tends to  inhibit inspiration  and stimulate expiration;  2) a deflation
     reflex in which  lung deflation tends to inhibit expiration and  stimulate
     inspiration; and 3) a  "paradoxical reflex," described but largely disre-
     garded by  Breuer and Hering, in which  sudden inflation may stimulate
     inspiratory muscles.
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Bronchiole:   One  of the finer subdivisions of the airways, less than 1 mm in
     diameter, and  having no cartilage in its wall.

Bronchiolitis:  Inflammation of the bronchioles which may be acute or chronic.
     If the etiology is  known, it should be stated.  If permanent occlusion of
     the  lumens  is  present, the term bronchiolitis  obliterans  may be used.

Bronchitis:   A non-neoplastic disorder of structure or function of the bronchi
     resulting from infectious or noninfectious irritation.  The term bronchitis
     should be modified  by  appropriate words or phrases to indicate its etiol-
     ogy,  its chronicity,  the presence of associated airways dysfunction, or
     type  of  anatomic  change.  The  term  chronic bronchitis, when  unqualified,
     refers to  a  condition associated with prolonged exposure to nonspecific
     bronchial  irritants and  accompanied by mucous hypersecretiori and  certain
     structural alterations in the  bronchi.   Anatomic changes may  include
     hypertrophy  of the mucous-secreting apparatus and epithelial  metaplasia,
     as well  as  more  classic  evidences  of inflammation.  In epidemiologic
     studies, the presence  of cough or sputum production on most days for at
     least three  months  of  the year has sometimes been accepted as a criterion
     for the  diagnosis.

Bronchoconstrictor:   An  agent  that  causes a reduction in the caliber (diame-
     ter) of  airways.

Bronchodilator:   An agent that causes an increase  in the caliber (diameter) of
     airways.

Bronchus:   One of the subdivisions of the trachea serving to convey air to and
     from the lungs.   The trachea divides into right  and  left  main bronchi
     which in turn  form  lobar, segmental, and subsegmental  bronchi.

BTPS conditions (BTPS):   Body temperature, barometric pressure, and  saturated
     with water vapor.   These are the conditions  existing  in the  gas phase of
     the lungs.    For man the normal  temperature is taken as 37°C,  the pressure
     as the barometric pressure,  and the partial  pressure of water vapor as 47
     torr.

Carbachol:  A parasympathetic stimulant (carbamoylcholine chloride, CgH15ClN?02)
     that produces constriction of the bronchial  smooth muscles.

Carbon dioxide production (VC02):   Rate of carbon dioxide production by organ-
     isms, tissues,  or cells.   Common units:   ml  C02 (STPD)/kg-min.

Carbon monoxide (CO):   An odorless, colorless, toxic gas formed by incomplete
     combustion,  with  a strong affinity  for  hemoglobin  and cytochrome;  it
     reduces oxygen absorption capacity,  transport, and utilization.

Carboxyhemoglobin  (COHb):   Hemoglobin  in which the  iron is  associated with
     carbon monoxide.    The  affinity  of  hemoglobin for CO  is about 300 times
     greater than  for 0.
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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 VENTfL°ATION and RESISTANCE.

Collateral  ventilation:   Ventilation  of  air  spaces  via indirect pathways,
     e.g.,  through pores in alveolar septa, or anastomosing respiratory bron-
     chioles.

Compliance  (C,,C  .):   A  measure  of distensibility.   Pulmonary compliance  is
     given  by  thl slope  of a static volume-pressure curve at a point, or the
     linear approximation  of  a nearly  straight portion of such a curve, ex-
     pressed  in  liters/cm  HLO  or ml/cm HLO.  Since the static  volume-pressure
     characteristics of  lungs  are nonliriear (static compliance decreases  as
     lung volume  increases) and  vary according to the previous volume history
     (static  compliance  at a given volume  increases  immediately  after full
     inflation and decreases  following  deflation),  careful specification  of
     the conditions of measurement are necessary.   Absolute values also depend
     on organ size.  See also DYNAMIC COMPLIANCE.

Conductance  (G):   The reciprocal  of  RESISTANCE.   See  AIRWAY CONDUCTANCE.

Diffusing capacity of  the  lung  (D, , D,02,  D.CO,, D.CO):   Amount of gas  (0.,
     CO, C0?)  commonly expressed 5s ml gas CSTTO) diffusing between alveofar
     gas ana  pulmonary capillary blood per torr mean gas pressure difference
     per  min,  i.e.,  ml  02/(min-torr).    Synonymous with  transfer  factor and
     diffusion factor.

Dynamic compliance  (C,  ):   The ratio  of the  tidal  volume to the change  in
     intrapleural pres^uYe between the points  of  zero  flow at  the  extremes of
     tidal  volume in  liters/cm H^O or ml/cm H20.  Since  at the points of zero
     airflow  at  the  extremes  of Tidal  volume, volume acceleration is usually
     other  than  zero,  and since, particularly in abnormal  states,  flow may
     still  be  taking  place within  lungs between regions which are exchanging
     volume,  dynamic  compliance  may differ  from static  compliance,  the  latter
     pertaining to  condition  of zero volume acceleration  and  zero gas flow
     throughout the lungs.  In normal lungs at ordinary volumes and respiratory
     frequencies, static and dynamic compliance are the same.
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Elastance (E):  The  reciprocal  of  COMPLIANCE;  expressed  in  cm  H?0/liter  or  cm
     H20/ml.

Electrocardiogram (ECG,  EKG):   The graphic record of the electrical currents
     that are associated with the heart's contraction and relaxation.

Expiratory reserve volume  (ERV):   The maximal volume of air exhaled from the
     end-expiratory level.

FEV+/FVC:  A  ratio of timed (t = 0.5, 1,  2,  3 s) forced expiratory  volume
     (FEV,) to  forced vital  capacity (FVC).  The ratio is often expressed  in
     percent 100 x FEV./FVC.   It is an index of airway obstruction.
't
Flow volume  curve:   Graph  of  instantaneous  forced expiratory flow recorded at
     the  mouth,  against corresponding lung volume.   When recorded over the
     full vital  capacity,  the curve  includes  maximum expiratory flow  rates at
     all  lung  volumes  in  the VC range and is  called a maximum  expiratory
     flow-volume curve  (MEFV).   A partial expiratory flow-volume curve (PEFV)
     is one which describes maximum expiratory flow  rate  over a  portion of the
     vital capacity only.

Forced  expiratory  flow (FEFx):   Related to some  portion of the  FVC  curve.
     Modifiers refer to the amount of the FVC already exhaled when the measure-
     ment is made.   For example:

          FEF7r
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Gas exchange:  Movement of oxygen from the alveoli  into the pulmonary capillary
     blood as  carbon  dioxide  enters  the alveoli from the blood.  In broader
     terms, the exchange of gases between alveoli  and lung capillaries.

Gas exchange ratio (R):  See RESPIRATORY QUOTIENT.

Gas trapping:  Trapping  of gas behind small airways that were opened during
     inspiration but closed during forceful expiration.   It is a volume differ-
     ence between FVC and VC.

Hematocrit (Hct):  The percentage  of the volume of  red blood cells  in whole
     blood.

Hemoglobin (Hb):  A hemoprotein  naturally  occurring  in most vertebrate blood,
     consisting of four  polypeptide  chains (the globulin) to each  of which
     there is  attached a heme+ group.  The heme is made of four pyrrole rings
     and a divalent iron (Fe   -protoporphyrin) which combines reversibly with
     molecular oxygen.

Histamine:    A  depressor  amine  derived  from  the ami no acid  histidine  and found
     in all body tissues, with the highest concentration in the lung; a powerful
     stimulant of gastric secretion,  a constrictor of bronchial  smooth muscle,
     and a vasodilator that causes a fall in blood pressure.

Hypoxemia:    A  state  in  which the oxygen  pressure  and/or concentration in
     arterial and/or venous blood is lower than its normal value at sea level.
     Normal  oxygen pressures  at  sea  level  are 85-100 torr in arterial blood
     and 37-44  torr in mixed  venous  blood.   In adult humans the  normal oxygen
     concentration is  17-23 ml 02/100 ml arterial  blood; in mixed venous blood
     at rest it is 13-18 ml 02/lDO ml blood.

Hypoxia:   Any  state in which  the oxygen  in  the  lung, blood, and/or  tissues  is
     abnormally low compared  with  that of  normal resting  man  breathing air  at
     sea level.   If  the PQ2 is  low  in the environment, whether because of
     decreased barometric  pressure or decreased fractional concentration of
     0?, the condition is termed environmental hypoxia.  Hypoxia when referring
     to the  blood is  termed hypoxemia.  Tissues are said  to  be  hypoxic when
     their Pn? is low, even if there is no arterial hypoxemia, as in "stagnant
     hypoxiaw  which occurs when  the  local circulation is low compared to the
     local metabolism.

Inspiratory capacity  (1C):  The  sum of IRV and TV.

Inspiratory  reserve volume (IRV):  The maximal  volume  of  air  inhaled from the
     end-inspiratory  level.

Inspiratory  vital  capacity (IVC):  The maximum  volume  of  air  inhaled from the
     point of maximum  expiration.

Kilogram-meter/min (kgm/min):  The work performed each min to move  a mass of 1
     kg  through a vertical  distance of 1  m  against the  force of  gravity.
     Synonymous with  kilopond-meter/min.

Lung volume  (V,):   Actual volume  of  the  lung,  including the volume  of  the
     conducting airways.

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Maximal aerobic capacity  (max VO^):   The rate of  oxygen  uptake by the body
     during repetitive maximal  respiratory  effort.   Synonymous with maximal
     oxygen consumption.

Maximum breathing capacity (MBC):  Maximal volume of air which can be breathed
     per minute by  a subject breathing as quickly and as deeply as possible.
     This tiring lung function test is usually limited to 12-20 sec, but given
     in liters (BTPS)/min.  Synonymous with maximum voluntary ventilation (MVV).

Maximum expiratory  flow (V      ):  Forced  expiratory flow, related to  the
     total lung capacity or Ine actual volume of the lung at which the measure-
     ment is  made.   Modifiers refer to the  amount  of lung volume remaining
     when the measurement is made.  For example:

          V    7ro; = instantaneous forced expiratory flow when the
           max                      Qf its T[_c
          V    , n = instantaneous forced expiratory flow when the
           max J'u   lung volume is 3.0 liters
Maximum expiratory flow rate (MEFR):  Synonymous with

Maximum mid-expiratory  flow rate (MMFR or MMEF):  Synonymous with ^25-75%'

Maximum ventilation (max Vr):  The volume of air breathed in one minute during
     repetitive maximal respiratory effort.  Synonymous with maximum ventilatory
     minute volume.

Maximum voluntary  ventilation  (MVV):   The  volume of  air  breathed  by  a  subject
     during voluntary  maximum  hyperventilation lasting a specific period  of
     time.  Synonymous with maximum breathing capacity (MBC).

Methemoglobin  (MetHb):   Hemoglobin in  which iron is  in the ferric state.
     Because the iron is oxidized, methemoglobin is  incapable of oxygen trans-
     port.  Methemoglobins are formed by various drugs and occur under pathol-
     ogical conditions.   Many methods  for hemoglobin measurements  utilize
     methemoglobin (chlorhemiglobin, cyanhemiglobin).

Minute  ventilation (Vr):    Volume  of  air breathed in  one minute.   It  is a
     product of  tidal S/olume (VT)  and  breathing frequency (fR).   See VENTILA-
     TION.                      '                             e

Minute volume:   Synonymous with minute ventilation.

Mucociliary transport:  The process by which mucus is  transported, by  ciliary
     action, from  the lungs.

Mucus:  The clear, viscid  secretion of mucous  membranes,  consisting  of mucin,
     epithelial cells,  leukocytes,  and various  inorganic salts  suspended  in
     water.

Nasopharyngeal  :   Relating  to the nose  or  the  nasal  cavity  and the  pharynx
     (throat).
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Nitrogen oxides:  Compounds of N and 0 in ambient air; i.e., nitric oxide (NO)
     and others  with a higher oxidation state of N, of which N0? is the most
     important toxicologically.                                 ^

Nitrogen washout (AN,,  dNJ:   The curve obtained by  plotting the  fractional
     concentration  of Np n'n  expired alveolar gas vs. time,  for a subject
     switched from breatfiing ambient air to an inspired mixture of pure CL.   A
     progressive  decrease of N2 concentration ensues which  may be analyzed
     into  two  or more exponential  components.  Normally, after 4 min of pure
     CU breathing  the fractional  N? concentration in expired alveolar gas is
     down  to less than 2%.

Normoxia:   A state in which the ambient oxygen pressure is approximately 150 ±
     10 torr  (i.e.,  the  partial  pressure  of oxygen  in  air  at  sea level).

Oxidant:   A chemical compound that has the ability to remove, accept, or share
     electrons from another chemical species, thereby oxidizing it.

Oxygen  consumption  (V0?,  Q0?):   Rate of oxygen uptake of organisms, tissues,
     or cells.   Commpn^unitf:  ml  02  (STPD)/(kg-min)  or  ml 0? (STPD)/(kg-hr).
     For whole organisms the oxygenTonsumption is commonly expressed per unit
     surface area  or some power of the body  weight.   For tissue samples or
     isolated cells QQ2 = u1 02/hr per mg dry weight.

Oxygen  saturation  ($02):   The  amount of oxygen  combined with  hemoglobin,
     expressed as  a  percentage of  the oxygen  capacity of  that hemoglobin.   In
     arterial  blood, SaO?.

Oxygen  uptake  (V02):  Amount of oxygen taken  up by the body  from the environ-
     ment,  by the  blood  from the alveolar gas, or by an  organ or tissue from
     the blood.  When this amount  of  oxygen  is expressed  per unit  of time one
     deals with  an "oxygen uptake rate."  "Oxygen  consumption"  refers more
     specifically to  the  oxygen uptake rate by all tissues of the  body and  is
     equal  to the  oxygen  uptake rate of the organism only when the 0? stores
     are constant.

Particulates:   Fine solid particles such as dust,  smoke,  fumes,  or smog,  found
     in the air or in emissions.

Pathogen:   Any  virus,  microorganism, or  etiologic  agent  causing  disease.

Peak expiratory  flow  (PEF):  The highest forced expiratory flow measured with
     a peak flow meter.

Peroxyacetyl  nitrate  (PAN):  Pollutant  created by action of UV component of
     sunlight on hydrocarbons and NO  in the air;   an ingredient of photochem-
     ical  smog.

Physiological  dead  space  (VQ):  Calculated  volume  which accounts  for the
     difference between the pressures of  C0? in expired  and alveolar gas (or
     arterial  blood).  Physiological  dead  space  reflects the combination of
     anatomical  dead space and  alveolar  dead space, the  volume  of the latter
     increasing  with  the  importance  of  the  nonuniformity   of   the
     ventilation/perfusion ratio in the  lung.


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Plethysmograph:   A  rigid chamber placed  around  a living structure for  the
     purpose of measuring changes in the volume of the structure.  In respira-
     tory measurements, the entire body is ordinarily enclosed ("body plethys-
     mograph") and  the plethysmograph  is  used  to  measure  changes  in volume of
     gas  in  the  system  produced 1) by solution  and volatilization (e.g.,
     uptake of  foreign gases  into the blood), 2) by changes in pressure or
     temperature  (e.g.,  gas  compression  in the lungs, expansion  of gas  upon
     passing into the warm, moist lungs),  or 3) by breathing through a tube to
     the  outside.   Three  types of plethysmograph are  used:  a)  pressure,  b)
     volume, and  c) pressure-volume.   In  type  a,  the body chambers  have  fixed
     volumes and  volume changes  are measured in terms  of  pressure change
     secondary to gas  compression  (inside the  chamber, outside the  body).  In
     type b, the  body  chambers  serve essentially  as  conduits between the body
     surface and devices (spirometers or integrating flowmeters) which measure
     gas  displacements.  Type  c combines  a and b by appropriate summing of
     chamber pressure and volume displacements.

Pneumotachograph:   A device for measuring instantaneous  gas flow rates in
     breathing by recording  the pressure  drop across a fixed flow resistance
     of  known  pressure-flow characteristics, commonly connected  to  the airway
     by  means  of  a  mouthpiece, face mask, or  cannula.   The flow resistance
     usually consists  either of parallel  capillary tubes  (Fleisch type)  or of
     fine-meshed screen (Silverman-Lilly type).

Pulmonary alveolar  proteinosis:  A  chronic or  recurrent disease  characterized
     by  the  filling of alveoli with an insoluble exudate,  usually poor in
     cells, rich in lipids and proteins,  and accompanied by minimal  histologic
     alteration of  the alveolar walls.

Pulmonary edema:  An  accumulation  of excessive amounts of  fluid  in the  lung
     extravascular  tissue and air spaces.

Pulmonary emphysema:   An abnormal enlargement  of  the air  spaces  distal to the
     terminal nonrespiratory bronchiole,  accompanied by destructive changes of
     the  alveolar walls.   The  term emphysema  may be  modified by words  or
     phrases to indicate its etiology,  its anatomic subtype, or any associated
     airways dysfunction.

Residual volume (RV):  That volume of air remaining in the lungs after maximal
     exhalation.   The  method of measurement  should  be indicated  in the  text
     or, when necessary, by appropriate qualifying symbols.

Resistance flow  (R):   The  ratio of the flow-resistive components of pressure
     to simultaneous flow,  in cm HpO/liter per sec.  Flow-resistive components
     of pressure are obtained by subtracting any elastic or inertia! components,
     proportional respectively  to volume  and  volume acceleration.  Most flow
     resistances  in the  respiratory system are nonlinear,  varying  with  the
     magnitude and  direction of flow, with lung volume and lung volume history,
     and possibly with volume acceleration.  Accordingly,  careful specification
     of  the  conditions of  measurement is  necessary;  see  AIRWAY  RESISTANCE,
     TISSUE RESISTANCE,  TOTAL  PULMONARY  RESISTANCE,  COLLATERAL  RESISTANCE.
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Respiratory cycle:   A respiratory cycle  is  constituted  by the inspiration
     followed by the expiration of a given volume of gas,  called tidal  volume.
     The duration of  the  respiratory cycle is the respiratory or ventilatory
     period, whose reciprocal  is the ventilatory frequency.

Respiratory exchange ratio:   See RESPIRATORY QUOTIENT.

Respiratory frequency (fn):  The number of breathing cycles per unit of time.
     Synonymous with breathing frequency (fg).

Respiratory quotient  (RQ, R):  Quotient of the volume of (XL produced divided
     by the volume of 02 consumed by an organism, an organ, or a tissue during
     a given period of "time.   Respiratory quotients are measured by comparing
     the composition of an incoming and an outgoing medium, e.g.,  inspired and
     expired gas, inspired gas and alveolar gas,  or arterial  and venous blood.
     Sometimes the phrase  "respiratory exchange  ratio"  is used to designate
     the ratio  of C0? output  to  the 0? uptake  by  the  lungs,  "respiratory
     quotient" being ^restricted to the actual metabolic  C(L  output and 02
     uptake by the  tissues.   With this definition, respirarory quotient and
     respiratory exchange ratio are identical in the steady state,  a condition
     which implies constancy of the 02 and C0« stores.

Shunt:  Vascular  connection between  circulatory  pathways so that venous blood
     is diverted  into vessels containing  arterialized  blood  (right-to-left
     shunt, venous admixture)  or vice  versa  (left-to-right shunt).  Right-to-
     left  shunt within the  lung, heart, or large  vessels due to malformations
     are more  important  in  respiratory physiology.  Flow  from  left to right
     through a shunt should be marked with a negative sign.

Specific airway conductance  (SGaw):   Airway conductance divided by the lung
     volume at  which  it was measured,  i.e.,  normalized  airway conductance.
     SGaw = Gaw/TGV.

Specific airway resistance (SRaw):  Airway resistance multiplied by the volume at
     which it was measured.  SRaw = Raw x TGV.

Spirograph:  Mechanical  device,  including  bellows or other scaled, moving
     part, which  collects  and  stores gases and provides a  graphical record of
     volume changes.  See BREATHING PATTERN, RESPIRATORY CYCLE.

Spirometer:  An apparatus similar to a spirograph but without recording facil-
     ity.

Static lung compliance (C,  t):  Lung compliance measured at zero flow (breath-
     holding) over linear portion of the volume-pressure curve above FRC.   See
     COMPLIANCE.

Static transpulmonary pressure (P,f):   Transpulmonary pressure measured at a
     specified lung volume; e.g., rstTLC is static recoil pressure measured at
     TLC (maximum recoil pressure).

Sulfur dioxide (S0?):  Colorless gas with pungent odor, released primarily from
     burning of fossil fuels,  such as  coal, containing sulfur.
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STPD conditions  (STPD):   Standard temperature and pressure,  dry.   These  are
     the conditions  of  a volume of gas  at  0°C,  at 760 torr, without water
     vapor.  A  STPD  volume  of  a given  gas contains a  known  number  of moles of
     that gas.

Surfactant,  pulmonary:   Protein-phospholipid (mainly  dipalmitoyl  lecithin)
     complex which lines alveoli (and possibly small  airways) and accounts for
     the low surface tension which makes air space (and airway) patency possible
     at low transpulmonary pressures.

Synergism:    A  relationship  in  which the combined  action  or effect  of two or
     more components  is  greater than  the sum of effects  when the  components
     act separately.

Thoracic gas volume  (TGV):   Volume of communicating  and  trapped gas  in the
     lungs  measured  by  body plethysmography at  specific lung volumes.   In
     normal  subjects, TGV  determined  at end expiratory  level corresponds to
     FRC.

Tidal volume (TV):   That volume of air  inhaled  or exhaled with each breath
     during  quiet  breathing,   used  only to  indicate  a subdivision of lung
     volume.   When  tidal volume is used in gas  exchange formulations, the
     symbol V-r should be used.

Tissue resistance (R+,-):   Frictional resistance of the pulmonary and thoracic
     tissues.
                                                      2
Torr:  A unit  of pressure equal to 1,333.22 dynes/cm   or 1.33322  millibars.
     The torr is equal to the pressure required to support a column of mercury
     1 mm high when the mercury is of standard density and subjected to standard
     acceleration.   These standard conditions are met at 0°C and 45° latitude,
     where the acceleration of gravity is 980.6 cm/sec .  In reading a mercury
     barometer at other temperatures and latitudes, corrections, which commonly
     exceed  2  torr,  must be introduced  for  these  terms and for the thermal
     expansion  of  the measuring  scale used.  The torr  is  synonymous  with
     pressure unit mm Hg.

Total lung  capacity  (TLC):   The sum of all  volume compartments or the volume
     of air in the lungs after maximal  inspiration.  The method of measurement
     should be indicated, as with RV.

Total pulmonary resistance (R,):  Resistance measured by relating flow-dependent
     transpulmonary pressure TO airflow at  the mouth.   Represents  the total
     (frictional) resistance of the lung tissue (R+.-) and the airways (Raw).
     RL = "aw + Rti'
Trachea:   Commonly known  as the windpipe; a cartilaginous air tube extending
     from the larynx (voice box) into the thorax (chest) where it divides into
     left and right branches.
019CC/C                            A-11                          May 1984

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Transpulmonary pressure  (P.):   Pressure  difference  between airway opening
     (mouth, nares, or  canrrula  opening)  and the visceral  pleura!  surface, in
     cm H20.  Transpulmonary in the sense used  includes extrapulmonary struc-
     tures, e.g.,  trachea and extrathoracic  airways.   This usage has come
     about for want of  an anatomic term which includes all  of the airways and
     the lungs together.

Ventilation:  Physiological  process by which gas is renewed in the lungs.   The
     word ventilation sometimes designates ventilatory flow rate  (or ventila-
     tory minute  volume) which is the  product  of the tidal  volume  by the
     ventilatory frequency.   Conditions are  usually  indicated as modifiers;
     i.e.,

               Vr- = Expired volume per minute (BTPS),
               ^   and
               Vr = Inspired volume per minute (BTPS).

     Ventilation is often referred to as "total  ventilation" to distinguish it
     from ''alveolar ventilation" (see VENTILATION, ALVEOLAR).

Ventilation, alveolar (V*):  Physiological  process by which  alveolar gas is
     completely removed  and replaced with fresh gas.  Alveolar ventilation is
     less than total ventilation because when a tidal volume of gas leaves the
     alveolar spaces, the last  part  does not get  expelled  from the body  but
     occupies the  dead  space,  to be  reinspired with the next inspiration.
     Thus the volume of alveolar gas actually expelled completely is equal to
     the tidal volume minus  the volume of the dead space.   This truly complete
     expiration volume times the ventilatory frequency constitutes the alveolar
     ventilation.

Ventilation, dead-space  (VQ):  Ventilation per  minute of  the  physiologic  dead
     space  (wasted  ventilation),  BTPS, defined by the following equation:

          VD = VE(PaC02 - PEC02)/(PaC02 - PjC02)

Ventilation/perfusion ratio (V./O):  Ratio of the  alveolar  ventilation to the
     blood perfusion volume flow through the pulmonary parenchyma.  This ratio
     is a  fundamental determinant  of the Op and COp pressure of the alveolar
     gas  and  of the  end-capillary  blood.  Throughout the  lungs  the local
     ventilation/perfusion ratios vary, and  consequently the local alveolar
     gas and end-capillary blood compositions also vary.

Vital capacity  (VC):  The maximum volume of  air  exhaled  from the point  of
     maximum inspiration.
              US E-wlronmenta! Protection Agency
                                n  Street

                              606M
019CC/C                            A-12                          May 1984

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