Mo-o' 

United States Environmental Criteria and EPA/600/8-84/020eF 

Environmental Protection Assessment Office August 1986 

Agency Research Triangle Park, NC 27711 

Research and 

Air Quality 

Criteria • 

Ozont&-;% . i Othe 

Photochemical 

• t` 

>".0'000 

EPA/600/8-84/020eF 

August 1986, 

Air Quality Criteria 

for Ozone and Other 

Phot®chernical Oxidants 

VolurneVofV 

Environmental Criteria and Assessment Office 

Office of Health and Environmentai Assessment 

Office of Research and Development 

U.S. Environmental Protection Agency 

Research Triangle Park, N.C. 27711 
DISCLAIMER 

This document has been reviewed in accordance with U.S. Environmental 

Protection Agency policy and approved for publication. Mention of trade 

names or commercial products does not constitute endorsement or recommendation 

for use. 

ii 
ABSTRACT 

Scientific information is presented and evaluated relative to the health 

and welfare effects associated with exposure to ozone and other photochemical 

oxidants. Although it is not intended as a complete and detailed literature 

review, the document covers pertinent literature through early 1986. 

Data on health and welfare effects are emphasized, but additional information is provided for understanding the nature of the oxidant pollution problem and for evaluating the reliability of effects data as well as their 

relevance to potential exposures to ozone and other oxidants at concentrations 

occurring in ambient air. Information is provided on the following exposurerelated topics: nature, source, measurement, and concentrations of precurssors 

to ozone and other photochemical oxidants; the formation of ozone and other 

photochemical oxidants and their transport once formed; the properties, 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 epidemiological 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. 

i7i 
AIR QUALITY CRITERIA FOR OZONE 

AND OTHER PHOTOCHEMICAL OXIDANTS 

Pa e 

VOLUME I 

Chapter 1. Summary and Conclusions ..................... ...... 1-1 

VOLUME II 

Chapter 2. Introduction ... ............. ....... ... ....... 2-1 

Chapter 3. Properties, Chemistry, and Transport of Ozone ~>and 

Other Photochemical Oxidants and Their Precursors .... 3-1 

Chapter 4. Sampling and Measurement of Ozone and Other 

Photochemical Oxidants and Their Precursors .%:........ 4-1 

Chapter 5. Concentrations of Ozone and Other Photochemical 

Oxidants in Ambient Air .............................. 5-1 

VOLUME III 

Chapter 6. Effects of Ozone and Other Photochemical Oxidarits 

on Vegetation ........................................ 6=1 

Chapter 7. Effects of Ozone on Natural Ecosystems and Their 

Components .................... ... ... ........... 7-1 

Chapter 8. Effects bf Ozone and Other Photochemical Oxidants 

on Nonbiological'Materials ........................... 8-1 

VOLUME IV 

Chapter 9. Toxicological Effects of Ozone and Other 

Photochemical Oxidants .................. ........... 9-1 

VOLUME V 

Chapter 10. Controlled Human Studies of the Effects of Ozone 

and Other Photochemical Oxidants ..... ... .......... 10-1 

Chapter 11. Field and Epidemiological Studies of the Effects 

of Ozone and Other Photochemical Oxidants ......:..... 11-1 

Chapter 12. Evaluation of Health Effects Data for Ozone and 

Other Photochemical Oxidants ......................... 12-1 

iv 
TABLE OF CONTENTS 

Pa e 

LIST OF TABLES ......................................................... viii 

LIST OF FIGURES ........................... . ............................. x 

LIST OF ABBREVIATIONS .................................................. xii 

AUTHORS, CONTRIBUTORS, AND REVIEWERS ............... . ................... xvii. 

10. CONTROLLED,HUMAN STUDIES OF THE EFFECTS OF OZONE AND 

OTHER PHOTOCHEMICAL OXIDANTS ............................... ..... 10-1 

10.1 INTRODUCTION ................................ .............. 10-1 

10.2 ACUTE PULMONARY EFFECTS.OF OZONE ............................ 10=6 

10.2.1 ~ Introduction ......................................... 10-6 

10.2.2 At-Rest Exposures ................................... 10-7 

10.2.3 Exposures with Exercise .................. . .......... 10-7 

10.2.4 Intersubject Variability and Reproducibility of 

Responses .... 4 .... ....... .............:.........., 10-22 

10.2.5 Prediction of Acute.Pulmonary Effects ............... 10-25 

10.2.6 ;Bronchial Reactivity ........f ....... ............ 10-28 

10.2.7 Mechanisms of Acute PulmonaryEffects ............... 10-30 

10.2.8 ..Preexisting Disease ................................. 10-32 

10.2.9 Other Factors Affecting Pulmonary Responses to 

Ozone ..... ........... ........................... 10-38 

10.2.9.1 Cigarette Smoking ......................... 10-38 

10.2.9.2 Age and Sex Differences .... ... ........ . 10-41 

10.2.9.3 Environmental Conditions .. .............. 10-44 

10.2.9.4 Vitamin E Su p lementation . ~ ...... 

PULMONARY EFFECTS FOLLOWING RE~ tATED EXPOSURE TO OZONE ...... 

10-45 

10.3 10- 47 

10.4 EFFECTS OF OZONE ON VIGILANCE AND EXERCISE PERFORMANCE ...... 10-60 

10.5 INTERACTIONS BETWEEN OZONE.AND OTHER POLLUTANTS ............. 10-65 

10.5.1 Ozone Plus Sulfates or Sulfuric Acid................. 10-65 

10.5.2 Ozone and Carbon Monoxide ......... ................ 10-74 

10.5.3 .Ozone and Nitrogen Dioxide ....,.................... 10-74 

10.5.4 Ozone and Other Mixed Pollutants ~.......... . .......... 10-76 

10.6 EXTRAPULMONARY EFFECTS OF OZONE ............................. 10-77 

10.7 PEROXYACETYL NITRATE ........................................ 10-84 

10.8 SUMMARY ................................. 10-87 

10.9 REFERENCES ...............:..........:....................... 10-97 

11. FIELD AND EPIDEMIOLOGICAL STUDIES OF THE EFFECTS OF OZONE 

AND OTHER PHOTOCHECMICAL OXIDANTS ....................:............ 11-1 

11.1 INTRODUCTION .. . . . ........ . .......... . ......... 11-1' 

11.2 FIELD STUDIES OF EFFECTS OF ACUTE EXPOSURE TO OZONE 

AND OTHER PHOTOCHEMICAL OXIDANTS ............................ 11-2 

11.2.1 Symptoms and Pulmonary Function in Field 

Studies of Ambient Air Exposures .................... 11-3 

11.2.2 Symptoms and Pulmonary Function in Field or 

Simulated High-Altitude Studies ..................... 11-12 

11.3 EPIDEMIOLOGICAL STUDIES OF EFFECTS OF ACUTE EXPOSURE ........ 11-13 

11.3.1 Acute Exposure Morbidity Effects .................... 11-13 

v 
TABLE OF CONTENTS (continued) 

Pa e 

11.3.1.1 Symptom Aggravation in Healthy 

Populations ............................... 11-13 

11.3.1.2 Altered Performance ....................... 11-14 

11.3.1.3 Acute Effects on Pulmonary Function ....... 11-14 

11.3.1.4 Aggravation of Existing Respiratory 

Diseases .................................. 11-24 

11.3.1.5 Incidence of Acute Respiratory Illness .... 11-34 

11.3.1.6 Physician, Emergency Room, and Hospital 

Visits .................................... 11-34 

11.3.1.7 Occupational Studies ...................... 11-40 

11.3.2 Trends in Mortality ................................. 11-40 

11.4 EPIDEMIOLOGICAL STUDIES OF EFFECTS OF CHRONIC EXPOSURE ...... 11-40 

11.4.1 Pulmonary Function and Chronic Lung Disease ......... 11-44 

11.4.2 Chromosomal Effects .................................. 11-48 

11.4.3 Chronic Disease Mortality ........................... 11-49 

11.5 SUMMARY AND CONCLUSIONS ..................................... 11-49 

11.6 REFERENCES .................................................. 11-55 

12. EVALUATION OF HEALTH EFFECTS DATA FOR OZONE AND OTHER 

PHOTOCHEMICAL OXIDANTS ............................................ 12-1 

12.1 INTRODUCTION ................................................ 12-1 

12.2 EXPOSURE ASPECTS ............... ................ .......... 12-5 

12.2.1 Potential Expbsures to Ozone ........................ 12-5 

12.2.2 Potential Exposures to Other Photochemical 

Oxidants ........... ................................ 12-11 

12.2.2.1 Concentrations ............................ 12-11 

12.2.2.2 Patterns ......................... ........ 12-14 

12.2.3 Potential Combined Exposures and Relationship of 

Ozone and Other Photochemical Oxidants .............. 12-14 

12.3 HEALTH EFFECTS IN THE GENERAL HUMAN POPULATION .............. 12-17 

12.3.1 Clinical Symptoms ................................... 12-17 

12.3.2 Pulmonary Function at Rest and with Exercise and 

Other Stresses ...................................... 12-19 

12.3.2.1 At-Rest Exposures ......................... 12-19 

12.3.2.2 Exposures with Exercise ................... 12-21 

12.3.2.3 Environmental Stresses .................... 12-35 

12.3.3 Other Factors Affecting Pulmonary Response to 

Ozone............................................... 12-35 

12.3.3.1 Age ........................................ 12-35 

12.3.3.2 Sex .... ............................... 12-36 

12.3.3.3 Smoking Status ............................ 12-37 

12.3.3.4 Nutritional Status ........................ 12-37 

12.3.3.5 Red Blood Cell Enzyme Deficiencies ........ 12-39 

12.3.4 Effects of Repeated Exposure to Ozone ............... 12-40 

12.3.4.1 Introduction .............................. 12-40 

12.3.4.2 Development'of Altered Responsiveness to 

Ozone ..................................... 12-40 

vi 
12.4 

12.5 

12.6 

12.7 

12.8 

12.9 

TABLE OF CONTENTS (continued) 

Page 

12.3.4.3 Conclusions Relative to Attenuation with 

Repeated Exposures ........................ 12-41 

12.3.5 Mechanisms of Responsiveness to Ozone ............... 12-42 

12.3.6 Relationship Between Acute and Chronic Ozone 

Effects ............................................. 12-45 

12.3.7 Resistance to Infection ............................. 12-49 

12.3.8 Extrapulmonary Effects of Ozone ..................... 12-50 

IN INDIVIDUALS WITH PREEXISTING DISEASE ...... 12-53 

12.4.1 

HEALTH_EFFECTS 

Patients with Chronic Obstructive Lung Disease 

(COLD) .............. ...... ....................... 12-53 

12.4.2 Asthmatics................................ ..... ... . 12-54 

12.4.3. Subjects with Allergy, Atopy, and Ozone-Induced 

Hyperreactivity ..................................... 12-56 

EXTRAPOLATION OF EFFECTS OBSERVED IN ANIMALS TO HUMAN 

POPULATIONS ......................... ..................... 12-57 

12.5.1 Species Comparisons ................................. 12-57 

12.5.2 Dosimetry Modeling .................................. 12-63 

HEALTH EFFECTS OF OTHER PHOTOCHEMICAL OXIDANTS AND POLLUTANT 

MIXTURES .............................................. .... 12-65 

12.6.1 Effects of Peroxyacetyl Nitrate ..................... 12-65 

12.6.2 Effects of Hydrogen Peroxide ........................ 12-66 

12.6.3 Interactions with Other Pollutants .................. 12-67 

IDENTIFICATION OF POTENTIALLY AT-RISK GROUPS ................ 12-69 

12.7.1 Introduction ........................................ 12-69 

12.7.2 -Potentially At-Risk Individuals ..................... 12-69 

12.7.3 Potentially At-Risk Groups .......................... 12-72 

12.7.4 Demographic Distribution of the*General 

Population .......................................... 12-75 

12.7.5 Demographic Distribution of Individuals with Chronic 

Respiratory Conditions .............................. 12-76 

SUMMARY AND CONCLUSIONS ..................................... 12-78 

12.8.1 Health Effects in the General Human Population ... . 12-78 

12.8.2 Health Effects in Individuals with Preexisting 

Disease ............................................. 12-86 

12.8.3 Extrapolation of Effects Observed in Animals to 

Human Populations .................................... 12-86 

12.8.4 Health Effects of Other Photochemical Oxidants and 

Pollutant Mixtures .................................. 12-87 

12.8.5 Identification of Potentially At-Risk Groups ........ 12-88 

REFERENCES .................................................. 12-90 

APPENDIXA .................................................. A-1 

vii 
LIST OF TABLES 

Table Page 

10-1 Human experimental exposure to ozone up to 1978 .............. 10-2 

10-2 Studies on acute pulmonary effects of ozone since 1978 ....... 10-8 

10-3 Estimated values of oxygen consumption and minute 

ventilation associated with representative types of 

exercise ...... .. ........... .. ......................... ... - s .... 10-14 

10-4 Ozone exposure in subjects with pulmonary disease ............ 10-33 

10-5 Changes in lung function after repeated daily exposure : 

to ambient ozone ..................................... ... ..... 10-48 

10-6 Effects of ozone on exercise performance ..................... 10-64 

10-7 Interactions between ozone and other pollutants .............. 10-66 

10-8 Human extrapulmonary effects of ozone exposure ............... 10-78 

10-9 Acute human exposure to peroxyacetyl nitrate ................. 10-85 

10-10 Summary table: controlled human exposure to ozone ........... 10-88 

11-1 Subject characteristics and experimental conditions in 

the mobile laboratory studies ...............'................. 11-4 

11-2 Symptom aggravation in healtfi populations exposed to 

photochemical oxidant pollution .......................... .. 11-15 

11-3 Altered performance associated with exposure to photochemical 

oxidant pollution ........ ...... .......... ............... 11-17 

11-4 Acute effects of photochemical oxidant pollution on pulmonary 

function of children and adults ..... .................. ... 11-18 

11-5 Aggravation of existing respiratory diseases by photochemical 

oxidant pollution ..... ......... ............................ 11-25 

11-6 Incidence of acute respiratory illness associated with 

photochemical oxidant pollution .............................. 11-35 

11-7 Hospital admissions in relation to photochemical 

oxidant pollution .....:...................................... 11-36 

11-8 Acute effects from occupational exposure to photochemical 

oxidants ... ...... ...... .............. ........ ....... 11-41 

11-9 Daily mortality associated with exposure to photochemical 

oxidant poliution ............................................ 11-43 

11-10 Pulmonary function effects associated with chronic 

photochemical oxidant exposure ............................... 11-45 

11-11 Summary table: acute effects of ozone and other photochemical oxidants in field studies with a mobile laboratory .. 11-51 

12-1 Number of times the daily maximum 1-hr ozone concentration 

was >0.06, >0.12, >0.18, and >0.24 ppm for specified 

consecutive days in Pasadena, Dallas, and Washington, 

April through September, 1979 through 1981 ................... 12-9 

12-2 Relationship of ozone and peroxyacetyl nitrate at urban 

and suburban sites in the United States in reports 

published 1978 or later ..... ....................... ....... 12-16 

12-3 Effects of intermittent exercise and ozone concentration on 

1-sec forced expiratory volume during 2-hr exposures ......... 12-29 

12-4 Comparison of the acute effects of ozone on breathing 

patterns in animals and man .................................. 12-60 

viii 
LIST OF TABLES (continued) 

Table Page 

12-5 Comparison of the acute effects of ozone on airway 

reactivity in animals and man ................................ 12-61 

12-6 Geographical distribution of the resident population of, 

the United States, 1980 ............ ........................ 12-77 

12-7 Total population of the United States by age, sex, and 

race, 1980 ........ ......................................... 12-78 

12-8 Prevalence of chronic respiratory conditions ,by sex and 

age for 1979 ................................................. 12-79 

ix 
LIST OF FIGURES 

Figure 

10-1 Change in forced vital capacity (FVC), forced expiratory 

volume in 1-sec (FEV l . o ), and maximal mid-expiratory flow 

(FEF25-75%) during exposure to filtered air or ozone 

(0.5 ppm) for 2 hr. Exercise at 45% maximal aerobic 

capacity (max V0 2 ) was performed for 30 min by Group A 

after 60 min of ozone exposure and by Group B after 

30 min of ozone exposure ........................................ 

10-2 Frequency distributions of response (percent change from 

baseline) in specific airway resistance (SR ) and forced 

expiratory volume in 1-sec (FEV l . o ) for indfViduals exposed 

to six levels of ozone. One individual with 260% increase 

in SR exposed to 0.4 ppm ozone is not graphed ................. 

10-3 ForceOwexpiratory volume in 1-sec (FEV l . o ) in two groups 

of subjects exposed to (A) 0.35 ppm ozone, and (B) 

0.50 ppm ozone, for 3 successive days. Numbers on the 

abscissa represent successive half-hour periods of 

exposure........................................................ 

10-4 Percent change (pre-post) in 1-sec forced expiratory 

volume (FEV i . o ), as the result of a 2-hr exposure to 

0.42 ppm ozone. Subjects were exposed to filtered air, 

to ozone for five consecutive days, and exposed to 

ozone again: (A) 1 week later; (B) 2 weeks later; and 

(C) 3 weeks later ............................................... 

11-1 Changes in mean symptom score with exposure for all 

subjects, for normal and allergic subjects, and for 

asthmatic subjects .............. ............................... 

11-2 Changes in group mean responses, including FEV l . o , symptoms, 

and exercise performance in 50 competitive cyclists exercising 

continuously for 1 hr while exposed to ozone .................... 

12-1 Distributions of the three highest 1-hr ozone concentrations 

at valid sites (906 station-years) aggregated for 3 years 

(1979, 1980, and 1981) and the highest ozone concentrations 

at NAPBN sites aggregated for those years (24 station-years) ... 

12-2 The effects of ozone concentration on 1-sec forced expiratory 

volume during 2-hr exposures with light intermittent 

exercise. Quadratic fit of group mean data, weighted by 

sample size, was used to plot a concentration-response 

curve with 95 percent confidence limits ........................ 

12-3 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 ........................ 

Pa e 

10-16 

10-23 

10-52 

10-54 

11-7 

11-10 

12-7 

12-25 

12-26 

x 
LIST OF FIGURES (continued) 

Figure Page 

12-4 The effects of ozone concentration on 1-sec forced expiratory 

volume during 2-hr exposures with heavy intermittent exercise. 

Quadratic fit of group mean data, weighted by sample size, 

was used to plot a concentration-response curve with 

95 percent confidence limits .................................... 12-27 

12-5 The effects of ozone concentration on 1-sec forced expiratory 

volume during 2-hr exposures with very heavy intermittent 

exercise. r°.Quadratic fit of group mean data, weighted by 

sample size, was used to plot a concentration-response 

curve with 95 percent confidence limits ......................... 12-28 

12-6 Group mean decrements in 1-sec forced expiratory volume 

during 2-hr ozone exposures with different levels of 

intermittent exercise: light (V < 23 L/min); moderate 

(V = 24-43 L/min); heavy (V E _44-63 L/min); and very 

he6y (VE > 64 L/min) ........................................... 12-81 

xi . 
11 

LIST OF ABBREVIATIONS 

ACh Acetylcholine 

AM Alveolar macrophage 

ANOVA Analysis of variance 

AOD Airway obstructive disease 

ATPS ATPS condition (ambient temperature and pressure, saturated 

with water vapor) 

BTPS BTPS conditions (body temperature, barometric press.ure, 

and saturated with water vapor) 

CC Closing capacity 

Cdyn Dynamic lung compliance 

CE Continuous exercise 

CHEM Gas-phase chemiluminescence 

CHESS Community Health Environmental Surveillance System 

C L Lung compliance 

CLst Static lung compliance 

CNS Central nervous system 

CO Carbon monoxide 

COHb Carboxyhemoglobin 

COLD Chronic obstructive lung disease 

COPD Chronic obstructive pulmonary disease 

CO2 Carbon dioxide 

CV Closing volume 

D L Diffusing capacity of the lungs 

DLCO Carbon monoxide diffusing,capacity of the lungs 

E Elastance 

ECG, EKG Electrocardiogram 

EEG Electroencephalogram 

EPA U.S. Environmental Protection Agency 

ERV Expiratory reserve volume 

FEFinax Maximal forced expiratory flow.achieved 

during an FVC test 

FEF Forced expiratory flow 

xii 
LIST OF ABBREVIATIONS.(con.tinued) 

FEF 200-1200 Mean forced expiratory flow between 200 ml and 1200 ml o"f 

the FVC [formerly called the maximum expiratory flow rate 

(MEFR)] 

FEF25-75% Mean forced expiratory flow during the middle half of the 

FVC [formerly called the maximum mid-expiratory flow rate 

(MMFR)] 

FEF750% Instantaneous forced expiratory flow after 757o of the FVC 

has been exhaled 

FEV Forced expiratory volume 

FEV1 Forced expiratory volume in 1 sec : 

FEVt/FVC A ratio of timed forced expiratory volume (FEV t ) 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 

H02 • Hydroperoxy radical 

IC Inspiratory capacity 

IE Intermittent exercise 

IRV Inspiratory reserve"volume 

IVC Inspiratory vital capacity 

LDH Lactate deyhydrogenase 

LD 50 Lethal dose (50 percent) 

LM Light microscopy' 

MAST KI-coulometric (Mast meter) 

xiii 
LIST OF ABBREVIATIONS (continued) 

6 

max VE Maximum ventilation 

max V02 Maximal aerobic capacity 

MBC Maximum breathing capacity 

MEFR Maximum expiratory flow rate 

MetHb Methemoglobin 

MMAD Mass median aerodynamic diameter 

MMFR or MMEF Maximum mid-expiratory flow rate 

MVV Maximum voluntary ventilation 

NBKI Neutral buff.ered potassium iodide 

(NH4 ) 2SO4 Ammonium sulfate 

NO2 Nitrogen dioxide 

AN2 , dN2 Nitrogen washout 

O2 Oxygen 

02- Oxygen radical 

03 Ozone 

P(A-a)02 Alveolar-arterial oxygen pressure difference 

PABA para-aminobenzoic acid 

PACO2 Alveolar partial pressure of carbon dioxide 

PaCO2 

~ 

Arterial partial pressure of carbon dioxide 

PAN Peroxyacetyl nitrate 

PA02 Alveolar partial pressure of oxygen 

Pa02 Arterial partial pressure of oxygen 

PBzN Peroxybenzoyl nitrate 

PEF Peak expiratory flow 

PEFV Partial expiratory flow-volume curve 

PG Prostaglandin 

pHa Arterial pH 

P L Transpulmonary pressure 

PMN Polymorphonuclear leukocyte 

P st Static transpulmonary pressure 

PUFA Polyunsaturated fatty acid 

R Resistance to flow 

xiv 
LIST OF ABBREVIATIONS (continued) 

Raw Airway resistance 

RBC Red blood cell 

Rcoll Collateral resistance 

rh Relative humidity 

R L Total pulmonary resistance 

RQ, R Respiratory quotient 

Rt Respiratory resistance 

Rti Tissue resistance 

RV Residual volume 

Sa0 2 Arterial oxygen saturation 

SBNT Single-breath nitrogen test 

SBP Systolic blood pressure 

SCE Sister chromatid exchange 

Se Selenium 

SEM Scanning electron microscopy 

SGaw Specific airway conductance 

SN Sulfhydryls 

SOD Superoxide dismutase 

S02 Sulfur dioxide 

SO4 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 

VA Alveolar ventilation 

1/A/0 Ventilation/perfusion ratio 

UC Vital capacity 

xv 
LIST OF ABBREVIATIONS (continued) 

iCO2 

VD 

1/D 

VD anat 

VE 

V I 

VL 

Vmax 

V02 

V02 , Q02 

Carbon dioxide production 

Physiological, dead space 

Dead-space ventilation 

Anatomical dead space 

Minute ventilation; expired.volume per minute 

Inspired volume per minute 

Lung volume 

Maximum expiratory flow 

Oxygen uptake 

Oxygen consumption 

MEASUREMENT ABBREVIATIONS 

g 

hr/day 

kg 

kg-m/min 

L/min 

L/s 

ppm 

mg/kg 

mg/m3 

min 

ml 

mm 

N9/m

3 

pm 

NM 

sec 

gram 

hours per day 

kilogram 

kilogram-meter/min 

liters/min 

liters/sec 

parts per million 

milligrams per kilogram 

milligrams per cubic meter 

minute 

milliliter 

millimeter 

micrograms per cubic meter 

micrometer 

micromole 

second 

xvi 
AUTHORS, CONTRIBUTORS, AND REVIEWERS 

Chapter 10: Controlled Human Studies of the Effects of Ozone 

and Other Photochemical Oxidants 

PrinciAal 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 additional persons reviewed Chapter 10 at the request of the U.S. Environmental 

Protection Agency. The evaluations and conclusions contained herein, however, 

are not necessarily those of the reviewers. 

Dr. Karim Ahmed 

Natural Resources Defense Council 

122 East 42nd Street 

New York, NY 10168 

Dr. David V. Bates 

Department of Medicine 

St. Paul's Hospital 

University of British Columbia 

Vancouver, British Columbia 

Canada.V6Z1Y6 

Dr. Philip A. Bromberg 

Department of Medicine 

School of Medicine 

University of North Carolina 

Chapel Hill, NC 27514 

Dr. George L. Carlo 

Dow Chemical, U.S.A. 

1803 Building, U.S. Medical 

Midland, MI 48640 

xvii 
Dr. Lawrence J. Folinsbee 

Combustion Engineering 

800 Eastowne Rd., Suite 200 

Chapel Hill, NC 27514 

Dr. Robert Frank 

Department of Environmental 

Health Sciences 

Johns Hopkins School of Hygiene 

and Public Health 

615 N. Wolfe Street 

Baltimore, MD 21205 

Dr. Judith A. Graham 

Health Effects Research Laboratory 

MD-51 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 27711 

Dr. Jack D. Hackney 

Rancho Los Amigos Hospital 

7601 East Imperial Highway 

Downey, CA 90242 

Dr. Milan J. Hazucha 

School of Medicine 

Center for Environmental Health 

and Medical Sciences 

University of North Carolina 

Chapel Hill, NC 27514 

Dr. Thomas J. Kulle 

Department of Medicine 

School of Medicine 

University of Maryland 

Baitimore, 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 , 

Xviii 
Dr. Harold A. Menkes 

Department of Environmental 

Health Sciences 

Johns Hopkins School of Hygiene 

and Public Health 

615 N. Wolfe Street 

Baltimore, MD 21205 

Dr. Walter S. Tyler 

Department of Anatomy 

School of Veterinary Medicine 

University of California 

Davis, CA 95616 

Chapter 11: Field and Epidemiological Studies of the Effects of Ozone 

and Other Photochemical Oxidants 

Contributing Authors 

Dr. David V. Bates 

Department of Medicine 

St. Paul's Hospital 

University of British Columbia 

Vancouver, British Columbia 

Canada V6Z1Y6 

Dr. Robert S. Chapman 

Health Effects Research Laboratory 

MD-58 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 27711 

Dr. Benjamin G. Ferris 

Schooi 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 Triangie Park, NC 27711 

Mr. James R. Kawecki 

TRC Environmental Consultants, Inc. 

2001 Wisconsin Avenue, N.W. 

Suite 261 

Washington, DC 20007 

xix 
Dr. Michael D. Lebowitz 

Department of Internal Medicine 

College of Medicine 

University of Arizona 

Tucson, AZ 85724 

Mr. James A. Raub 

Environmental Criteria and 

Assessment Office 

MD-52 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 27711 

Ms. Beverly E. Tilton 

Environmental Criteria and 

Assessment Office 

MD-52 

U.S. Environmenta1 Protection Agency 

Research Triangle Park, NC 27711 

Authors also reviewed individual sections of the chapter. The fol1owing additional persons reviewed Chapter 11 at the request of the U.S. Environmantal 

Protection Agency. The evaluations and conclusions contained herein, however, 

are not necessarily those of the reviewers. 

Dr. Karim Ahmed 

Natural Resources Defense Council 

122 East 42nd Street 

New York, NY 10168 

Dr. Patricia A. Buffler 

School of Public Health 

University of Texas 

P.O. Box 21086 

Houston, TX 77025 

Dr. George L. Carlo 

Dow Chemical, U.S.A. 

1803 Building, U.S. Medical 

Midland, MI 48640 

Dr. Robert Frank 

Department of Environmental 

Health Sciences 

Johns Hopkins School of Hygiene 

and Public Health 

615 N. Wolfe Street 

Baltimore, MD 21205 

xx 
Dr. Judith A. Graham 

Health Effects Research Laboratory 

MD-51 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 27711 

Dr. Jack D. Hackney 

Rancho Los Amigos Hospital 

7601 East Imperial Highway 

Downey, CA 90242 

Dr. Victor Hasselblad 

Center for Health Poiicy 

Duke University 

Box GM Duke Station 

Durham, NC 27706 

Dr. Milan J. Hazucha 

School of Medicine 

Center for Environmental Health 

and Medical Sciences 

University of North Caroiina 

Chapei Hi1l, 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 

School of Medicine 

University of Maryland 

Baltimore, MD 21201 

Dr. Lewis H. Kulier 

Department of Epidemiology 

Graduate School of Public Heaith 

University of Pittsburgh 

Pittsburgh, PA 15261 

Dr. Harold A. Menkes 

Department of Environmental 

Health Sciences 

Johns Hopkins School of Hygiene 

and Public Health 

615 N. Wolfe Street 

Baltimore, MD '21205 

Dr. Jonathan M. Samet 

Department of Medicine 

University of New Mexico Hospital 

Albuquerque, NM 87131 

xxi 
Dr. Jan A. J. Stolwijk 

Department of Epidemiology and 

Public Health 

School of Medicine 

Yale University 

New Haven, CT 06510 

Dr. Harry M. Walker 

H. M. Walker and Associates, Inc. 

Dickinson, TX 77539 

Chapter 12: Evaluation of Integrated Health Effects Data 

for Ozone and Other Photochemical Oxidants 

Contributing Authors 

Dr. Robert Frank 

Department of Environmental 

Health Sciences 

Johns Hopkins School of Hygiene 

and Public Health 

615 N. Wolfe Street 

Baltimore, 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-51 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 27711 

Dr. Milan J. Hazucha 

School of Medicine 

Center for Environmental Health 

and Medical Sciences 

University of North Carolina 

Chapel Hill, NC 27514 

Dr. Donald H. Horstman ` 

Health Effects Research Laboratory 

MD-58 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 27711 

xxii 
Dr. Michael D. Lebowitz 

Department of Internal Medicine 

College of Medicine 

University of Arizona 

Tucson, AZ 85724 

Dr. Daniel B. Menzel 

Laboratory of Environmentai Toxicology 

and Pharmacology 

Duke University Medical Center 

P.O. Box 3813 

Durham, NC 27710 

Dr. Frederick J. Miller 

Health Effects Research Laboratory 

MD-82 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 27711 

Mr. James A. Raub 

Environmental Criteria and 

Assessment Office 

MD-52 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 27711 

Ms. Beverly E. Tilton 

Environmental Criteria and 

Assessment Office 

MD-52 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 27711 

Dr. Walter S. Tyler 

Department of Anatomy 

School of Veterinary Medicine 

University of California, 

Davis, CA 95616 

Authors also reviewed individual sections of the chapter G. The following additional persons reviewed parts of 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. 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 Maryiand 

Baltimore, MD 21201 

xxiii 
SCIENCE ADVISORY BOARD 

CLEAN AIR SCIENTIFIC ADVISORY COMMITTEE 

The substance of this document was reviewed by the Clean Air Scientific 

Advisory Committee of the Science Advisory Board in public sessions. 

SUBCOMMITTEE ON OZONE 

Chairman 

Dr. Morton Lippmann 

Professor 

Department of Environmental Medicine 

New York University Medical Center 

Tuxedo, New York 10987 

Members 

Dr. Mary 0. Amdur 

Senior Research Scientist 

Energy Laboratory 

Massachusetts Institute of Technology 

Cambridge, Massachusetts 02139 

Dr. Eileen G. Brennan 

Professor 

Department of Plant Pathology 

Martin Hall, Room 213, Lipman Drive 

Cook College-NJAES 

Rutgers University 

New Brunswick, New Jersey 08903 

Dr. Edward D. Crandall 

Professor of Medicine 

School of Medicine 

Cornell University 

New York, New York 10021 

Dr. James D. Crapo 

Associate Professor of Medicine 

Chief, Division of Allergy, Critical 

Care and Respiratory Medicine 

Duke University Medical Center 

Durham, North Carolina 27710 

Dr. Robert Frank ° 

Professor of Environmental Health 

Sciences 

Johns Hopkins School of Hygiene 

and Public Health 

615 N. Wolfe Street 

Baltimore, Maryland 21205 

Professor A. Myrick Freeman II 

Department of Economics 

Bowdoin College 

Brunswick, Maine 04011 

Dr. Ronald J. Hall 

Senior Research Scientist and Leader 

Aquatic and Terrestrial Ecosystems 

Section 

Ontario Ministry of the Environment 

Dorset Research Center 

Dorset, Ontario 

Canada POA1E0 

Dr. Jay S. Jacobson 

Plant Physiologist 

Boyce Thompson Institute 

Tower Road 

Ithaca, New York 14853 

xxiv 
Dr. Warren B. Johnson 

Director, Atmospheric Science Center 

SRI International 

333 Ravenswood Avenue 

Menio Park, California 94025 

Dr. Jane Q. Koeni g 

Research Associate Professor 

Department of Environmental Health 

University of Washington 

Seattle, Washington 98195 

Dr. Paul Kotin 

Adjunct Professor of Pathology 

University of Colorado Medical School 

4505 S. Yosemite, #339 

Denver, Colorado 80237 

Dr. Timothy Larson 

Associate Professor 

Environmental Engineering and 

Science Program 

Department of Civil Engineering 

University of Washington 

Seattle, Washington 98195 

Professor M. Granger Morgan 

Head, Department of Engineering 

and Pubiic Policy 

Carnegie-Mellon University 

Pittsburgh, Pennsyivania 15253 

Dr. D. Warner North 

Principal 

Decision Focus Inc., Los Altos 

Office Center, Suite 200 

4984 E1 Camino Real 

Los Altos, California 94022 

Dr. Robert D. Rowe 

Vice President, Environmental and 

Resource Economics 

Energy and Resources Consultants, Inc. 

207 Canyon Boulevard 

Bouider, Colorado 80302 

Dr. George Taylor 

Environmental Sciences Division 

P.O. Box X 

Oak Ridge National Laboratory 

Oak Ridge, Tennessee 37831 

Dr. Michael Treshow 

Professor 

Department of Biology 

University of Utah 

Sa1t Lake City, Utah 84112 

Dr. Mark J. Utell 

Co-Director, Pulmonary Disease Unit 

Associate Professor of Medicine and 

Toxicology in Radiation Biology 

and Biophysics 

University of Rochester Medical 

Center 

Rochester, New York 14642 

Dr. James H. Ware 

Associate Professor 

Harvard School of Public Health 

Department of Biostatistics 

677 Huntington Avenue 

Boston, Massachusetts 02115 

Dr. Jerry Wesolowski 

Air and Industrial Hygiene Laboratory 

California Department of Health 

2151 Berkeley Way 

Berkeley, Caiifornia 94704 

Dr. James L. Whittenberger 

Director, University of California 

Southern Occupational Health Center 

Professor and Chair, Department of 

Community and Environmental Medicine 

California College of Medicine 

University of California - Irvine 

19772 MacArthur Boulevard 

Irvine, California 92717 

Dr. George T. Wolff 

Senior Staff Research Scientist 

General Motors Research Labs 

Environmental Science Qepartment 

Warren, Michigan 48090 

xxv 
PROJECT TEAM FOR DEVELOPMENT 

OF 

Air Quality Criteria for Ozone and Other Photochemical Oxidants 

Ms. Beverly E. Tilton, Project Manager 

and Coordinator for Chapters 1 through 5, Volumes I and Ir 

Environmental Criteria and Assessment Office (MD-52) 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 27711 

Mr. Norman E. Childs 

Environmental Criteria and Assessment Office (MD-52) 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 27711 

Dr. J.H.B. Garner 

Coordinator for Chapters 7 and 8, Volume III 

Environmental Criteria and Assessment Office (MD-52) 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 27711 

Mr. Thomas B. McMullen 

Environmental Criteria and Assessment Office (MD-52) 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 27711 

Mr. James A. Raub 

Coordinator for Chapters 9 through 12, Volumes IV and V 

Environmental Criteria and Assessment Office (MD-52) 

U.S. Environmental Protection Agency 

Research Triangle Park, NC 27711 

Dr. David T. Tingey 

Coordinator for Chapter 6, Volume III 

Environmental Research Laboratory 

U.S. Environmental Protection Agency 

200 S.W. 35th Street 

Corvallis, OR 97330 

xxvi 
10. CONTROLLED HUMAN STUDIES OF THE EFFECTS OF 

OZONE AND OTHER PHOTOCHEMICAL OXIDANTS 

10.1 INTRODUCTION 

Four major summaries on the effects of controlled human exposure to ozone 

(03 ) have been published (Nationai 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 photochemical oxidants stated a need for comprehensive human experimental studies that 

were carefully controlled and documented to ensure reproducibility. This 

statement was understandabie, 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 recommendations for future studies. The available data on controiled studies through 

1975 were limited to some 20 publications. Nonetheless, this data base represented a substantial increase above the information available prior to 1970, 

and it became evident that exposure to 0 3 at low ambient concentrations resulted in some degree of pulmonary dysfunction. Additional research was conducted in the intervening years, and by 1978 data were available from studies 

conducted on over 200 individuals (Table 10-1). By this time the first reports 

were. available indicating that under the same exposure conditions, greater 

functional deficits were measured during exercise than at rest. In addition, 

five studies in which several pollutants (nitrogen dioxide, sulfur dioxide, 

and carbon monoxide plus oxidants) were present during exposure became availab1e for review. Two reports on repeated daily exposure to 0 3 ("adaptation") 

had appeared, as well as one experimental study in which asthmatics were 

evaluated. This research was just the beginning of interest in 0 3 as an 

ambient pollutant affecting pulmonary functions of exposed man. Although the 

data base was still smaller than desirable, a general conception of this 

particular air pollutant's influence was beginning to form. 

The early reports summarized in Table 10-1 were described in detail in 

the previous 03 criteria document (U.S. Environmental Protection Agency, 

1978). In this chapter, emphasis has been placed on the more recent literature; how.ever, some of the older studies have been reviewed again. Tables 

10-1 
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1'0-5 
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 3 concentrations presented in the text and tables are the 1'evels 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 3 measurement 

can be found in Chapter 4. 

10.2 ACUTE PULMONARY EFFECTS OF OZONE 

10.2.1 Introduction 

The most prevalent and prominent pulmonary responses to 0 3 exposure are 

cough, substernal pain upon deep inspiration, and decreased lung volumes 

(forced vital capacity, FVC; forced expiratory volume in ls, FEV 1 , 0; tidal 

volume, VT). Less substantial increases in airway resistance (R aw) also 

occur. In most of the studies reported, greatest attention has been accorded 

decrements in FEV l , o , as this variable represents a summation of changes in 

both volume and resistance. While this is true, it must be pointed out that 

for exposure concentrations critical to the standard-setting process (i.e., 

<0.3 ppm 0 3 ), the observed decrements in FEV l , o primarily reflect FVC decrements of similar magnitude, with little or no contribution from changes in 

.resistance. As examples, for.subjects exposed to 0.3 ppm 0 3 and performing 

exercise with associated minute ventilations (VE ) of 31, 50, or 67 L/min, 

decrements in FEV l , o and FVC were 0.23 and 0.11, 0.31 and 0.29, 0.38 and 0.40 

liters, respectively (Folinsbee et al., 1978). For subjects performing heavy 

exercise (VE = 65 L/min) and exposed to 0.12, 0.18, 0.24, or 0.30 ppm 0 3 , 

decrements in FEV l ,o and FVC were 0.21 and 0.17, 0.29 and 0.23, 0.59 and 0.53, 

0.74 and 0.66 liters, respectively (McDonnell et al., 1983). In another study 

of subjects performing heavy exercise (VE = 57 L/min and exposed to polluted 

ambient air (mean 0 3 concentration = 0.15 ppm), 0.16 or 0.24 ppm 0 3 , decrements 

in FEVl .o and FVC were 0.20 and 0.18, 0.24 and 0.24, 0.74 and 0.73 liters, 

respectively (Avol et al., 1984). Thus, it is highly probable that most of 

the decrements in FEV1 , o reported to result from 03 exposure are indicative of 

restrictive changes and that little or no change in FEV1,0/FVC occurs which 

would indicate resistive changes. 

10-6 
10.2.2At-Rest Exposures 

Results from studies reported prior to 1978 (Table 10-1) indicate that 

impairment of pulmonary function and pulmonary symptoms occur when normal 

subjects are exposed for 2 hr at rest to 1176-1568 pg/m 3 (0.6-0.8 ppm) of 0 3 

(Young et al:, 1964), and to 1479 pg/m 3 (0.75 ppm) of 0 3(Bates et al., 1972; 

Silverman et al., 1976). In addition to decrements in the usual indicators of 

pulmonary function, Young et al. (1964) also found decreases in diffusion 

capacity of the lung (D L

CO). 

Results from studies of at-rest exposures published since 1978 (Table 10-2) 

have generally confirmed these earlier findings. Folinsbee et al. (1978) 

observed decrements in FVC, FEV1 0 , and other spirometric variables when 

10 normal subjects rested for 2 hr while exposed to 980 pg/m 3 (0.5 ppm) of 0 3 ; 

Rawwas not affected. No changes in pulmonary function resulted from exposures to 588 or 196 pg/m3 (0.3 or 0.1 ppm) of 0 3 . Horvath et al. (1979) 

reported that decreases in FVC and FEV 1 0resulted from 2-hr at-rest exposures 

of 15 subjects (8 males, 7 females) to 980 and 1470 pg/m3 (0.50 and 0.75 ppm) 

of 03 ; the decreases at 0.75 ppm were greater than those at 0.50 ppm of 0 3 . 

No changes in pulmonary function were observed at 490 pg/m3 (0.25 ppm) of 0 3 . 

Kagawa and Tsuru (1979a) observed small decreases in specific airway 

conductance (SGaw) when three subjects rested for 2 hr while exposed to 588 

and 980 pg/m 3 (0.3 and 0.5 ppm) of_0 3 . In contrast to other studies, this is 

the only report of changes in airway resistance resulting from at rest exposures to 0 3 . 

Kbnig et al. (1980) exposed 14 healthy nonsmokers (13 men, 1 woman) for 2 

hr at rest to 0, 196, 627, and 1960 pg/m 3 (0.0, 0.10, 0.32, and 1.0 ppm) of 

03 . Specific airway conductance was measured and samples of arterialized ear 

lobe capillary blood were taken for determinations of oxygen tension (P0 2 ) 

before and after the exposures. No changes i n P0 2or SGawwere observed. 

Subjective symptoms (substernal burning) were reported by two individuals at 

196 pg/m3 (0.1 ppm), by three at 627 pg/m 3 (0.32 ppm), and by eight at 1960 

hg/m3 (1.0 ppm) of 0 3 . 

10.2.3Exposures With Exercise 

The majority of controlled human studies since 1978 have been concerned 

with the effects of combined rest and exercise exposures to various concentrations of 03for variable periods of time (Table 10-2). Exercise during these 

10-7 
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exposures has been at different intensities and at different times during the 

exposures. The level of minute ventilation (VE ), which varies with exercise 

intensity, is a primary determinant of the magnitude of pulmonary effects 

resulting from exposure to a given level of 0 3 . Therefore, results from 

studies using different regimens of exercise, even with exposure to the same 

03 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 i f sub j ects had been exposed on two sequenti al days , as noted i n 

Section 10.3 entitled."Pulmonary Effects Following Repeated Exposure to Ozone." 

Other factors that may influence the results obtained by different investigators and account for some of the inconsistencies observed among the findings from various studies are discussed in this chapter. Such factors include 

experimental design (more specifically: number of subjects, exposure time, 

recurrent exposures, length of and sequencing of exercise periods, and time of 

measurements), and specific measurement techniques used to determine 0 3 concentration (see Chapter 4) and to characterize pulmonary responses. The variability of intrinsic responsiveriess of individual subjects to 03, effects of 0 3 on 

subjects with pulmonary disease, and other factors affecting the responsiveness 

of subjects to 0 3 , such as smoking history, sex, and environmental conditions, 

are discussed in this section. Studies on the interaction between 0 3 and other 

pollutants are presented in Section 10.5. 

As previously stated, increased VE accompanying exercise is one of the 

most important contributors to pulmonary decrements during 0 3 exposure. While 

the more recent reports include actual measurements of VE obtained during 

exposure, earlier publications often included only a description of the exercise 

regimen. Table 10-3 may aid the reader in estimating the V E associated with a 

given exercise regimen. 

The values for 0 2 consumption and V E in Table 10-3 are approximate estimates for average physically fit males exercising on a bicycle ergometer at 50 

to 60 rpm (if rpms are higher or lower, values may be different). Note that 

individual variability is great and that the level of physical fitness, age, 

level of training, and other physiological factors may modify the estimated 

values. The only precise method of obtaining these data is to actually measure 

10-13 
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10-14 
the V E and 02 consumption. If exercise is conducted on a treadmill, adequate 

relative standards for 02 consumption and VE can not be estimated. Thus, with 

such activity, there is an absolute need to measure these variables. 

Bates et al. (1972) and 8ates and Hazucha (1973), as described in the 

previous 0 3 criteria document (U.S. Environmental Protection Agency, 1978), 

were the first to consider the role of increased ventilation due to exercising 

in an 03 environment. These observations emphasized an important aspect of 

ambient exposure; namely, that individuals who are engaged in some type of activity during ambient exposure to polluted air experience greater pulmonary 

function decrement than resting individuals. 

Hazucha et al. (1973) reported data obtained on 12 subjects exposed for 

2 hr to either 725 (n=6) or 1470 (n=6) pg/m 3 (0.37 or 0.75 ppm) of 03 . These 

subjects performed light exercise (VE reported to be double resting ventilation) 

alternately every 15 minutes. Three subjects also had total lung capacity 

(TLC), residual volume (RV), and closing capacity (CC) measured before and 

after 2-hr exposure to 1470 pg/m 3 (0.75 ppm) of 03 . 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 3 ; the 

decrease was greater at the higher level of 0 3 . 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, the mean RV and CC increased and TLC was unchanged after exposure to 

0.75 ppm of 0 3 . 

Kerr et al. (1975) reported small, but significant, decreases in FVC, 

FEV3 01 RL , and SGaw when 20 subjects were exposed to 980 pg/m 3 (0.5 ppm) of 

0 3 for 6 hr with two 15-min periods of inedium exercise (100 W). The symptoms 

of dry cough and chest discomfort were also experienced after exposure. No 

changes in TLC, FRC, Cst, dN29 or D LCO were observed. 

Folinsbee et al. (1977b) demonstrated that the heightened pulmonary 

effect of 03 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 

980-pg/m3 (0.50-ppm) 03 exposure, the maximum impairment of forced expiratory 

spirometry appeared immediately (2 to 4 min) after exercise (Figure 10-1). 

Despite continued exposure to 0 3 , but at rest, puimonary function either 

improved or showed no further impairment. No change in RV or R aw was observed, 

while TLC was reduced. 

10-15 
~ GROUP A GROUP B 

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EXERCISE EXERCISE 

EXPOSURE, minutes 

Figure 10-1. Change in forced vital capacity (FVC), forced 

expiratory volume in 1-sec (FEV 1.0), and maximal midexpiratory flow (FEF26_7s%) during exposure to filtered air 

(0) or ozone (0) (0.5 ppm) for 2 hr. Exercise at 45% 

maximal aerobic capacity (max V0 2) was performed for 30 

min by Group A after 60 min of ozone exposure and by 

Group B after 30 min of ozone exposure. 

Source: Folinsbee et al. (1977b). 

M-15 
Folinsbee et al. (1978) reported results from 40 subjects in studies 

designed to evaluate the effects of various concentrations of 0 3 at several - - 

different leveis of activity from rest through heavy exercise. Haif of the 

subjects had previously resided in an area having high 0 3 concentrations; 14 

reported symptoms associated with irritation or breathing"difficulty on highpollution 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 pg/m 3 (0, 0.10, 0.30, or 0.50 ppm) 

of 03 . One group rested throughout the exposure. The other three groups 

exercised at four intervals throughout the exposure; each 15-min exercise 

period was followed by a 15-min rest period. Each subject in the three exercise groups walked on a treadmill at a level of activity to produce minute 

ventilations of approximately 30, 50, or 70 L/min, respectively. The integrated 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 

exposure to filtered air or 196 pg/m3 (0.10 ppm) of 03 at any workload. At 

rest (10.L/min), pulmonary function changes were confined to 980 pg/m3 (0.50 

ppm) 03 exposures. Some changes were apparent at the lowest work load (30 L/ 

min) and 588 pg/m 3 (0.30 ppm) of 03, and effects were more marked at 980 pg/m3 

(0.50 ppm) of 0 3 . At the two.highest work loads (49 and 67 L/min), pulmonary 

function changes occurred at both 588 and 980 pg/m 3 (0.30 and 0.50 ppm), with 

the changes at 980 pg/m3 (0.50 ppm) of 0 3 usually significantly greater than 

those at 588 pg/m3 (0.30 ppm) of 0 3 . During exercise, respiratory frequency 

was greater and tidal volume lower with 0 3 exposure than with sham exposure. 

The change in respiratory pattern was progressive and was most striking at the 

two heaviest work loads and at the highest 0 3 concentrations. Reductions in 

TLC and inspiratory capacity (IC), but not RV or functional residual capacity 

(FRC), were also noted. 

Von Nieding et al. (1977) exposed normal subjects to 196 pg/m 3 (0.1 ppm) 

0 3 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 H 20/L/s) and a significant decrease in Pa0 2 (-7 mm Hg). 

These data were later reanalyzed (von Nieding et al., 1979) using more stringent 

statistical criteria and the changes in both airway resistance and Pa0 2 were 

10-17 
found to be nonsignificant. In both analyses, the nonparametric YJilcoxen 

procedure which ranks paired differences was used. In the 1977 analysis, Pa0 2 

= and airway resistance changes <5 mm Hg and 0.5 cm H 20/L/s, respectively, were 

° considered as zero but used in the analysis. In the 1979 analysis, Pa0 2 and 

airway resistance changes <5 mm Hg and 0.5 cm H 20/L/s, respectively, and 

within the range of normal variation for each individual subject were not 

included in the analysis. Thus, data from about half the subjects analyzed in 

1977 were included in the 1979 analysis. 

In a study similar to that of von Nieding et al. (1977; 1979), Linn et 

al. (1979) exposed normal subjects to 392 pg/m 3 (0.2 ppm) of 0 3 . The 18 

subjects exercised at twice resting ventilation for 15 min of every half hour. 

Blood and alveolar gas samples were taken shortly after 1 and 2 hr of their 

2.5 hr of exposure. Blood samples were taken both from an arterialized ear 

lobe and a brachial artery. No significant differences between air and 0 3 

exposures were observed for changes in PA0 2 , Pa0 2 or P

(A-a) 0 2' 

Adams et al. (1981) required eight subjects (22 to 46 years of age) to 

exercise continuously (i.e., no rest periods) while orally inhaling 0.0, 392, 

588, and 784 pg/m3 (0.0, 0.2, 0.3, and 0.4 ppm) of 0 3 . 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 observed for exposures to 588 and 784'pg/m 3 (0.30 and 0.40 ppm) of 0 3 with the 

magnitude of decrement greater at the higher minute ventilation. The magnitude 

of decrement also increased with increasing exposure time. No pulmonary 

effects were observed for exposures to clean air or 392 pg/m 3 (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 (VE 

of —62 L/min) occurred between 03 concentrations of 392 and 588 pg/m 3 (0.2 and 

0.3 ppm). The responses to continuous exercise were similar to those observed 

in studies using intermittent but equivalent exercise. 

Kagawa (1983a; 1984) presented data on 15 subjects exercising intermittently (15 min exercise, 15 min rest) during a 2-hr exposure to 294 or 588 pg/m 3 

(0.15 or 0.30 ppm) of 0 3 . These subjects reported the typical symptoms at the 

higher 03 concentrations. Paired t-tests were used to compare responses to 

filtered3 air and 03 . SGaw decreased 6.4 percent (P <0.05) following the 3 

294-pg/m (0.15-ppm) exposure and 16.7 percent (P <0.01) following the 588-pg/m 

10-18 
(0.30-ppm) exposure. In the latter environment, only FVC showed a significant 

(P <0.05) decrement; FEV 1 was unaffected. -These subjects. had resided in a 

low-oxidant-pollutant environment. 

McDonnell et al. (1983) provided-further information related to high 

levels of ventilation during exercise in 135 healthy subjects exposed to 03 . 

Subjects were excluded from the study if they had smoked within 3 yr or had a 

history of asthma, allergy, rhinitis, cardiac disease, chronic respiratory 

disease, recent acute respiratory illness, or extensive exposure to pollutants. 

They divided their subjects into six groups, each group exposed to a different 

concentration of 03 ; viz. 0.0 (n=20), 0.12 (n=22), 0.18 (n=20), 0.24 (n=21), 

0.30 (n=21), and 0.40 (n=29) ppm, equivalent to 0.0, 235, 353, 470, 588, and 

784 pg/m3 of 03 . The subjects were exposed for 2.5 hr, with exposure consisting of aiternating 15-min periods of rest and exercise (VE/BSA of -"35 L/m2 or 

VE = 64 to 68 L/min) during the first 120 min. Forced expiratory spirometry 

and pulmonary "symptoms were measured between 5 and 10 min after the fanal 

exercise (i.e., at 125 min of exposure), while plethysmography was performed 

between 25 and 30 min after the final exercise (i.e., at 145 min of exposure). 

The pulmonary symptom, cough, showed the greatest sensitivity to 0 3 (it occurred 

at the lowest concentration, 235 pg/m3 or 0.12 ppm of 03 ). Small changes in 

forced expiratory spirometric measures (FVC, FEV J , maximal mid-expiratory flow 

[FEF25-75Y]) were suggested at 235 pg/m 3 (0.12 ppm) of 03 and were definitely 

present at 353 pg/m3 (0.18 ppm) of 0 3 . Greater changes were found at and 

above 470 pg/m3 (0.24 ppm) of 0 3 . Significant decreases in tidal volume (V T ) 

and increases in respiratory frequency (fR) during exercise (similar changes 

had,been reported by other investigators) and specific airway resistance 

(SRaw), pain on deep inspiration, and shortness of breath occurred at 03 

levels of >470 pg/m 3 (0.24 ppm). The sigmoid-shaped dose-response curves 

indicated a relatively large decrease in FVC, FEV 1 , and FEF25-75% between 353 

and 470 pg/m3 (0.18 and 0.24 ppm) 0 3 . However, in contrast to the results of 

other investigations, a plateau in response was suggested at the higher levels 

(>470 pg/m3 ; 0.24 ppm) of 0 3 . Regarding SRaw , a s"ignificant increase was 

observed beginning at 470 pg/m3 (0.24 ppm) of 0 3 and the magnitude of this 

change was greater with increasing 0 3 levels. These findings are in agreement 

with the results of other investigators. The two different patterns in 

response plus the observation that individual changes in SR aW and FVC were 

poorly correlated prompted these investigators to suggest that more than a 

single mechanism might have to be implicated to define the effects of 0 3 on 

10-19 
pulmonary functions. Findings from this study are particularly relevant in 

that a large subject population was studied and pulmonary effects were suggested 

at an 03concentration (235 pg/m3 ; 0.12 ppm) lower than that for which they 

had previously been observed. 

More recent studies on well-trained subjects have become available. Six 

well-trained men and one well-trained woman (all of the subjects except one 

male being a competitive distance cyclist) exercised continuously on a bicycle 

ergometer for 1 hr while breathing filtered air or 412 pg/m 3 (0.21 ppm) of 03 

(Folinsbee et al., 1984). They worked at 75 percent maximal aerobic capacity 

(max 1f02) with mean minute ventilations of 89 L/min. Pulmonary function 

measurements were made pre- and post-exposure. Decreases occurred in FVC 

(6.9 percent), FEVI 0 (14.8 percent), FEF25-75% (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-pg/m 3 (0.35-ppm) 03 environment. 

Symptoms included laryngeal and/or tracheal irritation and soreness as well as 

chest tightness upon taking a deep breath. 

Adams and Schelegle (1983) exposed 10 well-trained distance runners to 

0. 0, 392, and 686 pg/m 3 (0. 0, 0. 20, and 0.35 ppm) of 03whi 1 e the runners 

exercised on a bicycle ergometer at work loads simulating either a 1-hr steadystate training bout or a 30-min warmup followed immediately by a 30-min competitive bout. These exercise levels were of sufficient magnitude (68 percent of 

their max V02 ) to increase mean VEto 77.5 L/min. In the last 30 min of the 

competitive exercise bout, minute ventilations were approximately 105 L/min. 

Subjective symptoms, including shortness of breath, cough, and raspy throat 

increased as a function of 0 3concentration for both continuous and competitive 

levels. The high ventilation volumes (77.5 L/min) resulted in marked pulmonary 

function impairment and altered ventilatory patterns (increased f Rand decreased 

VT) when exercise was performed in 392 pg/m3 (0.20 ppm) of 03 . Two-way analysis 

of variance (ANOVA) procedures performed on the pulmonary function data indicated significant decrements (P <0.0002) for FVC, FEV 1 , and FEF25-75%. The 

investigators noted that the decrements in FEV1 0were similar to those observed 

by Folinsbee et al. (1978) when the two studies were compared on the basis of 

effective dose. The concept of effective dose will be treated in a later 

section. 

Avol et al. (1984; 1985) randomly exposed trained cyclists (n = 50) to 0, 

157, 314, 470, and 627 }ag/m3 (0.0, 0.08, 0.16, 0.24, and 0.32) ppm 0 3 . Each 

10-20 
exposure consisted of 10 min warm-up, 60 min of exercise at 50% max V0 2 (VE = 

57 L/min), 5 min cool down (all performed on a bicycie ergometer), and 5 min 

post-exercise pulmonary function testing. Most subjects resided in the Los 

Angeies area and therefore were subject to prior exposure to ambient 0 3 . Two 

subjects had histories of asthma; all others were free of chronic respiratory 

disease. Three subjects were current smokers, while six others had previously 

smoked. Forced expiratory spirometry and respiratory symptoms were evaluated 

before exposure, immediately after exercise, and 1 hr after exposure. When 

compared to exposure at 0.0 ppm, significant decreases in FVC and FEV l.o and 

an increase in lower respiratory symptom score combined (cough, sputum, dyspnea, 

wheeze, substernal irritation, chest tightness) were observed following exposure 

at and above 314 pg/m3 (0.16 ppm) 0 3 ; no significant changes occurred with 

exposure to 157 pg/m3 (0.08 ppm) 03 . An increasing number of subjects could 

not complete the 1 hr of exercise at 03 concentrations of 470 and 627 pg/m3 

(0.24 and 0.32 ppm) without reducing their workloads. The magnitudes of 

change in FVC, FEV1 , and symptom score were concentration-dependent and remarkably consistent with those previously reported by McDonnell et al. (1983) (see 

Section 10.2.1). While they did not return to levels.observed prior to exposure, substantial recovery of both function and symptoms was observed 1 hr 

following exposure. Significant changes in FVC, FEVl, and lower respiratory 

symptom score aiso resulted from exposure to polluted ambient air with a mean 

0 3 concentration of 294 pg/m 3 (0.15 ppm) (see Section 11.2.1). Although the 

pulmonary changes in response to polluted ambient air appeared to be of lesser 

magnitude than those in reponses to the nearest generated 0 3 level (314 pg/m3 ; 

0.16 ppm), the difference between the two exposures was not statistically 

significant. 

Kulle et al. (1985) randomly exposed male nonsmokers (n = 20), with no 

history of chronic respiratory or cardiovascular disease, to 0,-196, 294, 392, 

and 490 pg/m3 (0.0, 0.10, 0.15, 0.20, and 0.25 ppm) 0 3 for 2 hr. Each exposure 

consisted of four cycles of 14 min treadmill exercise (VE = 68 L/min) alternated 

with 16 min of rest. Forced expiratory spirometry was performed before exposure 

and 9 min after each exercise. Measurements of R aw and Vts (FRC) were made 

prior to and after each exposure; respiratory symptoms were evaluated after 

each exposure. Significant concentration-dependent decreases in FVC, FEV 1 . 0 , 

FEF25-75, SGaw , IC, and TLC­and increases in respiratory symptoms (cough, 

nose/throat irritation, chest discomfort) were observed; RV and FRC did not 

10-21 
change with exposure to any concentration. Significant responses were best 

modeled as an exponential function of 0 3 concentration. Additionally, FVC and 

FEVl , o decreased as a linear function of time of exposure. While these results 

are discussed by the authors as though significant changes resulted from exposure to 294 pg/m 3 (0.15 ppm) 0 3 , the magnitude of change at this concentration 

was quite small (<1 percent) when compared to preexposure levels. Moreover, 

while the statistical procedures (ANOVA) used by these investigators di.d indicate a significant 0 3 effect when data from exposures to all 0 3 concentrations 

were analyzed, no statistical comparisons of responses at indi,vidua1.0 3 concentrations were performed. Thus, the legitimacy of ascribing 0 3 effects at any 

individual 03 concentration•is questionable and discussion of data should be 

confined to the overall concentration-resp.onse relationship. 

10.2.4 Intersubject Variability and Reproducibility of Responses 

In the majority of the above studies, assessment of the significance of 

results was typically based on the mean ± variance of changes in lung function 

resulting from exposure to 0 3 as compared to exposure to clean air. Although 

consideration of inean changes is useful for making statistical inferences 

about homogeneous populations, it may not be adequate to describe the differences in responsiveness to 0 3 among individuals. While the significant mean 

changes observed demonstrate that the differences in response between 0 3 and 

cl ean ai r exposures were not due to chance, the vari ance of responses was 

quite large in most studies. While characterization of reports of individual 

responses to 0 3 is useful since it permits an assessment of the proportion of 

the population that may actually be affected during 03 exposure, statistical 

treatment of these data is still rudimentary and their validity is open to 

question. 

Results from a small number of studies (Horvath et al., 1981; Gliner et 

al. , 1983; McDonnell et al. , 1983; Kul le et al. , 1985) that have. reported 

individual responses indicate that a considerable amount of intersubject 

variability does exist in the magnitude of response to 03 . Figure 10-2 illustrates the variability of responses in FEVl 0 and SRaw obtained from subjects 

exposed to different 0 3 concentrations. 

Decreases in FEV1 0 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 

pg/m 3

(0.42 ppm) of 03 while performing moderate intermittent exercise. When 

10-22 
10 

5 

0 

10 

0.40 ppm 

0.30 ppm I 

0.40 ppm I 

0.30 ppm I 

5 

0 

~ 10 

H 

v w 5 

~ 

m 

cn 0 

w 

O 

cr. 

w 

co 10 

~ 

z 5 

0 

0.24 ppm I 

0.18 ppm I 0.18 ppm I 

10 

5 

0 

0.12 ppm I 

0.00 ppm I 

0.12 ppm I 

0.00 ppm I 

10 

5 

0 

-10 0 10 20 30 40 -20 0 20 40 60 80 

OFEV1,0(DECREASE), percent ASRaW(INCREASE), percent 

Figure 10-2. Frequency distributions of response (percent 

change from baseline) in specific airway resistance (SR aw) 

and forced expiratory volume in 1-sec (FEV I.o) for 

individuals exposed to six levels of ozone. ®ne individual 

with 260% increase in SRaWexposed to 0.4 ppm of ozone 

is not graphed. 

Source: 11AcDonnell et al. (1953). 

10-23 
these same subjects were exposed to clean air under the same conditions, the 

response of FEV1.0 ranged from an 8-percent increase to an 11-percent decrease 

(mean = 0 percent). 

Gliner et al. (1983) exposed subjects (13 females, 8 males) performing 

intermittent light exercise for 2 hr to clean air and 392 pg/m 3 (0.20 ppm) of 

03 . Changes in FEV1 0 resulting from clean-air exposure ranged between 

+7.8 percent and -7.5 percent (mean = 0 percent), while the range of changes 

in F3 V1.0 was +6.0 to -16.6 percent (mean =-3 percent) with exposure to 392 

pg/m (0.20 ppm) of 0 3 . 

For subjects performing 2 hr of intermittent heavy exercise while exposed 

to 03 , McDonnell et al. (1983) observed changes in FEV1 0 ranging from -1 to 

-45 percent (mean =-18 percent) at 784 pg/m3 (0.40 ppm), -1 to -42 percent 

(mean =-17 percent) at 588 pg/m3 (0.30 ppm), -1 to -36 percent (mean = 

-15 percent) at 470 pg/m 3 (0.24 ppm), 0 to -23 percent (mean =-6 percent) at 

353 Ng/m3 (0.18 ppm), +7 to -16 percent (mean =-4 percent) at 235 pg/m3 (0.12 

ppm), and +2 to -6 percent (mean =-1 percent) in clean air. Large intersubject variability was also reported for changes in SRaw during these exposures 

(Figure 10-2). 

Kulle et al. (1985) exposed each of their 20 subjects to four 0 3 concentrations for 2 hr with heavy intermittent exercise. For these subjects, changes 

in FEV1 . o ranged from +5 to -2 (mean =+1 percent) in clean air, +10 to -4 

percent (mean =+1 percent) at 196 pg/m3 (0.10 ppm), +3 to -9 percent (mean =-1 

percent) at 294 pg/m3 (0.15 ppm), +3 to -16 percent (mean =-3 percent) at 392 

pg/m3 (0.20 ppm), and +1 to -36 percent (mean =-6 percent) at 490 pg/m 3 (0.25 

ppm). Concentrati on- response curves were also constructed for individual 

subjects and individual 0 3 responsiveness assessed. Three subjects exhibited 

a slight increase in FEV1 following exposures to all four of the 0 3 concentrations. Most of the remaining subjects demonstrated progressive decreases in 

FEVl , o with increasing 03 concentrations. Five subjects exhibited FEVl.o 

decreases of <5 percent, seven subjects were between 5 and 10 percent, three 

subjects were between 10 and 15 percent, and two subjects exhibited FEVi,o 

decrease of >15 percent. The reported symptom of cough correlated with the 

observed decrements in FVC and FEV1 (r = 0.52) and nose and throat irritation 

correlated with FEV1 changes (r = 0.49). 

The degree to which a subject's response to a given 03 concentration can 

be reproduced is an indication of how precisely the measured response estimates 

10-24 
that subject's intrinsic responsiveness. In a 1983 study, Gliner et al. 

exposed s'ubjects performing intermittent light exercise for 2 hr to 392 pg/m 3 

(0.20 ppm) of 0 3 on three consecutive days, followed the next day by an exposure to either 823 or 980 pg/m3 (0.42 or 0.50 ppm) of 0 3 . Each subject had 

also been exposed prior to or was exposed after the study to 823 or 980 pg/m 3 

(0.42 or 0.50 ppm) 0 3 . For individuai responses of FEV1 01 a moderate correlation (r = 0.58) between changes resulting from the first exposure to 392 

pg/m3 (0.20 ppm) of 0 3 and the second exposure to 823 or 980 pg/m 3 (0.42 or 

0.50 ppm) of 0 3 was observed. When responses i n FEVI 0 from the fi rst and 

second exposures to 0.42 or 0.50 ppm 0 3 were compared, .the correlation between 

the two exposures was quite high (r = 0.92). Althaugh these comparisons were 

confounded by possible effects of prior 0 3 exposure, they do suggest. that individual changes in FEV1 0 resulting from 03 exposure are reasonably reproducible. 

Moreover, a given individual's response to a sing1e.0 3 exposure is probably a 

reliable estimate of that individual's intrinsic responsiveness to 0 3 . 

McDonnell et al. (1985a) exposed each of 32 subjects for 2 hr to one of 

five different 0 3 concentrations (235, 353, 470, 588, and 784 pg/m3 ; 0.12, 

0.18, 0.24, 0.30, and 0.40 ppm) with intermittent heavy exercise. Each subject 

was exposed at least twice to the same 0 3 concentration at 3 to 75-week 

intervals. The correlation coefficients between the two exposures closest in 

time (mean ± S.D. = 9± 4 weeks) for individual changes in FVC, FEV 1 , 0 , and 

FEF25_757o were 0.89, 0.91, and 0.83, respectiveiy. Correlation coefficients 

were moderate for changes in SR aw (r = 0.63) and the pulmonary symptoms of 

cough (r = 0.75), shortness of breath (r = 0.65), and pain upon deep respiration 

(r = 0.48). with a longer time between exposures (mean ± S.D. = 33 ± 20 

weeks), changes in FVC (r = 0.72), FEV leo (r = 0.80), and FEF25_75% (r = 0.76) 

were nearly as reproducible. This high degree of reproducibility indicates 

that the magnitude of response to a single exposure is a reliable estimate of 

that subject's intrinsic responsiveness to 0 3 . Moreover, intersubject variability in magnitude of 0 3-induced effects is probably the result of large differences in intrinsic responsiveness to 0 3 . 

10.2.5 Prediction of Acute Pulmonary Effects 

Nomograms for predicting changes in lung function resulting from the 

performance of light intermittent exercise rvhile exposed to different 0 3 

concentrations were included in one of the earliest reports of the effects of 

10-25 
03 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 3 , defined as the 

product of concentration, exposure duration, and VE . Equations were derived 

from lung function measurements at 1 and 2 hr of exposure to 725, 980, and 

1470 pg/m3 (0.37, 0.50, and 0.75 ppm) of 0 3 under conditions of both rest and 

intermittent exercise sufficient to increase VE 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 concentration of 03 for a short period of time induced greater functional decrements 

than a longer exposure to a lower concentration. This phenomenon implies that 

03 concentration is a more important contributor to response than is exposure 

duration. Moreover, they also observed extensive individual variability in 

pulmonary function changes, suggesting that use of effective dose is not 

satisfactory for predicting individual responses to 0 3 exposure. 

Since the inception of the concept of an effective dose, additional 

studies have used, and in some cases refined it for prediction of pulmonary 

responses to 03 exposure. However, these prediction models must be interpreted 

with extreme caution since the data base is limited and the great intersubject 

variability in responsiveness to 03 makes truly refined modeling of effective 

dose highly improbable. Extension of the effective-dose concept was accomplished 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 pg/m3 (0.0, 0.10, 0.30, and 0.50 ppm) of 0 3 . 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 3 concentration x 

VE (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 VE , and second on all subject groups together 

after computing the effective dose. Predictions of pulmonary function changes 

in FEV1 based on effective doses up to 1.5 ml 0 3 agreed with data collected by 

other investigators. Prediction equations using the effective dose for all 

measured pulmonary functions were constructed. All equations were significant 

at the 0.01 level. These investigators also used a multiple regression approach 

to refine further the prediction of changes in pulmonary function resulting 

from 03 exposure. Duration of exposure was not analyzed as a contributing 

10-26 
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 3 concentration and V E . For example, these two predictors accounted for 

approximately 80 percent (multiple r= 0.89) of the variance in FEV1.0. 

Moreover, 0 3 concentration accounted for more of variance than did V E , and for 

a given effective dose, exposure to a high concentration with a low V E induced 

greater functional decrements than exposure to a lower concentration with 

elevated VE . Equations (with appropriately weighted 0 3 concentration and VE ) 

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 essentialiy the same conclusions reached by Folinsbee et al. (1978), namely that most of the variance 

for pulmonary function variables could be accounted for by 0 3 concentration, 

followed by VE, and then by exposure time. Adams et al. emphasized the predominant importance of 0 3 concentration and suggested that the detectable level 

for 0 3 functional effects in healthy subjects during sustained exercise at a 

moderately heavy work load (VE — 62 L) occurred between 0 3 concentrations of 

392 and 588 pg/m3 (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 3 based on results combined from many different laboratories. Basically, he examined changes in Raw and FEVI 0 as functions of 

exposure rate (0 3 concentration x VE ) and tota`7 exposure dose (exposure rate x 

duration of exposure), which is equivalent to effective dose. The correlation 

for changes in Raw was slightly better than that for changes in FEV l 0 . The 

author states that he elected to use linear eqdations to fit the data rather 

than polynomials because he found little difference in the degree of correlation between the two methods. The analysis al°so found an attenuation in the 

rate of increase of SRaw as VE increased to higher levels; there was no I attenuation of the decrease in FEVl 0 as a function of increasing VE . This observation suggested to Colucci that different mechanisms may be involved in the 

effects on Raw and FEVl 0 . whether expressed as functions of exposure rate or 

total exposure dose, the patterns of pulmonary responses were approximately 

10-27 

o* 
t 

equivalent. This is not surprising since both Folinsbee et al. (1978) and 

Adams et al. (1981) had previously shown that most of the variance in pulmonary 

. response depended primarily on 03 concentration and VE . The overall finding, 

that increases in Raw and decreases in FEV1 0 are reasonably correlated with 

increases in effective dose of 0 3 , only confirms the results reported by 

previous investigators. As proposed by Folinsbee et al. (1978) and Adams 

et al. (1981), a better fit of the data may have been obtained had Colucci 

used multiple regression and equations thAt appropriately weighted the relative 

contributions of each of the exposure variables to pulmonary decrements. 

10.2.6 Bronchial Reactivity 

In addition to overt changes in pulmonary function, several studies have 

reported increased nonspecific airway sensitivity resulting from 0 3 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 

1176 pg/m3 (0.6 ppm) of 0 3 . The resting subjects breathed orally (a nose-clip 

was worn). These investigators concluded that 0 3 exposure at this concentration 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 pg/m 3 (0.0, 0.3, and 0.5 ppm) 0 3 . Their three nonsmoking 

subjects were exposed for 2 hr.followed by measurements of bronchial reactivity to ACh. They found that these subjects demonstrated an increased 

reactivity to ACh. However, because of the small number of subjects and the 

large variability of responses, the results may not represent a significant 

effect. 

The bronchial reactivity of atopic and nonatopic sUbjects was evaluated 

by Holtzman et al. (1979). They studied 16 healthy nonsmoking subjects and 

found that nine could be classified as "atopic" based on medical history and 

allergen skin testing. A11 subjects had normal pulmonary functions determined 

in preliminary screening tests and were asymptomatic. Both atopic and nonatopic subjects performed intermittent exercise while wearing noseclips and 

exposed by mouthpiece to filtered air and 1176 pg/m 3 (0.6 ppm) of 03 . Bronchial 

10-28 
reactivity was determined 1 hr after exposure to each condition (when postexposure SRaw had returned to normal) by measuring the increase in SR aw produced 

by inhalation of histamine or methacholine aerosols. In both atopic and nonatopic subjects, the bronchial response to histamine and methacholine was 

enhanced after 03 exposure when compared to exposure in filtered air. The 

increase in SRaw resulted predominantly from an increase in airway resistance, 

with only small changes in trapped gas volume. Symptoms of bronchial irritation 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 pr.olonged period. 

Premedication with atropine sulfate aerosol prevented the increase in SRaw 

after 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 0 3 

were unrelated to the presence of atopy. 

Konig et al. (1980) exposed 14 healthy nonsmokers (13 men, 1 woman) for 

2 hr to 0, 196, 627, and 1960 pg/m 3 (0.0, 0.10, 0.32, and 1.00 ppm) of 0 3 . 

Bronchial reactivity to ACh was determined after exposure. Significant increases in bronchial reactivity were observed with the ACh challenge following 

exposure to 627 pg/m3 (0.32 ppm) and 1960 pg/m3 (1.0 ppm) of 0 3 . 

Bronchial reactivity of normal adult subjects was assessed by measuring 

the increase in SRaw produced by inhalation of histamine aerosol (Dimeo et al., 

1981). Seven subjects, intermittently exercising (15 min exercise, 15 min 

rest) at a load sufficient to double their resting VE , were exposed to 392 pg/m 3 

(0.2 ppm) of 0 3 over a 2-hr period. Two air exposures preceded the 0 3 exposure, 

which was followed by another air exposure. Another group (five individuals) 

were only repeatedly tested pre- and post-air exposure for their response to 

histamine. In these two groups, the bronchial responsiveness to histamine was 

not different in the air exposures. The bronchomotor response to inhaled 

histamine aerosol was not altered following the 392-pg/m 3 (0.2-ppm) 0 3 exposure. 

However, a third group (seven individuals) was also exposed to air for 2 days 

and to 784 pg/m3 (0.4 ppm) of 0 3 on the following day. The mean bronchial 

responsiveness to inhaled histamine was increased following exposure to 784 

pg/m3 (0.4 ppm) of 0 3 . Baseline SR aw (i.e., before histamine) after tfie 

0.4-ppm exposure remained unchanged. 

10-29 
As part of a study of repeated exposures to 0 3 (discussed in detail in 

Section 10.3), Kulle et al. (1982b) exposed two separate groups of subjects 

(13 males, 11 females) for 3 hr to filtered air and then 1 week later to 784 

Ng/m3 (0.4 ppm) of 0 3 . One hour before the end of exposure, 15 min of exercise 

at 100 W was performed approximating a VE 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 

03 as compared to filtered-air exposure. 

Two hypotheses have been proposed that are consistent with the observations 

of increased airway reactivity to histamine and methacholine following 0 3 

exposure (Holtzman et al., 1979). The first suggests that 0 3 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 03 or a byproduct of 03 causes an increase in the 

number or the binding affinity of acetylcholine receptors on bronchial smooth 

muscle. 

10.2.7 Mechanisms of Acute Pulmonary Effects 

The primary acute respiratory responses to 0 3 exposure are decrements in 

variables derived from measures of forced expiratory spirometry (volumes and 

flows) and respiratory symptoms (notably, cough and substernal pain upon deep 

inspiration). Altered ventilatory control during exercise (increased f R and 

decreased VT with VE remaining unchanged) and small increases in airway resistance have also been observed. 

Decrements in FVC observed at relatively high (1470-pg/m3 ; 0.75-ppm) 0 3 

concentrations have been associated with increases in RV (Hazucha et al., 

1973; Silverman et al., 1976). Since increased RV occurs only at higher 0 3 

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 3 on small airway smooth muscle or by interstitial pulmonary 

edema. 

At 03 concentrations of 980 pg/m3 (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 

10-30 
effort, rather than a decrease in lung compliance, most likely causes the 

reduced inspiratory capacity resulting from 0 3 exposure (Bates and Hazucha, 

1973; Silverman et al., 1976; Folinsbee et al., 1978). Ozone is thought to 

"sensitize" or stimulate irritant (rapidly adapting) and possibly other airway 

receptors (Folinsbee et al., 1978; Golden et al., 1978; Holtzman et al., 1979; 

McDonnell et al., 1983). This results in vagally mediated inhibition of 

maximal inspiration, either involuntarily or due to discomfort (Bates et al., 

1972; Silverman et al. , 1976; Folinsbee et al. , 1978; Adams et al. , 1981). 

Stimulation of irritant receptors is also believed to be responsible for the 

occurrence of respiratory symptoms (Folinsbee et al., 1977b; McDonnell et al., 

1983) and for alterations in ventilatory control (Folinsbee et al., 1975; 

Adams et al., 1981; McDonnell et al., 1983). These hypotheses remain to be 

proven. 

Unless measured at absolute lung volumes, decrements in forced expiratory 

flows (e.g., FEV1 01 

FEF25-75%) 

 are difficult to interpret. A small portion 

of the decrease in f1ow may be related to airway narrowing (Folinsbee et al., 

1978; McDonnell et al., 1983). Airway narrowing, as indicated by increased 

airway resistance, probably results from either smooth-muscle contraction, 

mucosal edema, or secretion of mucus. These can be initiated by vagally 

mediated reflexes from irritant receptor stimulation, by the interaction of an 

endogenous or exogenous substance with the vagal efferent pathway, or by the 

direct action of 0 3 (or an 03-induced, locally released substance) on smooth 

muscle or mucosa (Folinsbee et al., 1978; Holtzman et al.; 1979; McDonnell 

et al., 1983). Beckett et al. (1985) effectively blocked 0 3-induced increases 

in airway resistance by having subjects breathe aerosols of atropine, a 

muscarinic cholinergic antagonist, prior to exposure. These findings support 

the conclusion that 0 3-induced increases in airway resistance involve parasympathetic neural release of acetylcholine at the site of muscarinic receptors 

on the smooth muscle of large airways and suggest mediation of this response 

by vagal efferent reflex pathways. 

It is probable that stimulation of airway receptors is an afferent mechanism common to changes in airway resistance as well as changes in volumes and 

flows. However, McDonnell et al. (1983) postulated the existence of more than 

one mechanism for the normal processing of this sensory input, implying that a 

different efferent mechanism is responsible for 0 3-induced changes in lung 

volume. They based th7s postulation on their observed lack of correlation 

10-31 
between individual changes in lung volumes and airway resistance and on differences in the concentration-response curves for these variables. Kulle et al. 

(1985) also observed a lack of'correlation between individual changes in SGaw 

and FVC (r = 0.09) and in SG aw and FEV1 (r = 0.24). Beckett et al. (1985) 

provide strong support for the involvement of more than one mechanism in 0 3- 

induced pulmonary responses. While pretreatment with atropine blocked increased airway resistance in their 0 3-exposed subjects, it had no effect on 

the 03-induced decreases in lung volumes (FVC, TLC). Thus, while these findings 

indicate increased airway resistance is via a reflex stimuiation of airway 

smooth muscle, the failure of atropine to block the decrease in lung volumes 

suggests a separate mechanism for this response which is not dependent on 

functioning muscarinic receptors. 

10.2.8Preexisting Disease 

According to the National Health Interview Survey for 1979 (U.S. Department of Health and Human Services, 1981), there were an estimated 7,474,000 

chronic bronchitics, 6,402,000 asthmatics, and 2,137,000 individuals with 

emphysema in the United States. Although there is some overlap of about 

1,000,000 in these three categories, it can be reasonably estimated that over 

15,000,000 individuals reported chronic respiratory conditions. In clinical 

studies that have been published, individuals with asthma or chronic obstructive 

lung disease (COLD) do not appear to be more responsive to the effects of 0 3 

exposure than are healthy subjects. Table 10-4 presents a summary of data from 

03 exposure in humans with pulmonary disease. 

Linn et al. (1978) assessed pulmonary and biochemical responses of 22 

asthmatics (minimal asthma to moderately severe chronic airway obstruction 

with limited disability) to 2-hr exposures to clean air, sham 0 3 , and 392 pg/m3 

(0.20 ppm) 03 with secondary stressors of heat (31 ° C, 35 percent rh) and 

intermittent light exercise (VE = 2 x resting VE ). 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 3 ) studies were completed, subjects were exposed to 

filtered air, a sham (i.e., some 0 3 was initially present in the exposure 

chamber), and a 392- to 490-pg/m3 (0.20- to 0.25-ppm) 03 condition (a 3-day 

control study was conducted over 3 days [0 ppm 0 3 ] on 14 of these individuals). 

During each 2-hr exposure condition, subjects exercised for the first 15 min 

10-32 
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10-33 
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 VE so that inhaled 0 3 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 3 exposures, but this increase was 

not statistically different from sham or control conditions. A spectrum of 

biochemical parameters was measured in blood obtained only post-exposure. The 

significant biochemical changes reported were small, and probably only represent 

the normally found individual and group variability seen in these parameters 

despite the investigators' suggestion that asthmatics may react biochemically 

at lower 03 concentrations than nondiseased individuals. 

Clinically documented-asthmatics (16 years average duration of asthma) were 

exposed either to filtered air or 490 pg/m 3 (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 3 . However, some 

individual asthmatics did respond to 0 3 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 information would have been extremely valuable in providing opportunities to study 

this more susceptible portion of the asthmatic population further. 

Koenig et al. (1985) exposed 10 adolescent asthmatics at rest to clean 

air and to 235 pg/m3 (0.12 ppm) 03 . Exposure was via a rubber mouthpiece for 

1 hr. The subjects, aged 11 to 18 years old, had a history of atopic (Type I, 

IgE mediated) extrinsic asthma, characterized by documented reversible airways 

obstruction, elevated serum IgE levels, positive reaction to inhaled dust, 

mites, mold and/or pollen antigens, and exercise-induced bronchospasm. Because 

of the relative severity of their asthma, subjects maintained their usual 

medication therapy during testing. A comparable group of 10 healthy, nonatopic 

10-34 
adolescents, aged 13 to 18 years old, was also similarly exposed. No significant 

changes in pulmonary function or symptoms resulted from 0 3 exposure as compared 

to exposure to clean air in either the healthy or asthmatic adolescent subjects. 

Data from clinical studies have not indicated that asthmatics are more 

responsive to 03 than are healthy subjects. However, the relative paucity of 

studies and some of the experimental design considerations (subject population, control of inedication, exposure VE , appropriateness of pulmonary function 

measurements) in the three studies that have been published suggest that the 

responsiveness of asthmatics to 0 3 , relative to healthy subjects, may be an 

unresolved issue. (This issue is treated in more detail in Chapter 12). 

Linn et al. (1982a) studied 25 individuals (46 to 70 years old) with 

COLD (emphysema and chronic bronchitis); 12 percent were nonsmokers and the 

remainder were moderate to heavy smokers, with 11 individuals not smoking at 

this time. A11 had chronic respiratory symptoms with subnormal forced expiratory flow rates; the mean FEV1/FVC ratio was 50 percent. Each subject underwent a control filtered air and a 235-pg/m3 (0.12-ppm) 03 exposure (randomized) 

for 1 hr. These subjects first exercised for 15 min, then rested for 15 min, 

then exercised for 15 min, and finally rested for 15 min. Exercise loads were 

designed to elevate VE to 20 L/min (the physiological cost of this exercise to 

each of the wide variety of subjects was not identified). Pre- and post-exposure 

measurements of various pulmonary functions as well as arterial oxygen saturation 

(Sa02 ) (Hewlett-Packard ear oximeter) were made. No significant differences in 

forced expiratory performance or symptoms attributable to 0 3 were found. From 

pre-exposure values at rest (normal saturations) to mid-exposure values -during 

exercise, mean Sa02 increased by 0.65 ± 2.28 percent with purified air, but 

decreased by 0.65 ± 2.86 percent with 0 3 . This difference was significant. 

However, this small decrement attributable to 0 3 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, interpreting changes in Sa0 2 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 fiitered air (sham 0 3 ) and one to 392 pg/m3 (0.2 ppm) of 0 3 in a 

10-35 
randomized fashion. Subjects maintained their usual patterns of activity, 

drug use, etc., except for an imposition of no smoking for 1 hr prior to the 

baseline studies. During the 2-hr exposures, the subjects exercised for 

7.5 min every half-hour at a load sufficient to increase V E to 20 to 30 L/min 

and an oxygen uptake of —1 L/min. Sa0 2 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 statistically significant difference between the effects of air exposure versus 0 3 

exposure in any of the spirometric measurement values or symptoms. The only 

significant alteration resulting from 03 exposure was found in Sa0 2 , 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 3 days. Again, knowledge of 

%COHb is necessary to interpret these small changes in Sa0 2 correctly. 

Kehrl et al. (1983) presented further information on individuals with 

COLD. They restudied eight subjects from the group that Solic et al. (1982) 

had exposed to 392 pg/m3 (0.2 ppm) of 0,. In this experiment the sub.lects 

were exposed to 588 pg/m3 (0.3 ppm) of 0 3 with a protocol similar to that used 

by Solic et al. Data presented consisted of ineasurements made during the 

392-pg/m3 (0.2-ppm) exposure, as well as new data obtained during the 588-pg/m 3 

(0.3-ppm) exposures. The second exposure occurred 6 to 9 months later. No 

statistically significant 0 3-induced changes in respiratory mechanics or 

symptoms were found in the COLD patients at either 0 3 concentration. Statistically significant changes in pulmonary function or symptoms were also not 

observed when the number of COLD patients exposed to 588 pg/m 3 (0.3 ppm) was 

increased to 13 (Kehrl et al., 1985). Arterial oxygen saturation (ear oximeter) 

measured in eight of these subjects during the last exercise interval was 0.95 

percent less with 03 exposure :as.opposed to clean air exposure; this difference 

nearly attained statistical significance (P = 0.07). 

Linn et al. (1983) presented data on 28 COLD patients exposed for 1 hr to 

0, 353, and 490 pg/m 3 (0.0, 0.18, and 0.25 ppm) of 03 . Subjects had chronic 

respiratory symptoms; their mean FEV1 , 0 /FVC was 58%, indicating a mild degree 

of obstruction for the group. Severity of COLD was classified as minimal for 

12 subjects, moderate for 14 subjects, and severe for 2 subjects. Two subjects 

had never smoked, while eleven were ex-smokers and 15 were current smokers. 

Subjects continued use of chronic medication during the study but avoided 

inhaled bronchodilators on testing days. Subjects exercised for the first 

10-36 
and third 15-min periods and rested in the second and fourth periods. The 

exercise performed varied in intensity as did the corresponding V E . 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 3 exposures even at levels of 0 3 exceeding first-stage 

alert levels. Arterial oxygen saturation (ear oximeter) was not changed 

during the second exercis_e 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 

0 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 

smal 1 changes i n Sa0 2 may be of some si gni fi cance, al though 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 3 

exposures where COLD patients exercised at higher intensities may be of interest. 

Konig et al. (1980) performed studies on 18 individuals, three of whom 

suffered from COLD and one of whom had extrinsic ailergic 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 

to 196 pg/m3 (0.1 ppm) of 0 3 as well as on a sham-exposure day. In two of the 

three patients with COLD, increases in SR aw of 37 and 39 percent were recorded 

after the 0 3 exposure. The asthmatic patient was not affected by exposure to 

this level of 0 3 . Whether the results presented represent the response to a 

bronchial reactivity test immediately post-exposure or to the 03 exposure is 

unclear. In addition, the small number of COLD subjects studied makes an 

adequate evaluation difficult. 

Kulle et al. (1984) exposed 20 chronic bronchitic smokers with some 

evidence of airway obstruction for 3 hr to filtered air and 804 pg/m 3 (0.41 ppm) 

of 03 . Fifteen minutes of bicycle exercise at 100 W was performed during the 

second hour of exposure. Forced vital capacity and FEV 3 decreased significantly 

with exposure to 0 3 compared to clean-air exposure; the decreases were small 

in magnitude (< 3 percent), and respiratory symptoms were mild. 

10-37 
One study (Superko et al., 1984) has attended the physiological responses 

of patients with ischemic coronary heart disease (n = 6) randomly expos'ed to 

0, 392, and 588 pg/m3 (0.0, 0.2, and 0.3 ppm) 0 3 . The diagnosis of coronary 

disease was made by documented previous myocardial infarction, angiography, or 

classic angina pectoris with reproducible ECG changes on graded exercise 

testing. Each patient had a well defined and reproducible symptomatic angina 

pectoris threshold. Three of the patients also exhibited evidence of obstructive pulmonary disease as indicated by FEV1 , o /FVC of less than 70 percent; 

smoking history of the subjects was not included. Each exposure was of 40 min 

duration and consisted of 10 to 15 min gradually incremented exercise warm-up 

followed by 25 to 30 min exercise at an intensity slightly below the subjects' 

symptom threshold (mean VE= 42 L/min). Changes in pulmonary function (RV, 

FVC, FEVl,o, FEF25-75) following exposures were not different among the three 

conditions. Considering the magnitude of exercise V E(42 L/min), changes in 

pulmonary function might have been expected. This lack of change may be 

related to the relatively short exposure duration, small number of subjects, 

or past smoking history of subjects. There were also no significant differences 

in cardiopulmonary responses (VE , fR , V02 , HR, SBP) during exercise, time to 

onset of angina, or ischemic cardiovascular changes among the three conditions. 

10.2.9 Other Factors Affecting Pulmonary Responses to Ozone 

10.2.9.1 Cigarette Smoking. Smokers have been studied as a population group 

having potentially altered sensitivity to oxidant exposures. Hazucha et al. 

(1973) and Bates and Hazucha (1973) reported the responses of 12 subjects 

divided by smoking history (six smokers and six nonsmokers) who were exposed 

to 725 and 1470 pg/m 3 (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 measurements were made after each exercise period. The characteristic odor of 0 3was 

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 FEF25-75% were greater for 

nonsmokers after either 0 3exposure, whereas smokers exhibited greater decrements in FEV1 0and 50% Vmax' .Smokers exposed to 1470 pg/m 3 (0.75 ppm) of 0 3 

had a greater decrease in FEF25-75% than did nonsmokers. The FEF25-75% changes 

were much larger than the changes in FEV 1 01 regardless of 0 3concentration, 

10-38 
exposure duration, and smoking habit. Smoking history (not given specifically) 

appeared to have different effects on the various pulmonary functions measured. 

Kerr et al. (1975) exposed their subjects (10 smokers and 10 nonsmokers) 

to 980 pg/m3 (0.5 ppm) of 03 for 6 hr, during which time the subjects exercised 

twice for 15 min each (VE = 44 L).' For the remainder of the exposure time the 

subjects were resting. Follow-up measurements were made 2 and 24 hr later. A 

control day on which subjects breathed filtered air preceded the 0 3-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 3 exposure, being most 

prominent for FVC and FEV3 . Similar significant decrements were observed for 

FEV1 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 ievel for MEF. A 

significant reduction in SG aw and increase in R

L were observed, for the most 

part in nonsmokers 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 filteredair environment or one containing 588 pg/m 3 (0.3 ppm) of 0 3 . Two periods 

(10 min in duration) during the 2-hr exposure were devoted to smoking a cigarette. 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 SGaw 

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 03 . 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 pg/m3 (0.15 ppm) of 0 3 for 2 hr to his standard intermittent 

rest-exercise regime. SG aw was measured three times: at 1 and 2 hr during 

exposure and also at 1 hr post-exposure. Significant decreases were found 

10-39 
during exposure, i.e., 4 percent at 1 hr and 10 percent at 2 hr in nonsmokers, 

No change from baseline occurred in the smokers. These data, which suggest 

significant differences in response between smokers and nonsmokers exposed to 

the low ambient level of 294 pg/m3 (0.15 ppm) of 03, were not presented in 

enough detail to permit in depth evaluation of the findings. Thus, the statistical significance, if any, of these findings is unclear. 

DeLucia et al. (1983) reported that smolcers (six men and six women) were 

relatively resistant to the oral inhalation of 588 pg/m 3 (0.3 ppm) of 0 3 . Few 

smokers detected the presence of 0 3 , whereas the majority of nonsmokers (six 

men and six women) experienced significant discomfort. Pulmonary function 

tests (FVC, FEV, and FEV25-75%) were made pre- and post-exposure (within 15 

min). Overall, the decrements in pulmonary functions were significant and the 

authors attributed them to 03 . 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 pg/m 3 (0.3 ppm) of 03 than 

women smokers. No apparent differences were noted for the men. 

Thirty-two moderate or heavy smoking subjects (26 men and 6 women) were 

divided into four groups and exposed randomly to air alone, air plus smoking 

(2 cigarettes/hr), 03 alone, and 03 plus smoking (Shephard et al., 1983). 

Four 03-exposure protocols were employed: 725 pg/m 3 (0.37 ppm) and 1470 pg/m 3 

(0.75 ppm) in subjects at rest; and 980 pg/m3 (0.50 ppm) and 1470 pg/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. Carboxyhemoglobin 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 significantly lower on those days when smoking was conducted in an 0 3 environment. 

Ozone exposure alone (no smoking during exposure) resulted in the typical and 

anticipated decreases in pulmonary functions (FVC, FEVl 0) 25% 

Vmax, 

 and 50% 

Vmax) as reported by others. However, the onset of these pulmonary changes 

was slower and the response less dramatic compared to data obtained on nonsmokers. The authors offered two explanations to account for the diminished 

response: (a) the presence of increased mucus secretion by these chronic 

smokers may have offered transient protection against 0 3 's irritant effect or 

10-40 
(b) the sensitivity of the airway receptors may have been reduced by chronic 

smoking. The chronic effect of smoking induced a delay in the bronchial 

irritation response to 0 3 exposure. There was no significant interaction 

between cigarette smoking and responses to 0 3 . 

10.2.9.2 Age and Sex Differences. Although a number of controlled human 

exposures to 0 3 have used both male and female subjects of, varying ages, in 

most cases the studies have not been designed to determine age or sex differences. 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 03 in a small number (n=8) of nonsmoking males varying in age from 22 to 46 

years. Comparison of the mean change in pulmonary function between the three 

oldest subjects (33 to 46 years old) and_the five youngest subjects (22 to 27 

years old) revealed only small, inconsistent differences. 

McDonnell et al. (1985b) exposed boys (n = 23), aged 8 to 11 yr, once to 

0.0 and once to 235 pg/m3 (0.12 ppm) 03 in random order. The exposure protocol 

was identical to that previously employed in their study of adult males 

(McDonnell et al., 1983). Exposure duration was 150 min, and the subjects 

alternated 15-min periods of rest and heavy exercise (VE = 35 L/min/m2 BSA) 

during the first 120 min of exposure. Forced expiratory spirometry and respiratory symptoms were measured before and at 125 min of exposure;,airway resistance 

was measured before and at 145 min of exposure. Definitive statistical analyses 

(paired t-tests) were restricted to testing changes in FEV 1 , o and cough since 

these variables demonstrated the most statistically significant changes in 

their previous study of adults. Exploratory statistical analyses.were performed 

for changes in the other measured variables; however, these analyses cannot be 

interpreted as tests of hypotheses. When compared with air exposure, a small 

(3.4 percent) but significant decrement in FEV 1.0 was observed, and exploratory 

anaiyses suggest that decrements in FVC and forced expiratory flow rates may 

al so have occurred. No si gni fi cant i ncrease i n cough was found due to. 0 3 

exposure, and the other exploratory functions and symptoms did not'change. 

Results from this study of boys were compared to those.of adult males exposed 

under identical conditions (McDonnell, 1985c). Actually, exercise V E was less 

in the children (39 L/min) than in the adults (65 L/min), however, when normalized for BSA, both children and adults were exercising at similar ventilation 

10-41 
rates (VE/BSA of - 35 L/min/m 2 ). Statistical comparisons of the 0 3 effects 

between children and adults were not performed due to the repeated measures 

design in the children's study and the use of independent samples in the adult 

study. With exposure to 235 Ng/m3 (0.12 ppm) 0 3 , FEVi , o decreased 3.4 percent 

for the children as compared to a 4.3 percent decrease for the adults. Exposure 

to 03 caused an increase in cough reported by adults while children experienced 

little or no increase in cough after 0 3 exposure. These results indicate that 

the effects of 0 3 exposure on lung spirometry were very similar for both 

adults and children. However, adults had an increase in cough as a result of 

exposure, while children reported no symptoms. The reason for this difference 

is not known and needs further study. 

Folinsbee et al. (1975), noting the lack of enough subjects for adequate 

subdivision, attempted to make sex comparisons in a group of 20 male and 8 

female subjects exposed to 0 3 . 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 pg/m 3 (0, 0.25, 0.50, and 0.75 ppm) of 0 3 . 

Forced expiratory function decreased immediately following exposure to 980 and 

1470 pg/m3 (0.50 and 0.75 ppm), with greater changes occurring at the highest 

03 concentration. The average decrements in FEV l 0 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 03 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 pg/m3 (0, 0.20, 0.20, 0.20, and 0.42 or 0.50 ppm) of 0 3 , 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 l 0 , and FEF25-75% indicated that prior exposure to 

392 pg/m3 (0.20 ppm) of 0, had no effect on functional decrements occurring 

after subsequent exposure Vto either 823 or 980 pg/m3 (0.42 or 0.50 ppm) of 03 

on the fourth day (see Section 10.3). Although differences between men and 

women were reported for all three measurements, with men having expected 

10-42 
larger expired volumes and flows, there were no gender by pollutant interactions, 

indicating that male and female subjects responded to 0 3 in a similar fashion. 

DeLucia et al. (1983) reported on 12 men and 12 women.(equally ~ divided by 

smoking history) exercising for 1 hr at 50 percent of their max V0 2 while 

breathing 588 pg/m (0.3 ppm) of 03 through a mouthpiece. Minute ventilation 2 

for the men averaged 51 L/min and for the women 34.7 L/min. Women nonsmokers 

who did not inhale as much 03 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 1 0 (7.9 percent), and FEF25-75% 

(12.9 percent), there were no significant differences between the sexes. 

These investigators also found increases in f 8 and decreases in VT during 

exercise. These effects are similar to those reported by other investigators. 

Gibbons and Adams (1984) reported the effects of exercising 10 young 

women for 1 hr at 66 percent of max V0 2 while the women breathed 0, 297, or 

594 pg/m3 (0, 0.15, or 0.30 ppm) of 0 3 . Significant decrements in forced 

expiratory function were reported at 594 pg/m 3 (0.30 ppm) of 0 3 . 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 effecti.ve dose.than 

the women. However, large individual variations in responsiveness were present 

in all groups. 

The possible enhancement of responses to 0 3 inhalation in female subjects 

was investigated in the same laboratory (Lauritzen and Adams, 1985). Comparisons 

between the sexes were made on a equivalent effective dose basis (0 3 concentrations x VE x exposure duration). Six young women exercised continuously for 

1 hr at three exercise levels (23, 35, and 46 L/min) while being exposed to 0, 

392, 588, and 784 pg/m3(0.0, 0.2, 0.3, and 0.4 ppm) 0 3 . Significant, 03- 

dependent decrements were observed for FVC, FEV 1 , and FEF25-75 along with 

changes in the exercise ventilatory pattern (i.e., increased f R and decreased 

VT ). A comparison of these effects with the responses reported in an equal 

number of young adult males previously studied by the authors (Adams et al.., 

1981) at the same total 0 3 effective doses revealed significantly greater 

effects on FVC, FEVl , and fR for the females. Many, but not all, of the 

gender differences were lost when responses were normalized for "relative 

effective dose." The ratio of V0 2 max or TLC in males compared to females 

was 0.68 and 0.69, respectively. Thus, when responses were expressed at the 

10-43 

m 
same relative exercise intensity or as dose per unit TLC, the gender 

differences were diminished. Sample sizes were too small (n=6), however, to 

quantitatively identify other specific factors that could account for the 

apparent differences between male and female subjects exposed to 0 3 . 

10.2.9.3 Environmental Conditions. Very few controlled human studies have 

addressed the potential influence environmental conditions such as heat or 

relative humidity (rh) may have on responses to 03 . In fact, most exposures 

have been performed under standard room temperature and humidity conditions 

(20-25°C, 45-50 percent rh). A series of studies by Hackney et al. (1975a,b,c; 

1977a) and Linn et al. (1978) were conducted at a higher temperature and lower 

humidity (31°C, 35 percent rh) to simulate ambient environmental conditions 

during smog episodes in Los Angeles. No comparisons were made to the effects 

from 03 exposure at standard environmental conditions in other controlled 

studies. 

Folinsbee et al. (1977b) studied the effects of a 2-hr exposure to 

980 pg/m3 (0.5 ppm) of 03 on 14 male subjects under four separate environmental 

conditions: (1) 25° C, 45 percent rh; (2) 31° C, 85 percent rh; (3) 35° C, 

40 percent rh; and (4) 40°C, 50 percent rh. Wet bulb globe temperature (WBGT) 

equivalents were 64.4, 85.2, 80.0, and 92.0 ° F, respectively. The subjects 

exercised for 30 min at 40 percent of their max V02 (Section 10.2.2 and Figure 

10-1). Decreases in vital capacity and maximum expiratory flow during 03 

exposure were most severe immediately after exercise. There was a trend for a 

greater reduction when heat stress and 0 3 exposure were combined (WBGT=92.0°F), 

but this effect was only significant for FVC. In a similar study with eight 

subjects exposed to 980 pg/m3 (0.5 ppm) of 03 plus 940 pg/m3 (0.5 ppm) of 

nitrogen dioxide (NO2 ) (Folinsbee et al., 1981) (Section 10.6.3), the effects 

of heat and pollutant exposure on FVC were found to be no greater than additive. 

Part of the modification of 03 effects by heat stress was attributed to increased ventilation since ventilatory volume and tidal volume increased significantly at the highest thermal condition studied (40°C, 50 percent rh). 

More recently, Gibbons and Adams (1984) had 10 trained and heat-acclimated 

young women exercise for 1 hr at 66 percent of their maximum oxygen uptake 

while breathing either 0.0 pg/m 3 (0.0 ppm), 297 pg/m 3 (0.15 ppm), or 594 pg/m3 

(0.30 ppm) of 03 . These studies were conducted at two ambient conditions, 

i.e. 240 or 35°C. (Whether these are only dry bulb (db) temperatures or 

represent WBGT values is unclear, since humidity was not reported). No significant changes in any measured function were observed at 0 pg/m 3 (0.00 ppm) or 

10-44 
297 pg/m3(0.15 ppm) of 03 . Significant reductions in FVC, FEV1 01 TLC,:and 

FEF25-75 (P < 0.004) were reported as a consequence of exercising at 594 ~ag/m3 % 

(0.30 ppm). Pre-post decrements in FVC, FEV1 01 and FEF25-751 in.the 0.30 ppm, 

24° C environment were 13.7, 16.5, and 19.4 percent respectively, compared to 

observed decrements of 19.9, 20..8, and 20.8 percent, respectively, in the 

0.30-ppm 0 3 and 35° C condition. Only FVC differed significantly between the 

two temperature conditions. Some subjects failed to complete the exercise 

period in 35° C and 0.30 ppm 03 , and one subject could not finish the exercise 

in 24° C and 0.30 ppm 03 . Subjects reported more subjective discomfort, (cough, 

pain on inspiration, throat tickle, dizziness, and nausea) as 03 concentrations 

increased. No other effects were reported, although it was observed that 0 3 

(0.30 ppm) exposure and ambient high temperature induced an interactive effect 

on VA and fR . 

10.2.9.4Vitamin E Suppiementation . The possible protective effects of 

vitamin E against short-term responses to 0 3 exposure have not been as extensively investigated in humans as they have in animals (see Chapter 10). Only 

two studies have been published on the pulmonary effects of vitamin E supplementation in healthy subjects exposed to 0 3 . Both of these have failed to 

show any protective effect against 0 3-induced changes in respiratory symptoms 

and 1ung function (Hackney et al., 1981) or against in vivolipid peroxidation 

of the lung, as measured by decreased pentane production (Dillard et al., 

1978). Additional studies demonstrating the lack of significant differerices 

between the extrapulmonary responses of vitamin-E supplemented and placebo 

groups exposed to 03 are discussed in Section 10.6. 

Dillard et al. (1978) studied ten vitamin,E-sufficient adults breathing 

filtered air or 588 ~ag/m (0.3 ppm) 0 3 3 on a mouthpiece while continuously 

exercising for 1 hr at 50 percent V02max' Pulmonary function was measured 

before and after each exercise period. Expired air samples were collected 

from five subjects at rest, after 5 min of exercise while breathing air, and 

after 5, 15, 30, 45, and 60 min of exercise while breathing 0 3 . Expired 

pentane, an index of lipid peroxidation, was. measured during the pre- and 

postexercise resting periods by gas chromatography. Exposure to 0 3 caused a 

significant increase in RV and significant decreases in VC and FEV l , o . Ail 

subjects reported throat tickle associated with 0 3 while some subjects experienced symptoms such as chest tightness, cough, pain on deep inspiration, 

congestion,' wheezing, or headache. Exercise alone resulted in an increased 

10-45 
production of pentane. However, there was no change in pentane production as 

a result of exposure to 0 3 above that caused by the stress of exercise. 

In a separate experiment, Dillard et al. (1978) tested six subjects 

exposed to hydrocarbon-scrubbed air during an initial 5-min rest, during 

graded exercise (25, 50, and 75 percent V02max) for 20, 40, and 60 min, and 

during a 20-min postexposure rest period. The same exercise protocol was 

repeated after supplementation of the subjects with 400 IU dl-a-tocopherol 

three times a day for 2 weeks, which increased plasma tocopheral levels 240 

percent. This treatment significantly reduced expired pentane levels at rest 

and during exercise. No significant differences in pulmonary function were 

obtained in response to 1 hr of exercise before and after vitamin E supplementation. 

Hackney et al. (1981) studied the effects of a 2-hr exposure to filtered 

air or 980 pg/m3 (0.5 ppm) 03 in healthy subjects (9 males and 25 females) 

receiving either 800 IU dl-a-tocopherol (n = 16) or a similar appearing placebo 

(n = 18) daily for 9 or 10 weeks. Mean serum vitamin E concentration increased 

by 70 percent over this period in the supplemented group while the mean concentration in the placebo group did not change significant1y. During exposure, 

the subjects alternated 15-min periods of rest and exercise at two times 

resting ventilation. Pulmonary function and respiratory symptoms were evaluated 

at the end of each exposure. No significant effects of vitamin E supplementation were found; however, a few of the supplemented ma1e subjects showed a 

possible beneficial effect. Since the sample size of male subjects was sma11 

(n = 9), a follow-up study was performed.. Subjects received either 1600 IU of 

dl-a-tocopherol (n = 11) or placebo (n = 11) daily for 11 or 12 weeks. The 

mean serum vitamin E concentration increased by 140 percent in the supplemented 

group and 30 percent in the placebo group. Exposures took place on three 

successive days during the last week of supplementation. The subjects were 

exposed to filtered air for 2 hr on the first day, followed by 2-hr exposures 

to 980 pg/m3 (0.5 ppm) 03 on the second and third days. The exercise protocol 

during exposure was similar to that described above. Pulmonary function and 

respiratory symptoms were evaluated at the end of each exposure. Ozone caused 

significant decreases in FVC, FEV l , o , FEV25/ , FEF50% , AN2 , and TLC in both the 

vitamin E-supplemented and placebo groups. The mean changes were not significantly different between groups. Although symptoms did not significantly 

increase with 0 3 exposure, there were no differences between the vitamin E. and 

10-46 
placebo groups. Results from these studies do not support a protective effect 

of vitamin E supplementation against short-term pulmonary responses in human 

subjects exposed to 0 3 . 

10.3 PllLMONARY EFFECTS FOLLOWING REPEATED EXPOSURE TO OZONE 

Just as pulmonary function decrements following a single exposure to 0 3 

are well documented, several studies of the effects of repeated daily exposures 

to 0 3 have also been completed (Table 10-5). In general, results from these 

studies indicate that with repeated daily exposures to 0 3 , decrements in pulmonary 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 0 3 exposure similar to that observed 

prior to repeated exposures. Repeated daily exposure to a given low concentration of 03 does not affect the magnitude of decrement in pulmonary function 

resulting from exposure at higher 0 3 concentration. 

A11 the reported studies of repeated responses to 0 3 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 (acciimation, acclimatization, desensitization, tolerance) 

have been recommended to replace adaptation and perhaps are more suitabie. 

However, the correct use of any of these terms requires knowiedge of (1) the 

physiological mechanisms involved in the original response, (2) which mechanisms 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 function are induced by 0 3 exposure, and of course, the pathways involved in 

attenuating these decrements and how they are affected with repeated 0 3 exposure 

are even less understood. Moreover, while attenuation of 0 3 -induced pulmonary 

10-47 
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10-48 
function decrements appears to reflect protective mechanisms primariiy 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 03 exposure, such as celi injury. Therefore, in the following 

discussion of specific studies, results will be presented without use of a 

specific term to describe observed phenomena generally. The use of response 

to imply pulmonary decrements resulting from 0 3 exposure and changes in response 

or responsiveness of the subject to imply alterations in the magnitude of 

these decrements will be retained. 

Hackney et al. (1977a) performed the initial experiments that demonstrated that repeated daily exposures to 0 3 resulted in augmented pulmonary 

function responses on the second exposure day and diminution of responses 

after sev,eral additional daily exposures. Six subjects who in prior studies 

had demonstrated responsiveness to 0 3 were studied during a season of iow smog 

to minimize potential effects from prior 0 3 exposure. A11 but one subject had 

a history of allergies. They were exposed.for approximately 2.5 hr to 980 pg/m3 

(0.5 ppm) of 0 3 for four consecutive days after.one sham exposure. Ambient 

conditions in the chamber were 31 ° C db and 35 percent rh. During the first 

2 hr, light exercise (of unknown level) was performed for 15 min every 30 min. 

The last half hour was used for pulmonary testing. Small decrements occurred 

in FVC and FEF?5 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 3 exposure day. Other pulmonary functions, 

i.e., totai airway resistances (R t) and nitrogen washout (AN2 ), 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 smali subject population, considerable variability in responses 

was noted (one subject with no history of allergies showed no pulmonary decrements , whi 1 e another sub ject had a i arge reducti on i n FVC and FEV I and an 

increase in ON 2 on day 2 with a return of responses to near control levels on 

day 4). 

Farrell et ai. (1979) investigated the pulmonary responses of 14 healthy 

nonsmoking (10 men and 4 women) subjects to five consecutive, daily 3-hr exposures to filtered air or 0 3 . In the first week, subjects were studied in a 

10-49 
filtered-air environment, followed in a second week with exposures to 784 pg/m 3 

(0.4 ppm) of 0 3 . Pulmonary function (FVC, FEV1 , FEV3 , SGaw , and FRC) was 

determined at the end of the 3-hr exposures. One bout of exercise (V E measured 

on one subject = 44 L/min) was performed after 1.5 hr of exposure. Statistical 

evaluations used a repeated measures analysis of variance for significant 

differences between the control and 03 exposure weeks, using each day of each 

exposure to make the comparisons. The analysis of variance showed that FVC, 

FEV1 , FEV3 , and SGaw differed significantly between control and 0 3 exposure 

weeks. No changes in FRC were found. In the 0 3 exposure, SGaw decreased 

significantly only on the first 2 days; this response was similar to air 

exposure day values on the last 3 days. Significant decreases in FVC occurred 

on the first three days only; however, the decrements were significantly - 

greater on the second day than on the first. Decrements in FEV 1 O and FEV3.0 

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 (FEV3.0) 

and fourth day (FEV1.0 ) of 03 exposures. The severity of symptoms generally 

corresponded to the magnitude of pulmonary function changes. ~ Symptoms were 

maximal on the first 2 days, decreasing thereafter with only one subject being 

symptomatic on the final day of exposure to 0 3 . Reporting of symptoms was 

maximal on the second 03 day. These investigators noted that five consecutive 

days of exposure (10 subjects) to 588 pg/m 3 (0.3 ppm) of 03 failed to induce 

significant changes in FVC or SGaw , implying that measurable changes are 

likely to occur in pulmonary function at 0 3 concentrations between 588 and 

784 Ng/m3 (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 environmental chamber at 35°C and 45 percent rh to filtered air on day 1, to 0 3 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 3 : group 1(n=10), 392 

pg/m3 (0.20 ppm) of 03 ; group 2(n=10), 686 pg/m 3 (0.35 ppm) of 03 ; group 3 

(n=8), 980 pg/m3 (0.50 ppm) of 0 3 . Subjects alternately rested and exercised 

at a VE of 30 L/min for 15-min periods. There were no significant acute or 

cumulative effects of repeated exposure to 392 pg/m3 (0.20 ppm) of 03 . With 

exposure to 686 pg/m3 (0.35 ppm) of 0 3 , decrements in forced expiratory var1ables appeared on the first 0 3 exposure day. Similar decrements occurred on 

the second 0 3 exposure day, although there was no significant difference.in 

responses observed on the first two exposure days. On the third day of exposure the pulmonary function changes were of lesser magnitude than on the first 

10-50 
2 days. In group 3, marked decrements in pulmonary function occurred (FEV1.0 

decreased 8.7 percent) after the first exposure to 980 pg/m 3 (0.50 ppm) of 03 ; 

these decrements were even greater (FEV1 0decreased 16.5 percent) after the 

second 03exposure (Figure 10-3). While not totally abolished, an attenuation 

of these decrements.(FEV1 0decreased 3.6 percent) was observed following the 

third 03exposure. The subjects claimed the most discomfort for the second 0 3 

exposure. Many noted marked reductions in symptoms on the third consecutive 

day of exposure to 0 3 . Two additional subjects were exposed to 980 pg/m3 

(0.50 ppm) of 03for four consecutive days. Although effects of 03on pulmonary 

function were observed on the first two days of exposure, few effects were 

seen on the third day, and no effect was .observed on the fourth day. The 

authors concluded that there were some short-term (2-day) cumulative effects 

of exposure to concentrations of 0 3that produced acute functional effects. 

This response period was followed by a period in which there was a marked 

1essening of the effect of 0 3on pulmonary function and on the subjective 

feelings of discomfort associated with exposure to 0 3 . The subjects for these 

studies represented a broad population mix in that some subjects had a prior 

history of respiratory difficulties, some essentially had no past respiratory 

history, and approximately two-thirds had prior experience with pollutant 

exposure. 

Horvath et al. (1981) performed studies designed not only to determine 

further the influence of five consecutive days of exposure to 823 pg/m 3 (0.42 

ppm), but to estimate the persistence of the attenuation of pulmonary responses. 

buring the 125 min of exposure, 24 male subjects alternately rested and exercised (VE= 30 L/min) for 15-min periods. Measurements of pulmonary functions 

were made daily pre- and post-exposure. A filtered-air exposure was conducted 

during the week prior to the 03 exposures. Selected subjects were then randomly 

assigned to return after 6 to 7, 10 to 14, and 17 to 21 days for a single 

exposure to 0 3 . Ambient 03levels in the locations where the subjects lived 

seldom exceeded 235.pg/m3 (0.12 ppm). The major pulmonary function measurements 

made—and subjected to statistical enalysis on these .subjects were FVC, FEV 1 , 

and FEF25-75,04' Changes with time in all three measurements were similar and 

major emphasis was ,directed toward FEV 1changes. Significant interaction 

effects occurred between the two within-subject factors (day of exposure and 

pre- and post-exposure change in FEV 1). The interaction resulted primarily 

from the post-exposure FEV1data, which revealed a"U"-shaped pattern across 

10-51 
A. GROUP 2 

5.2 

FILTERED FILTERED 

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4.8 

a t t- t 

°D 4.6 t 

~ o m ~ 

°• 4.4 ~ 

> 1 

~ ~ 4.2 1 

1 

4.0 

3.8 

~ 1 2 3 4 y 1~ 2 3 4 y ~ 1 Z 3 4 y ~ 1 2 3 4 y ~ 1 2 3 4 ~j 

a O a O a O a O a O 

c. n. I o. a a 

Figure 10-3. Forced expiratory volume in 1-sec (FEV 1 ,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). 

:L0-52 
days during 0 3 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 1 had returned to that 

observed on day l,.but it was still significantly greater than during room air 

exposure. The decrements in FEV1 from preexposure to postexposure on days 4 

and 5 were no longer significant although the absolute value of postexposure 

FEV 1 continued to be significantly less than the initial filtered air exposure. 

Subjective symptoms followed a similar pattern, with subjects on the fifth day 

indicating that they had not perceived any 0 3 . Two subjects showed little 

attenuation of response to 03 , and one subject was not affected by the 0 3 

exposures. Subjects who were more responsive on the first day of exposure 

required more consecutive days of daily exposure to attenuate response to 0 3 . 

A11 24 subjects returned for an additional exposure to 0 3 from 6 to 21 days 

later; of these, only 16 were considered to be sensitive to 0 3 , and their data 

are shown in Figure 10-4. Although the number of subjects in each repeat 

exposure was small, it was apparent that attenuation of response did not 

persi st l onger than 11 to 14 days , wi th some 1 oss occurri ng wi thi n 6 to 7 

days. in general, these authors made some interesting observations: (1) the 

time required to abolish pulmonary response to 0 3 was directly related to the 

magnitude of the initial response; (2) the time required for attenuation of 

pulmonary responses to occur was apparently inversely related to the duration 

of attenuation and (3) in one individual, attenuation of pulmonary response to 

03 persisted up to 3 weeks. The mechanism responsible for attenuation of 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 3 . Initially, 11 selected subjects, known to_have previously exhibited pulmonary decrements in response to 03 exposure, were exposed for 2 hr daily for four consecutive days to 921 pg/m 3 (0.47 ppm) 0 3 . Exposure consisted of alternating 

15-min periods of moderate exercise (VE = 3 x resting VE ) and rest. An exposure to filtered air, under otherwise equivalent conditions, was conducted on 

the day prior to the first 0 3 exposure. The pattern of change in pulmonary 

response to 03 was similar to that previously reported for repeated daily 

exposures. For example, while the initial exposure to filtered air produced 

essentially no change, on the first 0 3 exposure day FEVI decreased 11 percent, 

10-53 
FILTERED 

AIR 

PRE-EXPOSURE 

... 

+10 

c 

0 

~ 

0 

m 

Q -10 

0 

j -20 

W U. -30 

-40 

FILTERED 

AIR 

PRE-EXPOSURE 

DAILY 2-hr EXPOSURE 

TO 0.42 ppm 03 

1 2 3 4 ~ 

DAILY 2-hr EXPOSURE 

TO 0.42 ppm O, 

1 2 3 4 5 

I 

0.42 ppm Oa, 

1 WK 

POST-EXPOSURE 

A 

GROUP 1 

n =4 

0.42 ppm O,, 

2 WKS 

POST-EXPOSURE 

+10 

~ c 0 

m 

~ 

~ 

o, -10 

° -20 

> 

uW. -30 

4 

-40 

B 

GROUP 2 

n= 6 

FILTERED 

AIR 

PRE-EXPOSURE 

+ 10 r--- 

DAILY 2-hr EXPOSURE 

TO 0.42 ppm 03 

1 2 3 4 5 

~TT"T`TT' 

0.42 ppm O,, 

3 WKS 

POST-EXPOSURE 

~ 

m ~ 0 

~ L 

a -10 

° -20 

> 

`U. L-30 

4 

-40 

C 

GROUP 3 

n=6 

Figure 10-4. Percent change (pre-post) in 1- 

sec forced expiratory volume (FEV1.0), as the 

result of a 2-hr,exposure to 0.42 ppm ozone. 

Subjects were exposed to filtered air, to 

ozone for five consecutive days, and exposed 

to ozone again: (A) 1 wk later; (B) 2 wks 

later; and (C) 3 wks later. 

Source: Horvath et al. (1981). 

10-54 
with a further decline to 23 percent on the second day, returning to approximately 11 percent on the third day. By the fourth day, the mean response was 

essentially equivalent to that observed with exposure to filtered air. While 

most of the subjects demonstrated attenuation of response (complete data sets 

on only seven subjects), the response of one subject, who may have had a 

persistent low-grade respiratory infection, never diminished. Two others 

showed relatively little response to the initial daily exposures, but showed 

some severe responses during follow-up exposures. This pattern was not to be 

unexpected, based on other studies demonstrating similar atypical responses. 

To evaluate persistence of attenuated response, subjects repeated 0 3 exposures 

under the above conditions 4 days after the repeated daily exposures and 

thereafter at 7-day intervals for five successive weeks. Four days after the 

repeated daily exposures,' decrements in pulmonary function in response to 0 3 

exposure were not significantly different from the first exposure (FEV 1 , 0 

decreased 11.4 percent on the first day and decreased 8.6 percent four days 

after the repeated exposures). The decrement in FEV l . o on the subsequent 

weekly 03 exposures averaged 13.5 percent. Subjective symptoms generally 

paralleled lung-function studies, but were significantly fewer on the 0 3 

exposure which occurred four days after the repeated exposures. Since attenuation of pulmonary responses to 0 3 may fail to develop or may be reversed 

quickly in the absence of frequent exposure, these authors questioned the 

importance of attenuation of response in the public health sense. 

Following the design of an earlier protocol (Farrell et al., 1979), Kulle 

et al. (1982b) exposed 24 subjects (13 men and ll women) for 3 hr on five consecutive days beginning on Monday to filtered air during week 1 and to 784 

pg/m 3

(0.4 ppm) of 0 3 during week 2. Quring week 3, they exposed 11 subjects 

to filtered air on the first day and to 784 }ag/m 3 (0.4 ppm) of 0 3 on the 

second day, while they exposed the remaining 13 subjects for 4 days to filtered 

air and then to 784 pg/m3 (0.4 ppm) of 03 on the fifth day. One hour prior to 

the end of each exposure, the subjects performed 15 min of exercise at 100 W 

(VE = 4 to 5 times resting V E ). Although the magnitude of decrement was 

notably less, the patterns of change in responses of FVC and FEV1 were similar 

to those observed in previous studies, i.e., attenuation of response occurred 

during the 5 days of exposure. Attenuation of response was partially reversed 

4 days after and not present 7 days after repeated daily exposures. These 

results agree with those of Linn et al. (1982b), but contrast to those of 

10-55 
Horvath et al. (1981). Since the magnitude of decrements in pulmonary function (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 3 may be related to the magnitude of 

decrement in response observed with the initial exposure to 0 3 . 

Gliner et al. (1983) performed a study to determine whether daily repeated 

exposures to a low concentration of 0 3 (392 pg/m3 ; 0.20 ppm) would attenuate 

pulmonary function decrements resulting from exposure to a higher 0 3 concentration (823 or 980 pg/m ; 0.42 or 0.50 ppm). Twenty-one subjects (8 male, 3 

13 female) were exposed for 2 hr on five consecutive days to filtered air 

(0.0 ppm 0 3 ) on day 1, to 392 pg/m 3 3 (0.20 ppm) of 03 on days 2, 3, and 4, and 

to 823 or 980 pg/m (0.42 or 0.50 ppm) of 0 3 on day 5. For comparison, subjects 

who were exposed to 0.42 or 0.50 ppm of 0 3 were exposed to the same 0 3 concentration 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 pg/m 3 ; 0.20 ppm) did not alter expected pulmonary function 

response to a subsequent exposure to a higher 0 3 concentration (823 or 980 

pg/m3 ; 0.42 or 0.50 ppm). 

Sub jects were di vi ded i nto two groups based on the magni tude of thei r 

response to the acute exposure to 823 or 980 pg/m3 (0.42 or 0.50 ppm) 0 3 . 

Nine subjects were considered to be responsive (FEV 1 decrements averaged 

34 percent), and nine subjects were considered to be nonresponsive (FEV 1 

decrements averaged less than 10 percent). Statistical analysis based on this 

grouping indicated that responsive subjects exhibited pulmonary function 

decrements after both their first and second, but not their third, exposure to 

392 pg/m3 (0.20 ppm) ; decreases i n FVC and FEV I were about 9*percent. No 

significant effects of 392-pg/m3 (0.20-ppm) 03 exposure were found in the 

nonresponsive group. In both groups, repeated exposures to 0.20 ppm of 0 3 had 

no influence on the subsequent response to the higher ambient 03 exposure (823 

or 980 pg/m3 ; 0.42 or 0.50 ppm). Note that repeated exposures to the low 0 3 

concentration for only three consecutive days may have constituted insufficient 

total exposure (some combination of number of exposures, duration of exposures, 

10-56 
VE, and 0 3 concentration) to affect pulmonary function decrements resulting 

from exposure to higher 0 3 concentrations. Additional studies, with consideration 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 0 3 did not attenuate the response to 

a subsequent exposure at a higher effective dose of 0 3 . The pattern of pulmonary 

function decrements was evaluated following repeated daily 4-hr exposures to 

784 pg/m3 (0.40 ppm) of 0 3 with two 15 min periods of heavy exercise (VE = 57 

L/min). As expected, pulmonary function decrements were greater on the second 

of five consecutive days of 0 3 exposure.; thereafter, the response was attenuated. Exposure at rest to 784 pg/m 3 (0.4 ppm) of 03 for two consecutive days 

had no effect on pulmonary function. Ozone exposure on the next two succeeding 

days with heavy exercise produced pulmonary function decrements similar to 

those observed previously in this study for the first two_days of exposure to 

ozone. 

. Kulle et ai.. (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 l(control days), were exposed to 804 pg/m3 (0.41 ppm) 03 

for 3 hr/day on Monday through Friday of week 2, and on week 3 breathed filtered air on Monday, then were re-exposed to 0.41 ppm 0 3 on Tuesday. Bicycle 

ergometer exercise was performed at 2 hr of exposure at an intensity of 100 W 

for 15 min (VE ti 4-5 times resting). Spirometric measurements and recording 

of symptoms were made at the completion of all exposures. Small but significant decrements in FVC (2.6 percent) and FEV 3 (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 resul-ts indicate that individuals with chronic bronchitis also have attenuated responses with repeated 

exposures to 0 3 that persist for no.longer than 4 days. These results for 

smokers with chronic bronchitis contrast to those reported by the same investigators for normal nonsmoking subjects exposed under nearly identical conditions 

(Kulle et al., 1982b). Their normal subjects demonstrated larger decrements in 

FVC (8 percent) after the first and second exposures; thereafter the response 

was attenuated. This attenuation of response persisted beyond 4 days, and only 

with re-exposure. 7 days after repeated exposures did significant decreases in 

10-57 
FVC once again appear. These data also support the contention that persistence 

of an attenuated pulmonary response to 0 3 is related to the magnitude of the 

initial response. 

Bedi et al. (1985) performed a study to determine if lung responsiveness 

to ozone after an initial exposure would persist for 48 hr. Six healthy, nonsmoking audlts (5 females and 1 male) were exposed for 2 hr to filtered air on 

the first day, to 882 pg/m3 (0.45 ppm) 0 3 on the second day (day 1), and two 

days later to a second exposure to 0.45 ppm 0 3 (day 2). Subjects alternately 

rested and exercised at a VE of 27 L/min for 20-min periods. Forced expiratory 

spirometry was performed before the exposure started and 5 min after each 

exercise period. There were significant pulmonary function decrements on both 

03 exposure days. The decrements in FVC (DAY 1= 9.7 percent; DAY 2= 15.7 

percent), FEV1 (DAY 1= 13.3 percent; DAY 2= 22.8 percent), and FEF25-75% 

(DAY 1= 19.6 percent; DAY 2= 30.4 percent) were 6.0, 9.5, and 10.8 percent 

larger, respectively, after the day 2 exposure than after the day 1 exposure. 

Increased pulmonary responsiveness to 03 was, therefore, still present when 

exposures were separated by 48 hr. It is not known, however, if this pattern 

of every-other-day exposures would lead to attenuation of the response, as has 

been demonstrated for consecutive days of exposure. 

Folinsbee and Horvath (1986) studied the time course of hyperresponsiveness following acute ozone exposure. Four groups of healthy, nonsmoking 

adults (n=6,6,7,7) were exposed for 1 hr to 490 pg/m3 (0.25 ppm) 0 3 and then 

reexposed at 12, 24, 48, or 72 hr, respectively. Subjects exercised continuously at a VE of 63 L/min during exposure. Forced expiratory spirometry and 

maximal voluntary ventilation were performed prior to and within 10 min after 

exposure. As expected, 0 3 exposure was associated with a significant decline 

in FVC, FEVI, FEF25-75% , FEF75-85%, MVV, and IC. The general pattern for 

pulmonary function showed 'an increased responsiveness to 0 3 on the second 

exposure if it occurred within 24 hr. For example, the decreinents in FEV I 

were 6 percent larger in the 12-hr group (EXP 1= 13 percent; EXP 2= 19 

percent) and 14 percent larger in the 24-hr group (EXP 1= 20 percent; EXP 2= 

34 percent). An increased responsiveness to 0 3 persisted in some subjects for 

48 hr but it appeared to be lost within 72 hr. Symptoms generally paralleled 

the changes in lung function. Differences in persistence of respon~iveness to 

03 between the Folinsbee and Horvath (1986) and Bedi et al. (1985) studies are 

likely related to the different 0 3 concentrations used and the magnitude of 

the initial 03-induced decrements in lung function. 

10-58 
To determine, if nonspecific bronchial reactivity is a factor invoived in 

the attenuation of pul.monary responses to 0 3 , Dimeo et al: (1981) evaluated 

the effects of single and sequential 0 3 exposures on the bronchomotor response 

to histamine. To determine the lowest concentration of 0 3 that causes an 

increase in bronchial reactivity to histamine and to determine whether adaptation to this effect of 0 3 develops with repeated exposures, they studied 19 

healthy, nonsmoking normal adult subjects. Bronchial reactivity was assessed 

by measuring the rise in specific airway resistance (ASRaw) produced by inhalation of 10 breaths of histamine .aerosol (1.6-percent solution). In five 

subjects, bronchial reactivity was determined on four consecutive days without 

exposure to 0 3 (group I). In seven other subjects (group II), bronchial 

reactivity was assessed on two consecutive days; subjects were exposed to 

392 pg/m3 (0.2 ppm) of 03 on the third succeeding day and bronchiai reactivity 

was determined after exposure. Seven additional subjects (group III) had 

bronchial reactivity assessed for two consecutive days and then again on the 

next three consecutive days after 2-hr exposures to 784 pg/m 3 (0.4 ppm) of 03 . 

Exposures consisted of alternating 15-min periods of rest and light exercise 

(VE = 2x resting V E ). Pre-exposure bronchial reactivity of the groups was the 

same, and no change in bronchial reactivity occurred in group I tested repeatedly but not exposed to 0.3 . An increase in ©SRaw provoked by histamine was 

noted after the first exposure to 784 pg/m 3 (0.4 ppm) but not to 392 pg/m 3 

(0.2 ppm) of 03 . With three repeated 2-hr exposures to 0.4 ppm on consecutive 

days, the ©SRaw produced by histamine progressively decreased, returning to 

pre-exposure values after the third exposure. Their resuits 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 

784 pg/m3 (0.2-and 0.4 ppm), and that attenuation of this effect of 03 developed 

with repeated exposures. The lowest concentration of 0 3 (identified in other 

studies using light or moderate exercise) that caused changes in I symptoms, 

iung volumes, or airway resistance was also between 392 and 784 pg/m 3 (0.2 and 

0.4 ppm), and the time course for the development of attenuation of these 

responses to 03 was similar to that observed in this study. These authors 

propose that the appearance of symptoms, changes in pulmonary function, and 

the increase in bronchial reactivity may be related and caused by a change in 

the activity of afferent nerve endings in the airway epithelium. 

10-59 
Kulle et al. (1982b) also evaluated the effects of sequential 0 3 exposure 

on bronchial reactivity. Nonsmoking subjects (n = 24) were exposed for 3 hr 

on five consecutive days each week to filtered air during week 1 and to 784 

3 pg/m (0.4 ppm) 03 during week 2. During week 3, they exposed 11 subjects to 

filtered air on the first day and to 784 pg/m 3 (0.4 ppm) 03 on the second day, 

while they exposed the remaining 13 subjects for 4 days to filtered air and 

then to 784 pg/m3 (0.4 ppm) 0 3 on the fifth day. A 15-min period of exercise 

at 100 W(VE = 4 to 5 times resting VE) was performed 1 hr prior to the end of 

each exposure. After each exposure, a provocative bronchial challenge test 

was performed to determine bronchial reactivity to methacholine, defined as 

the log of the methacholine dose that provoked a 35 percent decrease in SGaw 

from control. Bronchial reactivity to methacholine observed after exposure to 

03 on the initial 2 to 3 days was significantly increased over that observed 

after exposure to filtered air. On the fourth and fifth consecutive days of 

03 exposure and with reexposure 7 days later, bronchial reactivity to methacholine was not significantly changed. The duration of the attenuated bronchial 

reactivity response was therefore much longer than that observed for FVC and 

FEV1.0 in the same subjects, as noted earlier in this section. 

An issue that merits attention is whether attenuated pulmonary responsiveness 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 3 is suggestive of reduced pulmonary responsiveness for 

chronically exposed residents of high-oxidant communities also remains unresolved. 

10.4 EFFECTS OF OZONE ON VIGILANCE AND EXERCISE PERFORMANCE 

Results from animal studies suggest that 0 3 causes alterations in motor 

activity and behavior, but whether these responses result from odor perception, 

irritation, or a direct effect on the central nervous system (Chapter 9) is 

unknown. In fact, modification of the inclination to respond was suggested as 

possibly being more important than changes in the physiological capacity to 

perform simple or complex tasks. Very few human studies are available to help 

resolve this issue. 

10-60 
Henschler et al. (1960) determined the olfactory threshold in 10 to 14 

male subjects exposed for 30 min to various 0 3 concentrations. In a subgroup 

of 10 subjects, 9 individuals reported detection when the ambient concentration 

was as low as 39.2 pg/m3 (0.02 ppm of 0 3 ). Perception at this low level did 

not persist, being seldom noted after some 0.5 to 12 min of exposure. The 

odor of 03 became more intense at concentrations of 98 pg/m3 (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 3 concentrations on the olfactory 

threshold and on the electrical activity of the cerebral cortex. He found in 

his 20 subjects that the minimum perceptible concentration (olfactory threshold) 

for 0 3 was between 0.015 and 0.04 mg/m3 (0.008 and 0.02 ppm). The few subjects 

on whom electroencephalograms (EEGs) were recorded showed a 30 to 40 percent 

reduction of cerebral electrical activity during 3 min of exposure to 0.02 mg/m 3 

(0.01 ppm) of 0 3 . The data are presented inadequately and can be considered J 

only suggestive. 

Gliner et al. (1979) determined the effects of 2-hr exposures to 0.0, 

490, 980, or 1470 pg/m3 (0.0, 0.25, 0.50, or 0.75 ppm) of 0 3 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 3 . However, when the 

ratio of signals was increased (five subjects), a deficit in performance 

beyond that of the normal vigilance decline was observed during the 1470-pg/m 3 

(0.75-ppm) 0 3 exposure. The results obtained were interpreted within the 

framework of an arousal hypothesis, suggesting that a high concentration of 0 3 

may produce overarousal. 

Five individuals (four men, one woman) served as subjects (Gliner et al., 

1980) i n studi es desi gned to eval uate the effects of 03 on the el ectri cai 

activity of the brain by monitoring the EEG during psychomotor performance. 

In the first experiment, a 2-hr visual sustained attention task was unaffected 

by exposure to filtered air or 1470 pg/m 3 (0.75 ppm) of 03 . The second experiment involved performing a divided-attention task, which combined a visual 

choice reaction time situation with an auditory sustained attention task. The 

10-61 
03concentrations were either 0.0, 588, or 1470.pg/m 3 (0.0, 0.3, or 0.75 ppm). 

Spectral and discriminant function analyses were performed on the EEGs collected during these studies. There was no clear discrimination between 0 3exposure and filtered air using the different parameters obtained from the EEG 

spectral analysis. Given the inability to obtain a discrimination between 

clean air and 1470 pg/m 3 (0.75 ppm) of 0 3using these techniques, EEG analysis 

does not appear to hol d any promi se as a quanti tati ve method of assess i ng 

health effects of low - concentration (i.e., < 1484 -pg/m3 ; 0.3-ppm) 0 3exposure. 

Mihevic et al. (1981) examined the effects of 0 3exposure (0.0, 588, 

980 pg/m3 ; 0.00, 0.30, and 0.50 ppm) in 14 young subjects who initially rested, 

then exercised for 40 min at heart rates of 124 to 130 beats/min, and finally 

rested for an additional 40 min. Pulmonary furiction measurements (FVC, FEV 1 , 

and MEF25-75) were made during rest periods and after exercise. The primary 

objective of the study was to examine the effects of exposure during exercise 

on perception of effort and to evaluate perceptual sensitivity to pulmonary 

responses. As expected, decrements in FVC, FEV 1 , and MEF25-75 were significantly greater (P <0.01) immediately after exercise than in the rest condition 

during either the 588- or 980-pg/m 3 (0.30- or 0.50-ppm) 0 3exposures. 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 0 3condition 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 3exposure (588, 980 pg/m3 ; 0.30, 0.50 ppm) indicated that 

the subject's sensitivity to a change in lung volume was greater than it was 

following filtered - air exposure. 

Early epidemiological studies on high school athletes (Chapter 11) provided suggestive information that exercise performance in an oxidant environment is depressed. The reports suggested that the effects may have been 

related to increased airway resistance or to the associated discomfort in 

breathing, thus limiting runners' motivation to perform at anticipated high 

10-s2 
levels. In controlled human studies, exercise performance has been evaluated 

during short-term maximal exercise or continuous exercise for periods up to 

1 hr (Table 10-6). Folinsbee et al. (1977a) observed that maximal aerobic 

capacity (max V02 ) decreased 10 percent, maximum attained work load was reduced 

by 10 percent, maximum ventilation (max VE ) decreased 16 percent, and maximum 

heart rate dropped 6 percent after a 2-hr 0 3 exposure (1470 pg/m3 ; 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 3 (0.15 and 0.30 ppm) 

03 (mouthpiece inhalation). No effects on maximum work rate or max V02 were 

found, although a significant reduction in max VE was observed during the 

588-pg/m3 (0.30-ppm) exposure. Similarly, max V02 was not impaired in men and 

women after 2-hr exposure and at-rest exposure . to 0. 0, 980, and 1470 pg/m 3 

(0.00, 0.50, and 0.75 ppm) of 03 (Horvath et al., 1979). 

Six well-trained men and one well-trained woman (all except one male 

being a competitive distance cyclist) exercised continuously on a bicycle 

ergometer for 1 hr while breathing filtered air or 412 pg/m 3 (0.21 ppm) of 0 3 

(Folinsbee et al., 1984). They worked at 75 percent max VQ 2 with mean minute 

ventilations of 81 L/min. As previously noted (Section 10.2.3}, pulmonary 

function decrements as well as symptoms of laryngeal and/or 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 3 levels. 

Adams and Schelegle (1983) exposed 10 well-trained distance runners to 

0.0, 392, and 686 pg/m3 (0. 0, 0.20, and 0.35 ppm) of 0 3 whi le 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 competitive bout. These exercise levels were of sufficient magnitude (68 percent 

of their max V02 ) to increase mean V E 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 3 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 leveis. Three subjects were unable to complete both 

the training and competitive simulation exercise bouts at 0.35 ppm 0 3 , while a 

10-63 
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fourth failed to complete only tho competitive ride. As previously noted 

(Section 10.2.3), the high ventilation volumes resulted in marked pulmonary 

function impairment and altered ventilatory patterns. The decrements were the 

result of physiologically induced subjective limitations of performance due to 

respiratory discomfort. The authors found it necessary to reduce the 68 percent 

max V02 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 suggested some decrement in performance associated with 0 3 exposure, 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 voiuntarily limit strenuous exercise during high-oxidant concentrations. However, 

increased ambient temperature and relative humidity are aiso associated with 

episodes of high-oxidant concentrations, and these environmental conditions 

may also enhance subjective symptoms and physiological impairment during 0 3 

exposure (see Section 10.2.9.3). Therefore, it may be difficult to differentiate any performance effects due to ozone from those due to other conditions 

in the environment. Several reviews on exercising subjects have appeared in 

the literature.(Horvath, 1981; Folinsbee, 1981; McCafferty, 1981; Folinsbee 

and Raven, 1984). 

10.5 INTERACTIONS BETWEEN OZONE AND OTHER POLLUTANTS 

An important issue is whether or not 0 3 interacts with other pollutants 

to produce additive as well as greater than additive effects beyond those 

resulting from exposure to 03 or the other pollutants alone. Also important 

to determine is whether no interactions occur when several pollutants are 

present simultaneously. Table 10-7 presents a summary of data on interactions 

between 03 and other pollutants. 

10.5.1 Ozone Plus Sulfates or Sulfuric Acid 

Several studies have addressed the possible interaction between 0 3 and 

sulfur compounds. Bates and Hazucha (1973) and Hazucha and Bates (1975) 

exposed eight volunteer male subjects to a mixture of 725 pg/m 3 (0.37 ppm) of 

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~ 
03 and 0.37 ppm of sulfur dioxide (S0 2 ) for 2 hr. Temperature, humidity, 

concentrations, and particle sizes of ambient aerosols (if any) were not 

measured. Sulfur dioxide alone had no detectable effect on lung function, 

while exposure to 0 3 alone resulted in decrements in pulmonary function. The 

combination of gases resulted in more severe respiratory symptoms and pulmonary 

changes than did 0 3 alone. Using the maximal expiratory flow rate at 50 percent 

vital capacity as the most sensitive indicator, no change occurred after 2 hr 

of exposure to 0.37 ppm S0 2 alone. However, during exposure to 725 pg/m 3 

(0.37 ppm) 0 3 a 13 percent reduction occurred, while exposure to the mixture 

of 725 pg/m3 (0.37 ppm) 03 and 0.37 ppm S02 resulted in a reduction of 37 percent in this measure of pulmonary function. The effects resulting from 0 3 and 

S02 i n combi nati on appeared i n 30 mi n, i n contrast to a 2-hr ti me 1 ag for 

exposure to 03 alone. 

Bell et al. (1977) attempted to corroborate these studies using four 

normal and four 03-sensitive subjects. They showed that the 0 3 + S02 mixture 

had an overall greater effect on pulmonary function measures than did 0 3 

alone. Differences ranging from 1.2 percent for FVC to 16.8 percent for V25 

were detected during 0 3 + S02 exposure relative to 03 exposure alone in normal 

subjects. The mean FEV l.o decreased 4.7 percent after 03 + S02 exposure 

relative to 03 alone in the sensitive subjects. When normals and sensitives 

were combined, the mean FEV l , o and FVC were both significantly lower after the 

03 + S02 exposure. Four of the Hazucha and Bates (1975) study subjects were 

also studied by Bell et al. (1977). Two of these subjects had unusually large 

decrements in FVC (40 percent) and FEV 1 (44 percent) in the first study (Bates 

and Hazucha, 1973), while the other two had small but statistically significant 

decrements. None of the subjects responded in a similar manner in the Bell 

et al. (1977) study. 

To determine why some of the Montreal subjects were less reactive to the 

S02-03 mixture when studied i.n 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 concentrated streams of S0 2 and 0 3 could have reacted rapidly with each other and 

with ambient impurities like olefins, to form a large number of sulfuric acid 

(H2SO4 ) nuclei which grew by homogeneous condensation, coagulation, and absorption of ammonia (NH 3 ) 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 

10-69 
chemical analysis in the chamber showed that acid sulfate particles could have 

been 10- to 100-fol d hi gher (100 to 200 pg/m3 ) , and thus mi ght have been 

responsible for the synergistic effects observed. However, recent studies 

conducted by Kleinman et al. (1981) involving identical concentrations of S0 2 

and 03 showed that the presence of 100 pg/m3 H2SO4 did not alter the response 

obtained with the S0 2-03 mixture alone. (See later discussion in this section.) 

Bedi et al. (1979) exposed nine young healthy nonsmoking men (18 to 27 

years old) to 784 pg/m 3 (0.4 ppm) 03 and 0.4 ppm S0 2 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 S02 showed no significant changes in pulmonary 

function. When exposed to either 0 3 or 03 plus S02 , the subjects showed 

statistically significant decreases in maximum expiratory flow (FEV1 

01 

FEF25-75%' and FEF509,) and FVC. There were no significant differences between 

the effects of 03 alone and the combination of 0 3 + 502 ; 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., ventilation 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 3 ; filtered air, 0.15 ppm of S0 2 ; filtered air; and 

finally 0.15 ppm of 03 + 0.15 ppm of S0 2 . 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 i n SG aw was used as the most sensi ti ve test of change i n functi on. 

They reported a significant decrease in five of the six young male subjects 

exposed to 03 alone. In three of the subjects, they reported a significantly 

greater decrease in SG aw after exposure to the combination of pollutants than 

with 03 exposure alone. Two other subjects had similar decreases with either 

03 or 03 + S02 exposure. Subjective symptoms of cough and bronchial irritation were reported to occur in subjects exposed to either 0 3 or the 03 + S02 

combination. The authors suggested that the combined effect of the two gases 

10-70 
on SGaw is more than simply additive in some exercising subjects. This conclusion is questionable, however, because of the small number of subjects responding 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 2 and 03 therefore remains unresolved 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 3 and S02 . While 

intermittently exercising (VE —30 L/min), eight young adult nonsmoking males 

were randomly exposed on separate occasions for 2 hr to filtered air, 0.4 ppm 

502 , 748 pg/m3 (0.4 ppm) of 03 , and 0.4 ppm of S0 2 plus 784 pg/m3 (0.4 ppm) of 

03 at 35°C and 85 percent rh. No functional changes in FEV I 0 occurred as a 

result of exposure to filtered air or 0.4 ppm of S0 2 , but decreases in FEV1 0 

occurred following exposure to either 784 pg/m 3 (0.4 ppm) of 0 3 (6.9 percent) 

or the combination of 784 pg/m 3 (0.4 ppm) of 03 plus 0.4 ppm of S02 (7.4 percent). Thoracic gas volume (TGV) increased and FEF 50% decreased in the 0 3 

exposures , whi 1 e FVC, FEF25-75%' FEF509,, ERV, and TLC al l decreased i n the 

03/S02 and 03 exposures. However, no significant differences were found 

between the 0 3 exposure and the 0 3 plus S02 exposure. In this study, statistical analyses were performed using ANOVA procedures. 

An analys i s of the data obtai ned i n the 1982 study and a pri or 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 synergistic effect consequent to exposure to 0.15 ppm of S02 and 294 pg/m3 (0.15 

ppm) of 03 using t-tests. The experimental designs of the Bedi et al. and the 

Kagawa and Tsuru studies were essentially similar. Reanalysis of the Bedi et 

al. data using t-tests and expressing data as relative changes indicated that 

the SGaw was not altered in the 25 0 C-45 percent rh environment but decreased 

10.6 percent (P < 0.05) in the S0 2 exposure and 19 percent (P <'0.01) in 0 3 

plus S02 exposure in hot, wet conditions. These investigators concluded that 

in one sense they confirmed the findings (based on t-tests) of Kagawa and 

Tsuru, but under different conditions. This might suggest a small potential 

effect on SG aw. They then stated, "Nonetheless, we believe that the use of a 

more stringent statistical approach provides for better analysis of collected 

data and that we are correct in stating that synergism had not occurred." 

10-71 
Folinsbee et al. (1985) exposed 22 healthy nonsmoking men (23.6 ± 8.1 

years of age) for 2 hr to a combination of 588 pg/m 3 (0.3 ppm) 0 3 and 1.0 ppm 

S02 as well as to each gas individually. The subjects alternated 30-min 

periods of treadmill exercise at a ventilation of 38 L/min with 10-min rest 

periods during the exposure. Forced expiratory maneuvers were performed 

before exposure and 5 min after each of three exercise periods; MVV, FRC, Raw' 

and TGV were measured before and after exposure. After 0 3 exposure alone, 

there were significant decreases in FVC, FEV I , and FEF25-75%. There were no 

significant changes in pulmonary function after S0 2 exposure alone. Combined 

exposure to S02 + 03 produced similar but smaller changes compared to those 

found after 0 3 exposure alone. These small differences were not in a direction 

that would support the hypothesis of either a synergistic or additive effect 

on pulmonary function. In general, there were no important health-related 

differences between the effects of 03 alone and 0 3 + S02 . 

Few studies have been reported in which subjects were exposed to 0 3 and 

H2SO4. Kagawa (1983a) summarized some results obtained on seven subjects 

intermittently resting and exercising during a 2-hr exposure to 294 pg/m 3 

(0.15 ppm) of 03 and 0.2 mg/m3 of H2SO4 . Using t-tests,to analyze his data, 

he reported a highly significant (P < 0.01) decrease (10.2 percent) in SGaw. 

However, not enough details are provided to allow adequate analysis. 

Kleinman et al. (1981) conducted studies i.n which 19 volunteers with 

normal pulmonary function and no history of asthma were exposed on two separate 

days to clean air and to an atmospheric mixture containing 0 3 (725 pg/m3 , 0.37 

ppm), S02 (0.37 ppm), and H 2SO4 aerosol (100 pg/m3 , MMAD = 0.5 pm; 6g = 3.0). 

Chemical speciation data indicated that 93 percent of the H 2SO4 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 2SO4 than they were at the end of exposures. During this 2-hr period, the subjects alternately exercised for 15 min, 

at a level calibrated to double minute ventilation, and rested for 15 min. 

Statistical analysis of the group average data suggested that the mixture may 

have been slightly more irritating to the subjects than 03 alone. A large 

percentage (13 of 19) of the subjects exhibited small decrements in pulmonary 

function following exposure to the mixture. The group average FEVI 0 on the 

exposure day was depressed by 3.7 percent of the control value. However, the 

magnitudes of the FEVl 0 changes were not higher than those observed in subjects 

10-72 
exposed to 0 3 alone (expected decreases of 2.8 percent). The authors concluded that the presence of H 2SO4 aerosols did not substantially alter the 

irritability resulting from 0 3-S02 . 

Stacy et al. (1983) studied 234 healthy men (18 to 40 years old) exposed 

for 4 hr to air, 03 , NO2 , or S02 ; to H 2SO4 , ammonium sulfate [(NH4) 2SO4 ], 

ammonium bisulfate (NH 4HSO4 ), or ammonium nitrate (NH4NO 3 ) aerosols; or to 

mixtures of these gaseous and aerosoi 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 pg/m 3 (0.4 ppm) of 0 3 

(n = 12) 3 100 pg/m3 of H2SO4 (n = 11)3 1 33 pg/m3 of (NH4 ) 2SO4 (n = 13); 

116 pg/m of NH4HSO4 (n = 15); 80 pg/m of NH4NO 3 (n = 12); and the mixtures 

03 + H2SO4 (n = 13), 0 3 +(NH4 ) 2SO4 (n = 15), 0 3 + NH4HSO4 (n = 11), and 0 3 + 

NH4NO 3 (n = 12). Ambient conditions were 30°C db, 85 percent rh because of 

the need to maintain the aerosol particles in proper suspension. Two 15-min 

bouts of treadmill exercise were performed, one beginning at 100 min into the 

exposure and the second beginning at 220 min. Minute ventilations were not 

reported. Pulmonary function was measured during a rest period before exposure, 5 to 6 min following the termination of the exercise, and 24 hr later. 

Data were analyzed by multivariate analyses of variance. Airway resistance, 

lung volume, and flow rates showed a statistically significant effect of the 

gaseous pollutant (03 ) with greater changes reported at 4 hr than at 2 hr of 

exposure. None of the particulates significantly altered pulmonary functions 

compared with the filtered-air exposure, and there was no indication of interaction between 0 3 and the particulates. Exposure to 0 3 alone and with particles 

was also associated with symptoms of irritation, such as shortness of breath, 

coughing, and minor throat irritation. At 24 hr post-exposure, all pulmonary 

values had returned to pre-exposure levels. 

Kulle et al. (1982a) studied the responses of 12 healthy nonsmokers 

(seven men, five w 3 en) exposed to 0 3 and H 2SO4 aerosols. Ozone co 3 entrations were 588 pg/m (0.3 ppm) and H2SO4 aerosol levels were 100 pg/m (MMAD = 

0.13 pm; 6g = 2.4). These studies were conducted over a 3-week period; a 2-hr 

exposure to 03 during the first week, a 4-hr exposure to H2SO4 during the 

second week, and a 2-hr exposure to 03 followed by a 4-hr exposure to H 2SO4 

during the third week. The protocol followed in each of these weekly exposure 

regimes was day 1- filtered air, day 2- pollutant, and day 3- filtered air. 

A methacholine aerosol challenge was made at the completion of each exposure 

day. Subjects were exercised for 15 min 1 hr prior to the completion of the 

10-73 
exposure. The work load was 100 W at 60 rpm, with an assumed V Eof approximately 30 to 35 L. No discernible risk was apparent as a consequence of 

exposing the nonsmoking healthy young adults to 0 3followed by respirable 

H2SO4aerosol. Bronchial reactivity decreased with H2 SO4aerosol exposure at 

a statistical level approaching significance (0.05 < p<0.10). Pulmonary 

function changes (SG aw , FVC, FEV1 , FEV3 , and bronchial reactivity to methacholine) following the 03 exposure were not significant. However, some subjects 

did report typical symptoms observed in other 03exposures. 

10.5.2Ozone and Carbon Monoxide 

DeLucia et al. (1983) reported the only study in which subjects were 

exposed to carbon monoxide (CO) and 03 . Subjects exercised at 50 percent max 

V02for 1 hr in the following ambient conditions: filtered air, 100 ppm of 

CO 3 588 pg/m3 (0.30 ppm) of 0 3 , and 100 ppm of CO plus 588 pg/m3 (0.30 ppm) of 

03 . 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 performance, heart rate, oxygen uptake, and minute ventilation were not substantially 

higher during exercise bouts where 0 3was present. A11 subjects exercised at 

50 percent max V02 , equivalent to a mean VEof 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 03than 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. 

Based on the limited data available, exposure to CO and 0 3does not 

appear to result in any interactions. The effects noted appear to be related 

primarily to 0 3 . 

10.5.3Ozone and Nitrogen Dioxide 

Studies describing the responses of subjects to the combination of these 

two pollutants are summarized in Table 10-7. Hackney et al. (1975a,b,c) and 

von Nieding et al. (1977, 1979) noted that no interactions were observed and 

that the pulmonary function changes were due to 0 3alone for the concentrations 

10-74 
present. Kagawa and Tsuru (1979b) evaluated the reactions of six subjects 

(one smoker) to .294 pg/m 3(0.15 ppm) 0 3 and 0.15 ppm NO2 , singly and in combination. They used the standard exposure time of 2 hr with alternating 

15-min periods of rest and exercise at 50 W. SGaw was determined prior to 

flow .volume measurements and prior to and at two intervals during the exposure 

perio.d. A fixed sequence of pollutant exposures was followed at weekly intervals, i.e.,. filtered air, 294 pg/m 3(0.15 ppm) of 03 , filtered air, 0.15 ppm 

of NO2 , filtered air, 0.15 ppm (0 3 + NO2 ), and filtered air. Statistical 

analyses were by t-tests. Subjective symptoms were reported in some subjects 

only when 03 was present. Significant decreases in SGaw occurred in five of 

six.subjects exposed to 0 3 , three of six subjects exposed to NO 2 , and six of 

six subjects exposed to 03 +.NO2 . 

Kagawa (1983a) briefly reported that under the conditions of his exposure 

(2 hr to 0.15 ppm 0 3 + 0.15 ppm NO2) SG

aw , 

 V50%, and VC decreased: However, 

no significant differences were observed between 0 3 alone and the combination 

of 03 + NO2 . Subjective symptoms were equivalent in both 0 3 exposures. 

Five subjects sitting in a body plethysmograph inhaled orally either 

filtered air, 0.7 ppm of NO2 , 1372 pg/m3(0.7 ppm) of 0 3 , or 0.5 ppm of 03 + 

0.5 ppm of NO2 for 1 hr (Toyama et al., 1981). Specific airway conductance 

and isovolume flows (Vmax 25% and Vmax 50%) were measured before and at the 

end of exposure, and 1 hr later. No significant changes were observed for any 

of the ambient conditions and consequently no interactions couid be detected. 

Folinsbee et al. (1981) exposed eight healthy men for 2 hr to either 

filtered air or 980 pg/m 3(0.5 ppm) of 03 plus 0.5 ppm of NO2 in fiitered 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 E of 40 L/min during the 

next half hour, and then rested for the final 30 min of exposure. Pulmonary 

function measurements were made prior to exposure, immediately after the 

exercise period, and again at the'end of the 2-hr period. Significant 

decreases occurred i n FVC, FEVI01 FEF25-75°l, and FEF50/duri ng the 03-NO2 

exposure. Ventilatory and metabolic variables, expired ventilation, oxygen 

uptake, tidal volume, and respiratory frequency were unaffected by, 0 3 and NO2 

exposure. , Thermal conditions modified heart rate, ventilation, and FVC. 

Greater changes in pulmonary functions were seen in both groups following the 

exercise period with recovery of the decrements toward the pre-exposure value 

during the succeeding half hour of rest. In this study, no synergism or 

10-75 

.~ 
interaction between 03 and NO2 was observed over the entire range of ambient 

temperatures and relative humidities. 

10.5.4 Ozone and Other Mixed Pollutants 

Von Nieding et al. (1979) exposed 11 subjects to 0 3 , NO2 , and S02 singly 

and in various combinations. The subjects were exposed for 2 hr with 1 hr 

devoted to exercise (intermittent), which doubled their ventilation. The work 

periods were of 15 min duration alternating with 15-min periods at rest. In 

the actual exposure experiments, no significant alterations were observed for 

P02 , PCO 2 , and pH in arterialized capillary blood or in TGV. Arterial oxygen 

tension (Pa0 2) was decreased (7 to 8 torr) by exposure to 5.0 ppm of NO 2 but 

was not further decreased following exposures to 5.0 ppm of NO 2 and 5.0 ppm of 

S02 or 5.0 ppm of NO 2 , 5.0 ppm of S0 2 and 196 pg/m3 (0.1 ppm) of 03 or 5.0 ppm 

of NO2 and 196 pg/m3 (0.1 ppm) of 0 3 . Airway resistance increased significantly (0.5 to 1.5 cm H 20/L/s) in the combination experiments to the same extent 

as in the exposures to NO 2 alone. In the 1-hr post-exposure period of the 

NO2 , 502 , and 03 experiment, R t continued to increase. Subjects were also 

exposed to a mixture of 0.06 ppm NO2 , 0.12 ppm of S02 , and 49 pg/m3 (0.025 ppm) 

of 03 . No changes in any of the measured parameters were observed. These 

same subjects were challenged with 1-, 2-, and 3-percent aerosolized solutions 

of ACh following control (filtered-air) exposure and exposure to 5.0-ppm NO 2 , 

5.0-ppm S02 , and 0.1-ppm 0 3 mixture, as well as after the 0.06-ppm NO 2 , 0.12- 

ppm S02 , and 49-pg/m3 (0.025-ppm) 0 3 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 aw x 

TGV) was significantly greater following the combined pollutant exposures than 

in the control study. 

In another study of simultaneous exposure to S0 2 , NO2 , and 03 , three 

groups of eight subjects, each of different ages (<30, >49, and between 30 to 

40 years) were exposed for 2 hr each day in a chamber on three successive days 

(Is1am 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 S0 2 , 5.0 ppm of NO 2 , and 196 pg/m3 (0.1 ppm) of 

03 ; and on the third day the environment was again 5.0 ppm of S0 2 , 5.0 ppm of 

NO2 , and 196 pg/m3 (0.1 ppm) of 0 3 , but the subjects exercised intermittently 

during the exposure. Statistical evaluation of data for the 11 lung-function 

test parameters and two blood gas parameters (Pa0 2 and PaCO2 ) was not reported. 

10-76 
These measurements were made before exposure, immediately post-exposure, and 

3 hr post-exposure. Individual variability was quite marked. The investigators concluded that no synergistic effects occurred in their healthy subjects. 

However, since they did not systematically expose these subjects to the individual 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 3 (0.34 ppm) S0 2 , 0.3 mg/m3 (0.16 ppm) NO 2 , and 0.15 mg/m3 

(0.08 ppm) 03 . Ten subjects were exposed to 1 day of fiitered 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 (Pa02 , 

PaCO2 , hemoglobin, and lactate dehydrogenase) were performed before and after 

the exposure. No impairments of lung functions, blood gases, or blood chemistry were found, but statistical analysis of the data was not reported. 

10.6 EXTRAPULMONARY EFFECTS OF OZONE 

The high oxidation potential of 0 3 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 Buckiey et al. (1975) suggested that 

statistically significant changes (P < 0.05) occurred in erythrocytes and sera 

of seven young adult men following exposure to 980 pg/m 3 (0.50 ppm) of 03 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 transitory and tended to disappear within several weeks. Although these changes 

were significant, that the alterations were such as to modify physiological 

systems or mechanisms is doubtful (see later reports in Table 10-8). 

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In the most comprehensive studies to date concerning the cytogenetic 

effects of inhaled 03 in human subjects, McKenzie and co-workers have investigated both chromosome and chromatid aberrations (McKenzie et al., 1977) as 

weil as sister chromatid exchange (SCE) frequencies (McKenzie, 1982). Blood 

samples from 26 normal male volunteers were collected before 0 3 exposure; 

immediately after exposure; and 3 days, 2 weeks, and 4 weeks after exposure to 

784 pg/m3 (0.4 ppm) of 0 3 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 3 under the conditions of the experiments. 

In later studies, McKenzie (1982) investigated the SCE frequency, in 

addition to the number of chromosomal aberrations in peripheral lymphocytes of 

human subjects exposed to 784 pg/m 3 (0.4 ppm) of 0, for 4 hr on one day and 

for 4 hr/day on four consecutive days, or to 1176 p9/m 3 (0.6 ppm) for 2 hr on 

one day only. 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 heaithy, nonsmoking human 

subjects. No statistically significant differences were observed in the 

frequencies of numerical aberrations, 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 3 exposures. 

Chromosome and chromatid aberrations were investigated by Merz et al. 

(1975) in lymphocytes collected from subjects exposed to 980 pg/m3 (0.5 ppm) 

of 03 for 6 to 10 hr. Increases in the frequency of chromatid aberrations 

(achromatic iesions and chromatid deletions) were observed in-lymphocytes 

after 0 3 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 resuits suggest human genotoxicity after 0 3 exposure, the results 

did not differ significantly from pre-0 3 chromatid aberration frequencies 

because of the small number (six) of subjects investigated. 

10-81 
Guerrero et al. (1979) exposed.31 male and female subjects to filtered 

air followed on a second day by 2-hr exposure to 980 pg/m3 (0.5 ppm) of 0 3 . 

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 circul.ating lymphocytes showed no change in lymphocyte chromosomes in either condition. However, SCE analysis performed on 

diploid human fetal lung cells (WI-38) exposed to 0.0, 490,.1470, and 1960 pg/m 3 

(0.0, 0.25, 0.75, and 1.00 ppm) of .0 3 for 1.hr in vitro was shown to have a 

dose-related increase in SCEs. The investigators suggested that the lack of 

SCE changes in lymphocytes in 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 3 exposures on leukocyte and lymphocyte function. In 1978, 

Peterson et al. (1978a) evaluated bactericidai and phagocytic rates in polymorphonuclear 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 pg/m3 (0.40 ppm) of 0 3 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 3 

exposure. No significant effect on. the phagocytic rate or intracellular 

killing was observed immediately after 0 3 exposure, or at 2 weeks after 03 

exposure. The nadir of neutrophil function was observed at 72 hours after 0 3 

exposure. Since the neutrophil has an average lifespan of 6.5 hr, the mechanism by which 03 produces an.effect on the neutrophil at 72 hr is open to 

speculation. Ozone may produce indirect effects on neutrophils through toxicity 

to granulocytic stem cells, or by altering humoral factors that facilitate 

phagocytosis. A similar experimental protocoi 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 i-s confusing, because 

variable numbers of subjects were studied under different'conditions. In the 

03 764-pg/m3 (0.39-ppm) exposure (20 subjects), lymphocyte transformation. 

responses to 2 pg/ml and 20 pg/ml of phytohemagglutinin (PHA) in cultures 

indicated significant (P < 0.01) suppression to 2 pg/ml of PHA in blood obtained 

immediately post-exposure but no effects with 20 pg/ml of PHA. The. data ; 

presented only in graphical form, suggested a wide variability in response, 

and consequently the significance of the observations may be minor. A third 

10-82 
study was conducted by these investigators (Peterson et a1., 1981) on 16 

subjects exposed to 1176 pg/m 3 (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 in vitro 

blastogenic response of the lymphocytes to PHA., concanavalin A.(con A), poleweed 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 significance 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 pg/m3 (0.4 ppm) 03 for 4 hr, B-lymphocyte rosette formation was significantly depressed. Rosette formation is an in vitro method that measures the 

binding of antigenic red blood cells with surface membrane sites on lymphocytes. 

Different antigenic red cell.s are used to distinguish T from B lymphocytes. A 

normal B-lymphocyte response was restored by 72 hr after 0 3 exposure. 

Biochemical parameters (erythrocyte fragility, hematocrit, hemoglobin, 

erythrocyte glutathione, acetylcholinesterase, glucose-6-phosphate dehydrogenase, and lactic acid dehydrogenase) were determined in blood obtained from 

subjects given either vitamin E or a placebo (Posin et al., 1979). Exposure 

conditions were filtered air on day 1 and 980 pg/m 3 (0.50 ppm) 0 3 on day 2; 

2 hr of exposure alternating with 15 min of exercise (double the resting 

minute ventilation) and 15 min of rest. Vitamin E intakes for nine or more 

weeks were 800 or 1600 IU. The number of subjects and the percent of inen and 

women differed in each of the three studies conducted. No significant differences between the responses of the supplemented and placebo groups to the 0 3 

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 experiments (800 IU vitamin E and piacebo). Blood was obtained before and after the 

2-hr exposures to filtered air or 980 pg/m 3 (0.5 ppm) of 0 3 . 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 celis occurs - as a 

consequence of exposure to 03 concentration under 980 pg/m3 (0.5 ppm). 

10-83 
10.7 PEROXYACETYL NITRATE 

Subjects exposed to peroxyacetyl nitrate (PAN) complain of eye irritation, 

blurred vision, eye fatigue, and of the compound's distinctive odor. Smith 

(1965) had 32 young male subjects breathe orally 0.30 ppm PAN for 5 min at 

rest and continue to inhale this pollutant during a subsequent 5-min period of 

light exercise. Oxygen uptake during exercise was found to be statistically 

higher while breathing PAN than while breathing filtered air. These observations were not confirmed in subsequent studies (Table 10-9). Gliner et al. 

(1975) studied 10 young men (22 to 26 years of age) and nine older men (44 to 

45 years) while they walked at 35 percent max V0 2for 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 V02 

max 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 cardiorespiratory functions or maximal aerobic capacity due to the pollutants were 

observed regardless of the ambient temperatures. Raven et al. (1974a) evaluated 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 

25 percent rh. These subjects inhaled either filtered air or air containing 

0.27 ppm PAN for 40 min. No effects of PAN were found. Effects related to 

age, smoking history, and ambient temperatures were as anticipated. 

In his studies of.young men orally inhaling 0.30 ppm PAN, Smith (1965) 

found a small reduction in MEFR following light exercise but no change in this 

function during resting exposures. Raven et al. (1976) observed a small but 

significant (4 percent) reduction in standing FVC in young men after 3.5 hr of 

light exercise (35 percent V02 max) during a 4-hr exposure to 0.24 ppm PAN. 

Drechsler-Parks et al. (1984) studied metabolic and pulmonary function 

effects in ten nonsmoking young men randomly exposed for 2 hr to each of four 

conditions: (1) filtered air, (2) 0.30 ppm PAN, (3) 882 pg/m 3 (0.45 ppm) 0 3 , 

and (4) 0.30 ppm PAN + 0.45 ppm 0 3PAN/03 ). The subjects alternated 15-min 

10-84 
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periods of rest and 20-min periods of moderate exercise (V E = 27 L/min) on a 

bicycle ergometer during the exposure. Forced expiratory volume and flow were 

determined before and after exposure and 5 min after each exercise period. 

Functional residual capacity was determined pre- and postexposure. Heart rate 

was measured throughout the exposure, and VE , V02 , fR , and VT were measured 

duri ng the 1 ast 2 mi n of each exerci se peri od. There were no si gni fi cant 

changes in exercise V0 2 or heart rate during any of the pollutant exposures. 

The changes in breathing patterns occurring during exercise were significant 

decreases in VT with exposure to 03 and PAN/0 3 and significant increases in f R 

with PAN/0 3 exposure. No effects on lung function or respiratory symptoms 

were reported after exposure to filtered air or PAN. Exposure to 0 3 and 

PAN/03 produced significant decrements in FVC, FEVl , FEV2 , FEV3, FEF25-75%' 

IC, ERV, and TLC. The decrements in TLC, FVC, FEV1 , and FEF25-75% were significantly greater (10 percent) with PAN/0 3 exposure and occurred in a-shorter 

period of time when compared with exposure to 0 3 alone. A wide range of 

individual responsiveness to 0 3 and PAN/03 was noted among subjects; four 

subjects had greater than 30 percent decrements in FEV 1 while one subject 

showed no change at all. Symptoms reported after 0 3 and PAN/0 3 exposures were 

similar, although a greater number of symptoms were reported after the PAN/0 3 

exposure. The results by Drechsler-Parks et al. (1984) suggest a simultaneous 

effect of the oxidants PAN and 03 . However, because the large individual 

responsiveness to 0 3 makes direct comparisons to extant data difficult to 

perform, it is not clear if the greater decrements observed after PAN/0 3 

exposure are related to total oxidant load. Additional research is needed to 

further clarify the relationship between PAN and 03 at concentrations found in 

ambient air. 

The interaction of PAN and CO was also evaluated in the series of studies 

on healthy young and middle-aged men exercising on a treadmill (Raven et al., 

1974a, 1974b; Drinkwater et al., 1974; Gliner et al., 1975). Both smokers and 

nonsmokers were exposed to 0.27 ppm PAN and 50 ppm C0. 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 V02 ) at ambient temperatures 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 3 0.27 ppm PAN, and a combination of 

50 ppm of CO and 0.27 ppm of PAN. Carboxyhemoglobin was measured in these 

~ • 
subjects. There was no significant change in maximal aerobic power reiated to 

the presence of these air pollutants, although total exercising time was 

lowered in the 25 ° C environment while exposed to C0. A decrement in max V02 

was found in middle-aged smokers breathing 50 ppm of C0. Another study conducted under simiiar 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 

infiuence of PAN and CO 3 singly or in combination, was evaluated in 10 young 

(22 to 26 years) and nine middle-aged (45 to 55 years) men performing submaximal work (35 percent max V02 ) for 210 min (Gliner et al., 1975). Five subjects 

in each age group were smokers. Studies were conducted at two different 

ambient temperatures, i.e., 25 ° C and 35° C, rh 30 percent. The pollutant 

concentrations were 0.25 ppm of PAN and 50 ppm of C0. Two physiological 

alterations were reported. Stroke volume decreased during long-term work, 

being enhanced in the higher ambient temperatures. Heart rate was significantly 

(P <0.05) higher when exercise was being performed during the CO exposures. 

No other alterations were found in relation to the pollutants. There were no 

differences in response related to age. 

10.8 SUMMARY 

A number of important controlled studies discussed in this chapter have 

reported significant decrements in pulmonary function associated with 0 3 

exposure (Table 10-10). In most of the studies reported, greatest attention 

has been accorded decrements in FEV I 01 as this variable represents a summation 

of changes i n both vol ume and res i stance. Whi 1 e thi s i s true, i t must be 

pointed out that for exposure concentrations critical to the standard-setting 

process (i.e., <0.3 ppm 0 3 ), the observed decrements in FEV 1 . 0 primarily 

reflect FVC decrements of similar magnitude, with little or no contribution 

from changes in resistance. 

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Results from studies of at-rest exposures to 0 3 have demonstrated decrements in forced expiratory volumes and flows occurring at and above 980 pg/m 3 

(0.5 ppm) of 0 3 (Folinsbee et al., 1978; Horvath et al., 1979). Airway resistance is not clearly affected at these 0 3 concentrations. At or below 588 

pg/m3 (0.3 ppm) of 03 , changes in pulmonary function do not occur during at 

rest exposure (Folinsbee et al., 1978), but the occurrence of some 0 3-induced 

pulmonary symptoms has been suggested (Konig et al., 1980). 

With moderate intermittent exercise at a VE of 30 to 50 L/min, decrements 

in forced expiratory volumes and flows have been observed at and above 588 

pg/m3 (0.30 ppm) of 0 3 (Folinsbee et al., 1978). With heavy intermittent 

exercise (VE = 65 L/min), pulmonary symptoms are present and decrements in 

forced expiratory volumes and flows are suggested to occur following 2-hr 

exposures to 235 pg/m3 (0.12 ppm) of 0 3 (McDonnell et al., 1983). Symptoms 

are present and decrements in forced expiratory volumes and flows definitely 

occur at 314 to 470 pg/m 3 (0.16 to 0.24 ppm) of 0 3 following 1 hr of continuous 

heavy exercise at a VE of 57 L/min (Avol et al., 1984) or very heavy exercise 

at a VE of 80 to 90 L/min (Adams and Schelegle, 1983; Folinsbee et al., 1984) 

and following 2 hr of intermittent heavy exercise at a VEof 65 to 68 L/min 

(McDonnell et al., 1983; Kulle et al., 1985). Airway resistance is only 

modestly affected with moderate exercise (Kerr et al., 1975; Farrell et al., 

1979) or even with heavy exercise while exposed at levels as high as 980 pg/m 3 

(0.50 ppm) 03 (Folinsbee et al., 1978; McDonnell et al., 1983). Increased f R 

and decreased VT , while maintaining the same VE , occur with prolonged heavy 

exercise when exposed at 392 to 470 pg/m 3 (0.20 to 0.24 ppm) of 0 3 (McDonnell 

et al., 1983; Adams and Schelegle, 1983). While an increase in RV has been 

reported to result from exposure to 1470 pg/m 3 (0.75 ppm) of 03 (Hazucha et 

al., 1973), changes in RV have not been observed following exposures to 

980 pg/m3 (0.50 ppm) of 0 3 or less, even with heavy exercise (Folinsbee et 

al., 1978). Decreases in TLC and IC have been observed to result from exposures to 980 pg/m 3 (0.50 ppm) of 03 or less, with moderate and heavy exercise 

(Folinsbee et al., 1978). 

Recovery of the lung from the effects of 0 3 exposure consists of return 

of pulmonary function (FVC, FEV1, and SRaw) to preexposure levels. The time 

course of this recovery is related to the magnitude of the 0 3-induced functional 

decrement (i.e., recovery from small decrements is rapid). Despite apparent 

functional recovery of most subjects within 24 hr, an enhanced responsiveness 

10-92 
to a second 03 challenge may persist in some subjects for up to 48 hr (Bedi 

et al., 1985; Folinsbee and Horvath, 1986). 

Group mean decrements in pulmonary function can be predicted with some 

degree of accuracy when expressed as a function of effective dose of 03 , the 

simple product of 0 3 concentration, VE , and exposure duration (Siiverman et 

al., 1976). The relative contribution of these variables to pulmonary decrements is greater for 0 3 concentration than for VE : 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 puimonary 

function responses to 0 3 (Horvath et al., 1981; Gliner et al, 1983; McDonnell 

et al., 1983; Kulle et al., 1985). Individual responses to a given 03 concentration have been shown to be quite reproducible (Gliner et al., 1983; McDonnell 

et al., 1985a), indicating that some individuals are consistently more responsive to 0 3 than are others. No information is available to account for these 

differences. Considering the great variability in individual pulmonary responses to 0 3exposure, prediction equations that only use some form of effective dose are not adequate for predicting individual responses to 0 3 . 

In addition to overt changes in pulmonary function, enhanced nonspecific 

bronchial reactivity has been observed following exposures to 03 concentrations 

>588 pg/m3 (0.3 ppm) (Holtzman et al., 1979; Konig et al., 1980; Dimeo et al., 

1981). Exposure to 392 pg/m 3 (0.2 ppm) of 0 3 with intermittent iight exercise 

does not affect nonspecific bronchial reactivity (Dimeo et al., 1981). 

Changes in forced expiratory volumes and flows resulting from 0 3 exposure 

reflect reduced maximal inspiratory position (inspiratory capacity) (Folinsbee 

et al., 1978). These changes, as well as altered ventilatory control and the 

occurrence of respiratory symptoms, most likely result from sensitization or 

stimulation of airway irritant receptors (Folinsbee et al., 1978; Holtzman et 

al., 1979; McDonneil et al., 1983). The increased airways resistance observed 

following 03 exposure is probably initiated by a similar mechanism. Different 

efferent pathways have been proposed (Beckett et al., 1985) to account for the 

lack of correlation between individual changes in SR aw and FVC (McDonnell 

et al., 1983). The increased responsiveness of airways to histamine and 

methacholine following 0 3 exposure most likely results from an 0 3-induced 

increase in airways permeability or from an alteration of smooth muscle characteristics. 

10-93 
Decrements in pulmonary function were not observed for adult asthmatics 

exposed for 2 hours at rest (Silverman, 1979) or with intermittent light 

exercise (Linn et al., 1978) to 0 3 concentrations of 490 pg/m 3 (0.25 ppm) and 

less. Likewise, no significant changes in pulmonary function or symptoms were 

found in adolescent asthmatics exposed for 1 hr at rest to 235 pg/m3 (0.12 

ppm) of 03 (Koenig et al., 1985). Although these results indicate that asthmatics are not more responsive to 0 3 than are healthy subjects, experimental-design 

considerations in reported studies suggest that this issue is still unresolved. 

For patients with COLD performing light to moderate intermittent exercise, no 

decrements in pulmonary function are observed for 1- and 2-hr exposures to 0 3 

concentrations of 588 pg/m 3 (0.30 ppm) and less (Linn et al. , 1982a, 1983; 

Solic et al. , 1982; Kehrl et al. , 1983, 1985) and only small decreases in 

forced expiratory volume are observed for 3-hr exposures of chronic bronchitics 

to 804 pg/m3 (0.41 ppm) (Kulle et al., 1984). Small decreases in Sa02 have 

also been observed in some of these studies but not in others; therefore, 

interpretation of these decreases and their clinical significance is uncertain. 

Many variables have not been adequately addressed in the available clinical data. Information derived from 0 3 exposure of smokers and nonsmokers is 

sparse and somewhat inconsistent, perhaps partly because of undocumented 

variability in smoking histories. Although some degree of attenuation appears 

to occur in smokers, all current results should be interpreted with caution. 

Further and more precise studies are required to answer the complex problems 

associated with personal and ambient pollutant exposures. Possible age differences in response to 03 have not been explored systematically. Young adults 

usually provide the subject population, and where subjects of differing age 

are combined, the groups studied are often too small in number to make adequate 

statistical comparisons. Children (boys, aged 8 to 11 yr) have been the 

subjects in only one study (McDonnell et al., 1985b) and nonstatistical comparison with adult males exposed under identical conditions has indicated that the 

effects of 0 3 on lung spirometry were very similar (McDonnell et al., 1985c). 

While a few studies have investigated sex differences, they have not conclusively demonstrated that men and women respond differently to 0 3 , and consideration of differences in pulmonary capacities have not been adequately taken 

into account. Environmental conditions such as heat and relative humidity may 

enhance subjective symptoms and physiological impairment following 0 3 exposure, 

but the results so far indicate that the effects are no more than additive. 

10-94 
In addition, there may be considerable interaction between these variables 

that may result in modification- of interpretations made based on.available 

information. 

During repeated daily exposures to 0 3 , decrements in pulmonary function 

are greatest on the second exposure day (Farrell et al., 1979; Horvath et al., 

1981; Kulle et al., 1982b; Linn et al., 1982b); thereafter, pulmonary responsiveness 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 3(Kulle 

et al., 1982b; Linn et al., 1982b) to 7(Horvath et al., 1981) days. Repeated 

daily exposures to a given low effective dose of 0 3 does not affect the magnitude of decrements in pulmonary function resulting from exposure at a higher 

effective dose of 03 (Giiner et al., 1983). 

There is some evidence suggesting that exercise performance may be limited 

by exposure to 0 3 . Decrements in forced expiratory flow occurring with 0 3 

exposure during prolonged heavy exercise (VE = 65 to 81 L/min) along with 

increased f R and decreased VT might be expected to produce ventilatory limitations at near maximal exercise. Results from exposure to ozone during high 

exercise levels (68 to 75 percent of max V0 2 ) indicate that discomfort associated with maximal ventilation may be an important factor in limiting performance (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 3 concentrations as high as 

784 to 1176 pg/m3 (0.4 to 0.6 ppm). Chromosome or chromatid aberrations would 

therefore be unlikely at lower 0 3 levels. Limited data have indicated that 0 3 

can interfere with biochemical mechanisms in blood erythrocytes and sera but 

the physiological significance of these studies is questionable. 

No significant enhancement of respiratory effects has been consistently 

demonstrated for combined exposures of 0 3 with S0 2 , NO 2 , 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 studies on the effects of peroxyacetyl nitrate (PAN) on healthy young and 

middle-aged males during intermittent moderate exercise. No significant 

effects were observed at PAN concentrations of 0.25 to 0.30 ppm, which are 

10-95 
higher than the daily maximum concentrations of PAN reported for relatively 

high oxidant areas (0.047 ppm). One study (Drechsler-Parks et al., 1984) 

suggested a possible simultaneous effect of PAN and 0 3 ; however, there are not 

enough data to evaluate the significance of this effect. Further studies are 

also required to evaluate the relationships between 0 3 and the more complex 

mix of pollutants found in the natural environment. 

10-96 
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Kagawa, J.; Toyama, T. (1975) Effects of ozone and brief exercise on specific 

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Kehrl, H. R.; Hazucha, M. J.; Solic, J. J.; Bromberg, P. A. (1985) Responses 

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111: 763- 773. 

Ketcham, B.; Lassiter, S.; Haak, E. D., Jr.; ICnelson, J. H. (1977) Effects of 

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10-103 
Konig, G. ; Rommelt, H. ; Kienele, H. ; Dirnagl , K. ; Pol ke, H. ; Fruhmann, G. 

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126: 996-1000. 

Kul le, T. J. ; Sauder, L. R. ; Kerr, H. D. ; Farrel l, B. P. ; Bermel , M. S. ; 

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Kul le, T. J. ; Mi lman, J. H. ; Sauder, L. R. ; Kerr, H. D. ; Farrel 1, B. P. ; 

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response relationships in healthy nonsmokers. Am. Rev. Respir. Dis. 

132: 36-41. 

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Linn, W. S. ; Buckley, R. D. ; Spier, C. E. ; Blessey, R. L. ;. Jones, M. P. ; 

Fischer, D. A.; Hackney, J. D. (1978) Health effects of ozone exposure in 

asthmatics. Am. Rev. Respir. Dis. 117: 835-843. 

Li nn, W. S. ; Jones, M. P. ; Bachmayer, E. A. ; C1 ark, K. W. ; Karuza, S. K. ; 

Hackney, J. D. (1979) Effect of low-level exposure to ozone on arterial 

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Dis. 125: 491-495. 

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chronic obstructive pulmonary disease. Arch. Environ. Health 38: 278-283. 

10-104 
McCafferty, W. B. (1981) Air pollution and athletic performance. Springfield, 

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Respir. Dis. 131: 36-40. 

J 

McDonnell, W. F., III; Chapman, R. S.; Leigh, M. W.; Strope, G. L.; Collier, 

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ozone at a concentration of 0.5 ppm for 6 and 10 hours. Mutat. Res. 

31: 299-302. 

Mihevic, P. M.; Gliner, J. A.; Horvath, S. M. (1981) Perception of effort and 

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Education, and Welfare, Public Health Service; NAPCA publication no. AP-63. 

Available from: NTIS, Springfield, VA; PB-190262. 

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leukocyte function in exposed human subjects. Environ. Res. 15: 485-493. 

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10-105 
Peterson, M. L.; Smialowicz, R.; Harder, S.; Ketcham, B.; House, D. (1981) The 

effect of controlled ozone exposure on human lymphocyte function. Environ. 

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(1979) Human biochemical response to ozone and vitamin E. J. Toxicol. 

Environ. Health 5: 1049-1058. 

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A.; Sutton, J. C.; Bolduan, N. W. (1974a) Age, smoking habits, heat 

stress, and their interactive effects with carbon monoxide and peroxyacetyl 

nitrate on man's aerobic power. Int. J. Biometeorol. 18: 222-232. 

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Gliner, J. A.; Horvath, S. M. (1974b) Effect of carbon monoxide and 

peroxyacetyl nitrate on man's maximal aerobic capacity. J. Appl. Physiol. 

36: 288-293. 

Raven, P. B.; Gliner, J. A.: Sutton, J. C. (1976) Dynamic lung function changes 

following long-term work in polluted environments. Environ. Res. 12: 18-25. 

Savin, W.; Adams, W. (1979) Effects of ozone inhalation on work performance 

and VO . J. Appl. Physiol.: Respir. Environ. Exercise Physiol. 46: 

309-31~

max 

Savino, A.; Peterson, M. L.; House, D.; Turner, A. G.; Jeffries, H. E.; Baker, 

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Characterization of T and B lymphocytes by rosette formation. Environ. 

Res. 15: 65-69. 

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ozone and cigarette smoke exposure. Environ. Res. 31: 125-137. 

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Health Perspect. 29: 131-136. 

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function changes in ozone - interaction of concentration and ventilation. 

J. Appl. Physiol. 41: 859-864. 

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10: 161-164. 

Solic, J. J.; Hazucha, M. J.; Bromberg, P. A. (1982) The acute effects of 

0.2 ppm ozone in patients with chronic obstructive pulmonary disease. Am. 

Rev. Respir. Dis. 125: 664-669. 

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(1983) Effects of gaseous and aerosol pollutants on pulmonary function 

measurements of normal humans. Arch. Environ. Health 38: 104-115. 

Superko, H. R.; Adams, W. C.; Daly, P. W. (1984) Effects of ozone inhalation 

during exercise in selected patients with heart disease. Am. J. Med. 

77: 463-470. 

10-106 
Toyama, T.; Tsumoda, T.; Nakaza, M.; Higashi, T.; Nakadato, T. (1981)°Airway 

response to short-term inhalation of NO 2 , 0 3 and their mixture in healthy 

men. Sangyo Igaku 23: 285-293. 

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the National Health Interview Survey: United States, 1979. Hyattsville, 

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10-107 

11. FIELD AND EPIDEMIOLOGICAL STUDIES OF THE EFFECTS OF OZONE 

AND OTHER PHOTOCHEMICAL OXIDANTS 

11.1 INTRODUCTION 

This chapter critically assesses field and epidemiological studies of 

health effects linked to ambient air exposure to ozone and other photochemical 

oxidants. In order to characterize the nature and extent of such effects, the 

chapter (1) delineates types of health effects associated with exposures to 

ozone or photochemical oxidants in ambient air; (2) assesses the degree to 

which relationships between exposures to these agents and observed effects are 

quantitative; and (3) identifies population groups at greatest risk for such 

health effects. Studies of both acute and chronic exposure effects are summarized and discussed. Tables are provided to give the reader an overview of the 

studies reviewed in this chapter. 

In many of the epidemiological studies available in the literature, 

exposure data or health endpoint measurements were used that were inadequate 

or unreliable for quantifying exposure-effect relationships. Aiso, results 

from these studies have often been confounded by factors such as variations in 

activity levels and time spent out of doors, cigarette smoking, coexisting 

pollutants, weather, and socioeconomic status. Thus, selection of those 

studies thought to be most useful in deriving health criteria for ozone or 

oxidants is of critical importance. Assessment of the relative scientific 

quality of epidemiological studies for standard-setting purposes is a difficult 

and often controversial problem; therefore, the following general guidelines 

(as modified from U.S. Environmental Protection Agency, 1982) have been suggested as useful for appraising individual studies: 

1. The aerometric data are adequate for characterizing geographic 

or temporal differences in pollutant exposures of study populations in the range(s) of pollutant concentrations evaluated. 

2. The study populations are well defined and allow for statisticaliy adequate comparisons between groups or temporal analyses 

within groups. 

3. The health endpoints are scientifically plausible for the 

pollutant being studied, and the methods for measuring those 

endpoints are adequately characterized and implemented. 

4. The statistical analyses are appropriate and properly performed, and the data analyzed have been subjected to adequate 

quality control. 

11-1 
5. Potentially confounding or covarying factors are adequately 

controlled for or taken into account. 

6. The reported findings are internally consistent and biologically 

plausible. 

For present purposes, studies most fully satisfying these suggested 

criteria provide the most useful information on exposure-effect or exposureresponse relationships associated with ambient air levels of ozone or photochemical oxidants likely to occur in the United States during the next 5 

years. Accordingly, the following additional guidelines were used to select 

studies for detailed discussion: (1) the results provide information on 

quantitative relationships between health effects and ambient air ozone or 

oxidant concentrations with emphasis on concentrations less than or equal to 

0.5 ppm (measurement methods and calibrations are reported when available); 

and (2) the report has been peer-reviewed and is in the open literature or is 

in press. A number of recent studies not meeting the above guidelines but 

considered to be sources of additional supportive information are also discussed 

below and their limitations noted. 

The remaining studies not rigorously meeting all of these guidelines are 

tabulated chronologically by year of publication within °each subject area. 

Since the lack of quantitative exposure data is a frequently noted limitation 

of epidemiological studies, an attempt has been made to provide as detailed a 

description as possible of the photochemical oxidant concentrations and averaging times reported in the original manuscripts. In addition, the tables 

summarize comments on earlier studies described in detail in the 1978 EPA 

criteria document for ozone and other photochemical oxidants (U.S. Environmental 

Protection Agency, 1978). 

11.2 FIELD STUDIES OF EFFECTS OF ACUTE EXPOSURE TO OZONE AND OTHER PHOTOCHEMICAL OXIDANTS 

• For the purposes of this document, field studies are defined as laboratory 

experiments where the postulated cause of an effect in the population or 

environment is tested by removing it under controlled conditions (Morris, 

1975; Mausner and Bahn, 1974; American Thoracic Society, 1978; World Health 

Organization, 1983). Field studies of symptoms and pulmonary function contain 

elements of both controlled human exposure studies (Chapter 10) and of epidemiologic studies. These studies employ observations made in the field along 

11-2 
with the methods and better experimental control typical of controlled exposure 

studies. Studies ciassified here as field studies used exposure chambers but 

exposed subjects to ambient air containing the pollutants of interest rather 

than to artificially generated pollutants, as well as to clean air as a control. 

These studies thus form a bridge or continuum between the studies discussed in 

the preceding chapter (Chapter 10) and the epidemiological studies assessed 

later in this chapter. 

11.2.1 Symptoms and Pulmonary Function in Field Studies of Ambient Air Exposures 

Researchers at the Ranchos Los Amigos Hospital in California (Linn et 

al., 1980, 1982, 1983; Avol et al., 1983, 1984, 1985a,b) have used a mobile 

laboratory containing an exposure chamber to study the effects of ambient air 

exposures on symptoms and pulmonary function in high-oxidant (Duarte) and 

low-oxidant (Hawthorne) areas of the Los Angeles Basin. In these field studies, 

pre- and post-exercise measurements of pulmonary function, often used in 

controlled human exposure studies, were made to compare the effects of shortterm exposures to ozone and oxidants in ambient air versus clean air (sham 

control) exposures. The subject characteristics and experimental conditions 

in the respective studies are summarized in Table 11-1. The mobile laboratory 

has been described previously (Avol et al., 1979), as have the methods for 

studies of lung function. 

In 1978 Linn et al. (1980, 1983) evaluated 30 asthmatic and 34 normal 

subjects exposed to ambient and purified air in a mobile laboratory in Duarte, 

CA, during two periods separated by 3 weeks. Only five subjects were smokers, 

and the two groups were similar with respect.to the age, height, and sex of 

subjects. Asthmatic subjects had heterogeneous disease characteristics, as 

determined by questionnaire responses. Of the "normal" group, 25 subjects 

were considered allergic based on a history of upper respiratory allergy or 

reported undiagnosed wheeze that they called "allergic." No definitive clinical 

evaluations were performed to verify the allergic status of these subjects. 

Ozone, nitrogen oxides (NO x ), sulfur dioxide (S0 2 ), sulfates, and total suspended particulate matter (TSP) were monitored inside and outside the chamber 

at 5-min intervals. Measurements of 0 3 by the ultraviolet (UV) method were 

calibrated against California Air Resources Board (CARB) reference standards 

and were corrected to those obtained by the KI method. 

Ozone and particulate poliutants predominated in the ambient air mixture, 

as shown in Table 11-1 for the 1978 study (Linn et al., 1980, 1983). Ozone 

11-3 
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11-4 

m 
levels (corrected to the KI method) averaged 427 pg/m 3 (0.22 ppm) inside the 

mobile laboratory chamber and 509 pg/m 3 (0.26 ppm) outside the laboratory 

during ambient air exposures; and 7.8 pg/m3 (0.004 ppm) during purified air 

exposures. The respective maximum 0 3 concentrations were 498 ± 186 pg/m 3 

(0.25 ± 0.10 ppm) inside; 597 ± 217 pg/m 3 (0.31 ± 0.11 ppm) outside; and 

19 ± 17 pg/m3 (0.01 ± 0.009 ppm) in purified air. Levels of TSP averaged 

182 pg/m3 inside the chamber and 244 pg/m 3 outside the laboratory during 

ambient air exposures, but 49 pg/m 3 inside the chamber during purified-air 

exposures. Average NO 2 , S02 , CO 3 and sulfate levels inside the chamber were 

uniformly low during ambient-air exposures (as shown in Table 11-1) and were 

even lower during purified-air exposures (i.e., 0.015 ppm for NO 2 ; 0.009 ppm 

for S02 ; 2.8 ppm for C0; 0.9 ppm for sulfates). Gases were monitored continuously, with inside and outside air sampled alternately for 5-min periods. 

Particles were measured during testing inside and outside the laboratory. 

Temperature and humidity were controlled inside the laboratory. 

During the exposure studies (Tuesday through Friday), four subjects 

(maximum) were tested sequentially in the morning at 15-min intervals, each 

first breathing purified air at rest followed by "pre-exposure" lung-function 

tests. Ambient-air chamber tests were performed in the early afternoon (after 

odors were masked by a brief outside exposure). The ambient-air exposure 

period lasted 2 hr and included exercise on bicycle ergometers for the first 

15 min of each half-hour; this was fol1owed by "post-exposure" lung function 

testing during continuing ambient-air exposure. Ergometer workloads ranged 

from 150 to 300 kg-m/min and were sufficient to double the respiratory minute 

ventilation relative to resting level. Lung function measures before and 

after exposure were compared by t-tests and nonparametric methods. The 

purified-air control study for each subject took place at least 3 weeks after 

the ambient-air exposure session, with identical procedures except for purified 

air in place of the ambient. Note that 12 healthy subjects from the project 

staff were tested apart from the study cohort in order to validate various 

aspects of the study. The validation tests were performed to determine whether 

there were any gross differences in response to indoor and outdoor ambient 

exposures. While no significant differences were found in this comparison, 

small differences would have been difficult to detect because of the small 

number of subjects tested. 

In the main set of experiments (Linn et al.; 1980, 1983), the asthmatic 

group experienced greater changes from baseline in residual volume (RV) and 

11-5 
peak flow measurements with exercise than did the "normals," based on data 

adjusted for subject age, height, and weight. The magnitude of these changes 

did not correlate with age. Both groups showed similar changes in most of the 

other lung-function measurements. Regression analysis showed no significant 

associations of functional changes with TSP, total sulfate, total NH3 , or NO 2 . 

Increasing 0 3 was correlated with decreasing peak flow and 1-sec forced expiratory volume (FEV 1). No explanation was given for the observed association of 

increasing CO with increasing RV and with the slope of the alveolar plateau 

(SBNT). Increasing S0 2 was significantly associated with increasing RV and 

total lung capacity (TLC). In multiple regression analysis, 0 3 was the variable 

contributing the most variation in FEV1 and maximum expiratory flow (Vmax25%)' 

as well as in the FEV1 normalized for forced vital capacity (FEV1/FVC%), TLC, 

and pulmonary resistance (Rt) in the normal/allergic group. Although other 

pollutant variables contributed to the observed effects, none did so consistently. Apart from 0 3 , functional changes on control days (intraindividual 

variability), smoking habits, and age appeared to explain the functional 

changes in normals/ allergics during exposure. In asthmatics, all pollutant 

variables except TSP were significant in one or more analyses, but not all 

consistently. Asthmatics and normals/allergics also had significantly increased 

symptom scores during ambient air exposure sessions (Figure 11-1). 

Nine of 12 subjects from this study (Linn et al., 1980, 1983) known to be 

highly reactive to 0 3 (four from the normal/allergic group and five asthmatics, 

a similar proportion from each group), who had experienced a fall in FEV 1 greater 

than 200 m1 during ambient exposure (compared to purified-air, exposure), underwent a controlled 2-hr exposure experiment at 392 pg/m 3 (0.2 ppm) with intermittent exercise. Among these nine reactive subjects, the mean FEV 1 change in the 

ambient exposure was -273 ± 196 ml (-7.8 ± 6.3 percent of pre-exposure). This 

change was significantly greater than the mean change of -72 ± 173 ml (3.1 ± 

6.6 percent pre-exposure) in the control setting. Although the authors suggested the possibility that ambient photochemical pollution may be more toxic 

than chamber exposures to purified air containing only ozone, other explanations 

for the differences were given, including the effect of regression toward the 

mean. More direct comparative findings published recently by Avol et al. 

(1984) (see following text) showed no differences in response between chamber 

exposures to oxidant-polluted ambient air and purified air containing a 

controlled concentration of 0 3 . Normal/allergic subjects in the validation 

11-6 
30 

W 

~ 20 

c~ N 

10 

AMBIENT AIR 

— — — PURIFIED AIR 

~ A 

i 

A•.O ~ 

♦ ' ` R w 

% ' 

A % 

M 

PE IC LD PE IC LD PE - IC LD 

ALL NORMAL ASTHMATIC 

AND 

ALLERGIC 

Figure 11-1. Changes in mean symptom score with 

exposure for all subjects, for normal and allergic subjects, 

and for asthmatic subjects. PE = pre-exposure; IC = in 

chamber (near end of exposure period); LD =later in day. 

Circles ( O or •) indicate total symptom scores; triangles 

( o or A) indicate lower-respiratory syrnptom scores. Solid 

symbols indicate that ambient exposure score is 

significantly higher for indicated time period and/or 

increased significantly more relative to pre-exposure value. 

Open symbols indicate that the difference between 

ambient and purified air scores was not significant. 

Source: Adapted from Linn et al. (1980). 

11-7 
studies also showed similar findings in the exposure chambers compared to the 

outside ambient air when the levels were similar inside and out. 

Linn et al. (1982, 1983) repeated the initial experiment (Linn et al., 

1980) with 64 different subjects, ages 18 to 55, in Hawthorne, CA, which had 

low 03 levels (0.04 ± 0.02 ppm, 82 ± 39 pg/m 3 ) but elevated levels of other 

pollutants. They found no statistically significant lung-function or symptom 

changes, and they concluded that 03 was primarily responsible for the effects 

seen in the original study. 

In 1980, a third experiment (Linn et al., 1983; Avol et al., 1983) was 

conducted at the original oxidant-polluted location (Duarte) with 60 physically fit subjects, aged 18 to 55, who exercised heavily (four to five times 

resting minute ventilation) and continuously for 1 hr. The mean 0 3 concentrati on was 314 pg/m 3 (0.16 ppm) i n ambi ent ai r(measured by the UV method) . 

Total reported symptoms, did not differ significantly between exposure and 

control (purified-air) conditions. For the complete group, small functional 

decrements in FEV1 were found (3.3 percent loss, P< 0.01), more or less 

comparable to those in the original (1978) study. A number of the subjects 

showed functional losses during exposure that were still present after a 1-hr 

recovery period at rest in filtered air. Those in the most reactive quartile 

(those who experienced 320 to 1120-m1 1osses, versus control) were compared 

with the least reactive quarti1e (increases of 60 to 350 ml). They did not 

differ by age, height, sex, smoking, medication use, prevalence of atopy, or 

asthma. Negative FFV 1 changes occurred more frequently (34 of 47 cases) at 0 3 

exposure concentrations above 235 pg/m3 (0.12 ppm), up to the maximum observed 

(549 pg/m3 ; 0.28 ppm) in the total study group (P = 0.02). Even at the upper 

end of this range, however, a number of subjects showed no decrement in function. The authors stated that the marked functional losses measured in the 

most reactive subjects in this study were not necessarily accompanied by 

symptoms, nor were they related to obvious prior physical or clinical status. 

In 1981, a fourth study (Linn et al., 1983; Avol et al., 1983) presented 

data on 98 subjects, including 50 asthmatics, who were exposed in Duarte to 

mean 03 levels of 306 pg/m 3 (0.156 ppm) and 166 pg/m 3 TSP (lower than in 

1980). The highest 0 3 exposure concentration was 431 pg/m 3 (0.22 ppm), which 

was lower than the levels measured in 1980. The subjects were exposed to 

heavy, continuous exercise (though at slightly lower exercise ventilation 

levels than in 1980). The normal subjects showed a pattern of forced expiratory changes that were similar to those reported in 1980; however, the mean 

11-8 

I 
FEV1 decrease with exposure to ambient air was much smaller. The only significant change reported for this group was for FVC (P <0.003). The asthmatics 

had decrements in forced expiratory performance during both exposures, but the 

mean FEV1 decrease remained depressed for up to 3 hr after exposure to ambient 

air. Maximum mean changes in FVC and FEV 1for asthmatics after exposure to 

ambient air were 122 ml and 89 ml, respectively, with the former returning 

more quickly to control ievels. The value for Vmax50% was more variable with 

a maximum mean change of 132 L/s after exposure to ambient air. There were 

also significant interactions of ambient and purified air after exposure in 

asthmatics for FEVI and Vmax50%' 

The subject population was expanded in the summer of 1982 to include , 

well-conditioned athletes undergoing 1 hr of continuous heavy exercise (six to 

ten times resting minute ventilation) (Avol et al., 1984, 1985c) Volunteer 

competitive bicyclists (n=50) were exposed in the mobile chamber to purified 

air containing 0, 157, 314, 470, and 627 pg/m 3 (0, 0.08, 0.16, 0.24, and 0.32 

ppm) 03 and to ambient air in the Duarte location. Pollution conditions were 

milder than in previous summers so that comparable ambient exposure data were 

available for only 48 subjects (Table 11-1). Mean concentrations during 

ambi 3 nt exposures were 294 pg/m 3(0.15 p pm) 03with a range of 235 to 372 

~ag/m (0.12 to 0.19 ppm) and 295 ~ag/m total suspended particulate matter 

(TSP). Mean particulate nitrate and sulfate concentrations were 40 pg/m 3 and 

13 pg/m3 , respectively. For the controlled exposure studies, no functional 

decrements in FEV1 were found at 0 or 157 pg/m 3 (0 or 0.08 ppm) 0 3 ; however, 

statistically significant decrements were found at 314, 470, and 627 pg/m 3 

(0.16, 0.24, and 0.32 ppm) 0 3(see Section 10.2.3). Symptom increases generally paralleled the FEV Idecrements (Figure 11-2). Statistically significant 

.decrements in FEV1were also observed during the ambient exposure studies (5 

percent) and were not significantly different from those obtained with 0.16 

ppm 03 . At the generated 0 3concentrations of 0.24 and 0.32 ppm, an increasing 

number of subjects could not complete the 1 hr of exercise without reducing 

their workloads. Exposure to ambient air or 0.16 ppm 0 3produced no decreases 

in workloads, even though statistically significant decrements in iung function 

and increased symptoms did occur. Comparisons on an individual basis showed 

that ambient exposure responses differed only randomly from predictions based 

on the generated 0 3concentration-response information. Symptom increases 

during ambient exposure were slightly less than predicted. Thus, no evidence 

11-9 
0 

~ j 40 100 ~ 

~ N 

N = 35 

N 

~ c0N i 

m o w. 

08 

~ 30 . = 

symptoms i 

0 

c y •5 20 50 £ 

J •O a9 

o~ 15 ~ 

W ~ 10 FEV~ cn 

LL m c -. 

5 Performance m a

~ O Reduction O 

CL O 

-5 ~ 

C~ 0 0.16 0.32 ~ 

Ozone Concentration, ppm 

Figure 11-2. Changes in group mean responses, including 

FEV1.0, symptoms, and exercise perFormance in 50 

competitive cyclists exercising continuously for 1 hr wrhile 

exposed to ozone. 

Source: Adapted from Avol et al. (1985c). 

11-10 
was found to suggest that any pollutant other than 0 3 contributed to the 

observed effects produced by ambient air. 

The mobile laboratory was used again in Duarte, CA, during the summer of 

1983 to determine if younger subjects were affected by exposure to ambient 

levels of photochemical oxidants. Avol et al. (1985a,b) studied forced expiratory function and symptom responses in 59 healthy adolescents, 12 to 15 years 

of age (Table 11-1). Each subject received a screening examination including 

medical history, pulmonary function tests, resting EKG, and exercise stress 

test. A11 subjects denied smoking regularly. Fifteen of the subjects had a 

history of allergy and two of the subjects gave a history of childhood asthma 

but denied recent asthmatic symptoms. The subjects were randomly exposed to 

purified air and to ambient air containing 282 pg/m 3 (0.144 ppm) 0, and 153 

pg/m3 total suspended particulates while continuously exercising on bicycle 

ergometers at moderate levels (VE = 32 L/min) for 1 hr. Pulmonary function 

tests were performed pre- and post-exposure. Symptoms were recorded at 15-min 

intervals and immediately post-exercise. Foliowing the exposure period, the 

subjects rested in purified air for 1 hr, after which symptoms and puimonary 

function were measured again. After ambient exposure, there were statistically 

s i gni f i cant decrements i n FVC (2.1 percent) , FEVO 75 (4.0 percent) , FEVI. 0 

(3.7 percent), and PEFR (4.4 percent) relative to control exposure. Although 

some reversal of these changes was evident at 1 hr post-exposure, decrements 

in pulmonary function were still present compared to the preexposure levels. 

A linear regression analysis showed that individual FEV 1 0 responses were 

negatively correlated (r = 0.37, P<0.01) wi.th individual ambient 03 exposure 

concentrations. Analysis of the data set revealed no significant differences 

in responses between the fifteen "allergic" subjects and the rest of the 

group. In addition, although girls tended to show larger decreases in FEV1.0 

with ambient exposure than boys (7.5 percent and 3.4 percent, respectively), 

the difference was not statisticaliy significant. The authors attributed the 

lack of significance as possibly due to the smallnumber (n = 13) of girls in 

the study. There were no significant increases in symptoms with ambient 

exposure relative to control. The lack of symptoms in adoiescents at ambient 

0 3 concentrations that produce statistically significant decrements in pulmonary 

function is an interesting and potentially important observation from this 

study, since adults exposed in the mobile laboratory under similar conditions 

report symptoms of lower respiratory irritation accompanying decrements in 

forced expiratory function (Linn et al., 1980, 1983; Avol et al., 1983, 1984). 

11-11 
Factors contributing to the differences in response between adolescents and 

adults are not yet known. 

11.2.2Symptoms and Pulmonary Function in Field or Simulated Hi h-Altitude 

Studies 

Early reports of high 03 concentrations in aircraft flying at high altitudes prompted a series of field and high-altitude simulation studies. In 

1973, Bischof reported that 03 concentrations (measured by a Comhyr ECC meter) 

during 14 spring polar flights (1967-1971) varied from 0.1 to 0.7 ppm, with 1-hr 

peaks above 1.0 ppm occurring, despite ventilation. More recently, Daubs (1980) 

reported 0 3 concentrations in Boeing 747 aircraft ranging from 0.04 to 0.65 ppm, 

with short-term (2 to 3 min) levels as high as 1.035 ppm. Other reports (U.S. 

House of Representatives, 1980; Broad, 1979) have indicated that 0 3 concentrations in high-altitude aircraft can reach excessively high levels; for example, 

on a flight from New York to Tokyo a time-weighted concentration of 0.438 ppm 

was recorded, with a maximum of 1.689 ppm and a 2-hr exposure of 0.328 ppm.* 

Flight attendants and passengers in high-altitude aircraft have complained 

of certain symptoms (chest pain, substernal pain, cough), which are.identical 

to those typically reported in subjects exposed to 03 and other photochemical 

oxidants (see 11.3.1.1). The symptoms were most prevalent during late winter 

and early spring flights. Similar symptoms have also been observed in more 

systematic studies of high-altitude effects, such as (1) the study by Reed 

et al. (1980), in which symptoms among 1,330 flight attendants were found to 

be related to aircraft aircraft type and altitude duration but not to sex, 

medical history, residence, or years of work; and (2) the Tashkin et al. 

(1983) study, in which increased 0 3 -related symptoms were reported by flight 

attendants on Boeing 747SP (higher-altitude) flights in comparison to attendants on lower-flying 747 flights. In neither of these two studies, however, 

were concentrations of 03 or other photochemical oxidants measured in the 

aircraft. 

*Note that, as ambient pressure decreases at high altitude, 0 3 concentrations remain the same as expressed in terms of ppm levels, but 0 3 mass concentrations (in pg/m3 ) decrease in direct proportion to increasing altitudes. 

Therefore, knowledge of prevailing atmosphere pressure and temperature is 

generally needed for correct conversion of ppm 03 readings to pg/m 3 03 concentrations under specific measurement conditions. 

11-12 
In a series of aititude-simulation studies, Lategola and,associates 

(1980a,b) attempted a more quantitative evaluation of effects on cardiopulmonary 

function and symptoms associated with 0 3 exposures of male and female flight 

attendants, crew, and passengers. Two studies (Lategola et a1., 1980a) were 

conducted on young surrogates of a mildly exercising flight attendant population, while a third study (Lategola et al., 1980b) evaluated older surrogates 

for :sedentary airline passengers and cockpit crew. A11 studies simulated 

in-flight environmental conditions at 1829 m(6000 ft) and all subjects served 

as their own controls. The results indicate increased symptoms and pulmonary 

function decrements among nonsmoking normal adult subjects at 0.30 ppm, but 

not 0.2 ppm under light exercise conditions. It should be noted that the 0 3 

levels-used in the Lategola studies are generally lower than 0 3 concentrations 

reported to occur in certain aircraft at high altitudes, as are the simulated 

altitudes employed in the studies. 

11.3 EPIDEMIOLOGICAL STUDIES OF EFFECTS OF ACUTE EXPOSURE 

Effects.of the acute exposure of communities to photochemicaT oxidants 

are generally assessed by comparing the functional or clinical status of 

residents during periods of high and low 0 3 or oxidant concentrations. Occasionally, two or more communities with different concentrations are compared. 

The concentrations measured have been 24-hr averages, maximum . .hourly averages, 

or instantaneous peaks. 

11.3.1. Acute Exposure Morbidity Effects 

For purposes of this document, indices of acute morbidity associated with 

photochemical oxidants include the.incidence of acute respiratory illnesses; 

symptom aggravation in healthy subjects and in patients with asthma and other 

chronic lung diseases; and effects on pulmonary fu.nction, athletic performance, 

auto accident rates, school absenteeism, and hospital admissions. 

11.3.1.1 Symptom Aggravation in Healthy Populations. Various symptoms, 

including eye irritation, headache, and respiratory irritation, have been 

reported during ambient air exposure in a number of studies (Table 11-2). Eye 

irritation, however, has not been associated with 0 3 exposure in controlJed 

laboratory studies (Chapter 10). This symptom has been associated with other 

photochemical oxidants such as peroxyacetyl nitrate (PAN) and with formaldehyde, 

acrolein, and other organic photochemical reaction products (National Air 

Pollution Control Administration, 1970; Altshuller, 1977; U.S. Environmental 

11-13 
Protection Agency, 1978; National Research Council, 1977; Okawada et al., 

1979). Of the biological effects caused by or aggravated by photochemical air 

pollution, eye irritation appears to have one of the lowest thresholds. It 

also appears to be a short-term, reversible effect, however, since damage to 

conjunctiva and subjacent tissue has not been reported. 

Qualitatively, the occurrence of an association between photochemical 

oxidant exposure and symptoms such as cough, chest discomfort, and headache is, 

plausible, given similar findings of occupational exposure to oxidants (see 

11.3.1.7) and of controlled human exposure studies (Chapter 10). The primary 

issues in question, however, in the studies cited in Table 11-2, are: (1) the 

composition of the mixture to which the subjects were exposed; (2) the concentrations and averaging times for oxidants in ambient air; and (3) the adequacy 

of inethodologic controls for other pollutants, meteorological variables, and 

non-environmental factors in the analysis. For these reasons, the studies are 

of limited use for developing quantitative exposure-response relationships for 

ambient oxidant exposures. 

11.3.1.2Altered Performance . The possible effects of photochemical oxidant 

pollution on athletic and driving performance have been examined in studies 

described in Table 11-3. The absence of definitive monitoring data for important pollutants as well as confounding by environmental conditions such as 

temperature and relative humidity detracts from the quantitative usefulness of 

these studies. Qualitatively, however, the epidemiological findings relative to 

athletic performance are consistent with the evidence from•field studies 

(Section 11.2.1) and from controlled human exposure studies (Section 10.4) 

indicating that exercise performance may be limited by exposure to 03 . 

11.3.1.3Acute Effects on Pulmonary Function . A summary of studies on the 

acute pulmonary function effects of photochemical oxidant pollution is given 

in Table 11-4. Previously reviewed studies (U.S. Environmental Protection 

Agency, 1978) suggested a possible association between decrements in pulmonary 

function in children and ambient ozone concentrations in Tucson, Arizona 

(Lebowitz et al., 1974) and Tokyo, Japan (Kagawa and Toyama, 1975; Kagawa et 

al., 1976). An additional study (McMillan et al., 1969) comparing acute 

effects in children residing in high- and low-oxidant areas of Los Angeles 

failed to show any significant differences in pulmonary function. None of 

these studies, however, meets the criteria necessary for developing quantitative exposure-response relationships for ambient ozone exposures. 

11-14 
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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 meas -urements 

included baseline and post-exercise spirometry (water-filled, no noseclips). 

Peak flow rates were obtained by Mini-Wright ® Peak Flow Meter at the beginning 

of the day or at lunch, adjusted for both age and height. No day-of-week 

effect was seen. Ambient air levels of TSP, hydrogen ions, and sulfates were 

monitored by a high-volume sampler on the rooftop of the day camp building. 

Ozone concentrations were estimated as a weighted average of data extrapoiated - 

from a monitoring site 20 mi south and a site 60 mi west, using two models 

that yielded 03 estimates within ±16 pg/m3 (0.008 ppm) on the average. Estimated 1-hr peak 03 ievels (early afternoon) varied from 90 to 249 pg/m3 (0.046 

to 0.122 ppm), and TSP levels were <103 pg/m 3 (6-hr samples) and maximum 

sulfuric acid (H 2SO4 ) concentrations were <6.3 pg/m 3 . 

Lippmann et al. (1983) reported significant inverse correiations between 

FVC and FEV1 and estimated maximum 1-hr 0 3 levels for 4 or more days on which 

0 3 concentrations covered a twofold range. Differences in correlations (i.e., 

slopes) were not related to other pollutants (TSP, H 2SO4) or ambient temperatures. Qualitatively, the Lippmann et al. (1983) study results suggest lowlevel 03 effects; however, because exposure modeling (rather than on-site 

monitoring) was used to estimate 0 3 levels, and because the effects were seen 

almost entirely on one day of the study, there is uncertainty about the precise 

quantitative interpretation of these findings. 

A similar group of children was studied during the summer at a day camp 

in Mendham, NJ (Lippmann and Lioy, 1985; Bock et al., 1985; Lioy et al., 

1985). Pulmonary function data were obtained from the children, aged 7 to 13 

years, during 16 days of a 5-week period from July 12 to August 12, 1982. In 

order to provide better air monitoring data, 0 3 concentrations were measured 

(UV) at the Mendham camp site and at a NJ sampling station 3.5 mi away. Only 

data from the sampling station were used in the analysis. The average highest 

peak 1-hr 03 concentration measured on a study day was 280 pg/m3 (0.143 ppm); 

values ranged from 39 to 353 pg/m3 (0.02 to 0.19 ppm) 0 3 during the 5-week 

period., Daily averages for ambient temperature, relative humidity, and precipitation were provided by the National Weather Service.' Ambient aerosol samples 

were also analyzed on a daiiy basis, but the results were not reported. A 

linear regression was calculated for each child between peak 1-hr 0 3 and each 

of four measures: FVC, FEV1 , PEFR, and MMEF. In addition, a summary weighted 

11-21 
correlation coefficient was calculated for all subjects. No adjustments.were 

made for covariates. Linear regressions were negative except for FVC in boys. 

Decrements in PEFR were significantly correlated with, peak 0 3 exposure but 

there were no significant correlations with FVC, FEV 1 , .: or MMEF. 

Several comparisons can be made between the data reported by Lippmann-et 

al. (1983) and those reported by Lippmann and Lioy (1985), Bock et al. ,(1985), 

and Lioy et al. (1985). There were 39 children (22 girls, 17 boys) in.the 

follow-up study for whom sufficient data existed for linear regression analysis. 

The children in Mendham, NJ, were not as physically active as the children 

studied in the previous study in Indiana, PA, which may account for some 

observed differences in results from the two. studies. While 0 37dependent 

changes in PEFR were reported in both studies, the authors did not observe the 

03-dependent change in FVC and FEV 1 in the follow-up study that they found.in 

the previous study. This lack of a significant effect for FVC and FEV 1 , which 

are known to have smaller coefficients of variation than PEFR, is surprising, 

especially considering the higher 0 3 concentrations reported in Mendham, NJ. 

Concentrations of inhalable particulate matter were also reported to be higher 

in association with a large-scale regional photochemical smog episode which 

may have had some effect on baseline lung function (Lioy et al., 1985). In 

addition, adjustments for covariates such as temperature and relative humidity, 

which might influence lung function, would have strengthened the reported 

results. The differences in transient reponses to 0 3 , the lack of definitive 

exposure data for other pollutants (particularly ambient aerosols), and the 

lack of adjustment for covariates limit the usefulness of these studies for 

determining quantitative exposure-response relationships for 0 3 . 

Lebowitz et al. (1983, 1985) and Lebowitz (1984) measured daily lung 

function in 24 Tucson, AZ, residents, aged 5 to 25 years. The subjects were 

part of a stratified sample of families from geographic clusters of a large 

community population under study. Over an 11-month period in 1979 and 1980, 

randomly chosen subsets of these subjects were tested during each season of 

the year. Measurements of peak flow were made in the late afternoon, using a 

Mini-Wright® Peak Flow Meter (Wright, 1978; Williams, 1979; van As, 1982; 

Lebowitz et al., 1982b). A11 age- and height-adjusted baseline peak.flows 

were within the published normal range. To adjust for seasonal effects and 

for inter-individual differences in means and variances, the daily peak flow 

for each person was transformed into a standard normal variable. Seasonal 

11-22 
Means and standard deviations were then used to generate daily z-scores, or 

standardized deviations from seasonal averages. 

Regional ambient 0 3 (measured by UV), CO3 and NO2 were monitored daily at 

three sites in'the Tucson basin (Lebowitz et al., 1984). Every 6 days, 24-hr 

TSP was measured at 12 sites, including stations at the center of each cluster 

of subjects within a 0.25- to 0.5-mi radius. Since previous ambient monitoring 

showed significant homogeneity of 0 3 in the basin, average regional vaiues 

were used for analysis of all geographic clusters, and closest-station values 

for individual clusters. Comparisons showed no significant changes in results 

when using regional averages or closest daily hourly maximum values. Indoor 

and outdoor monitoring was conducted in a random cluster sample of 41 representative houses. Measurements of air pollutants, pollen, bacilli, fungi, algae, 

temperature, and humidity were recorded once in each home for 72 hr during the 

two-year study period: Regional daily ambient maximum hourly 0 3 went up to 

239 pg/m3 (0.12 ppm) and was highest in the summer months. Indoor 0, concentrations were between 0 and 69 pg/m 3 (0 and 0.035 ppm). Levels of CO were 

less than 2.4 ppm (2736 g/m3 ) indoors and 3.8 to 4.9 ppm (4332 to 5586 g/m 3 ) 

outdoors. Indoor CO was correlated with gas-stove use only. Daily average 

ambient N0, ranged from 0.001 to 0.331 ppm (2 to 662 pg/m 3 ). Outdoor TSP 

ranged between 20 and 363 pg/m 3 for all monitoring days and between 27.5 and 

129 pg/m3 on days of indoor monitoring. Indoor TSP and respirable suspended 

particle (RSP) ranges were 5.7 to 68.5 pg/m3 and 0.1 to 49.7 pg/m3 , respectively, and were correlated with indoor cigarette smoking but not gas-stove 

use. 

In a preliminary analysis, 0 3 and TSP levels were I negatively correlated 

with peak flow, after correction for season and other pollutants. In a multivariate analysis of variance, controiling for person-days of observation, 

meteoroiogic factors, CO 3 NO2 , and TSP, a significant effect of 03 on peak 

flow remained (p <0.001). A significant interaction of 03 with TSP was also 

observed (z-scores more negative than predicted by an additive model at high 

03 and TSP levels). In multipie regression analyses, the z-scores for persondays with maximum hourly 0 3 level and mean 0 3 level of at least 0.08 ppm were 

statistically significant (p <0.007 and p<0.0001, respectively). These 

scores represented decreases in mean peak flow of 12.2 percent and 14.8 percent, 

respectively. These changes were significantly different (p <0.05) from 

changes reported in previously published data (Lebowitz et al., 1982b) on 

normal day-to-day variation in another, comparable group of children. 

11-23 
Lebowitz et al. (1983, 1985) and Lebowitz (1984) observed a consistent 

short-term effect of ambient ozone exposure on peak flow. The quantitative 

usefulness of the study, however, for standard setting is limited by several 

factors. Sample sizes were small in relation to the number of covariates. 

The fixed-station aerometric data employed did not allow quantitation of 

individual ambient pollution exposures. Likewise, since the time spent indoors 

and outdoors was not measured in the children, the proper relative weights of 

indoor and outdoor pollution measurements could not be determined for:quantitation of exposure. 

Selwyn et al. (1985) studied changes in ambient 03 concentrations in 

relation to changes in the pulmonary function of healthy adults after vigorous 

outdoor exercise. From May through October 1981, 24 local residents ran three 

miles twice a week between 4:30 and 6:30 PM at a track near Houston, Texas. 

Subjects kept their heart rates between 75 and 90 percent of heart rate during 

maximal oxygen consumption. Levels of 03 , S02 , NO2 , CO 3 temperature, and 

relative humidity (rh) were measured continuously beside the track. For each 

run, a subjects' 0 3 exposure was considered to be the time-weighted 15-min 

average of the maximum 03 concentrations measured during the run. Average 

inhalable particulate levels were obtained every 12 hr. The average 0 3 concentration during runs was 92 pg/m 3 (0.047 ppm), with a range of 8 to 265 pg/m 3 

(0.004 to 0.135 ppm). Temperature averaged 85 degrees F., and rh averaged 62 

percent during runs. Subjects performed forced expiratory maneuvers (FVC, 

FEVl, FEF25-75%, and FEFO 2-1 2) before and 15 min after each run. Changes in 

the pulmonary function measures (calculated as post-run minus pre-run values) 

were regressed against 0 3 concentration, with adjustment for temperature and 

rh. In these regressions, most lung function changes were negatiavely associated with 03 concentration, but the coefficients for 0 3 were not statistically significant at p= 0.05. 

11.3.1.4 Aggravation of Existing Respiratory Diseases. A number of studies 

have examined the effects of photochemical oxidants on symptoms and lung functions of patients with asthma, chronic bronchitis, or emphysema. Most of the 

earlier studies were evaluated in the 1978 EPA criteria document for ozone and 

other photochemical oxidants (U.S. Environmental Protection Agency, 1978). The 

results of these as well as more recent studies are summarized in Table 11-5. 

For 10 weeks from July to September 1976, Zagraniski et al. (1979) followed 

82 patients with asthma or hay fever (patient group) and 192 healthy telephone 

company employees (worker group) in New Haven, CT. Subjects were asked to 

11-24 
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complete daily symptom diaries, which were distributed and collected weekly. 

The groups differed in their distributions of age, gender, smoking history, 

and job type, though these variables, as well as ethnic group, appear to have 

been controlled in the statistical analysis. 

Air pollution was monitored at two downtown sites 1.2 km apart. Concentrations of S02 , TSP, sulfates (from dried glass-fiber filters), and 0 3 (by 

chemiluminescence) were measured, as was the pH of filter samples (using KC1 

in distilled water). Previously measured NO 2 and CO levels had been low. 

Daily maximum temperature was treated as a covariate. Maximum hourly 0 3 

levels ranged from 8 to 461 pg/m3 (0.004 to 0.235 ppm) and averaged 157 pg/m 3 

(0.08 ppm). Eight- and 24-hour mean TSP levels were 83 and 73 pg/m3 , respectively. The 24-hour mean SO 4 level was 12.5 pg/m3 . Ozone and SO4 peaks often 

occurred simultaneously. Reported outdoor exposure, working, and home conditions were judged to be equivalent for most subjects for most pollutants. 

The data were analyzed by pairwise correlation and multiple regression, 

in which daily symptom prevalence was the dependent variable. Few associations 

of symptoms with pollution levels were observed. The maximum hourly 0 3 , 

however, was positively and significantly correlated (p <0.05) with cough and 

nasal irritation in heavy smokers, with cough in hay fever patients, and with 

nasal irritation in asthmatics. In multiple regression analysis, the 0 3 level 

was associated with cough and eye irritation in heavy smokers, and with cough 

in hay fever patients. Cough frequency increased linearly with maximum_hourly 

03 levels, particularly in heavy smokers and in subjects with pre-existing 

illness. Filter pH was negatively associated with eye, nose, and throat 

irritation in most groups. Pollen was positively associated with sneezing in 

hay fever patients. Sulfate levels were not consistently associated with 

symptoms. 

Although it suggests a relationship between ambient ozone exposure and 

symptom prevalence, the study does not allow quantitative inference as to 

pollution exposures of individual subjects, largely because the distances 

between monitoring sites and respective homes and workplaces were not reported. 

Also, interpretation is limited by the fact that the dependent variable, 

symptom prevalence, ignores the potential dependence of present day's symptom 

on previous day's symptoms. Use of incidence, or adjustment for previous 

day's symptoms, would have been more appropriate than use of prevalence. 

Furthermore, the regression models were not clearly described, and thus the 

appropriateness of statistical corrections can not be assessed with confidence. 

11-28 
Whittemore and Korn (1980) applied multiple logistic regression analysis 

to asthma panel data collected in six southern California communities during 

1972 through 1975. The panels were recruited by the U.S. Environmental Protection Agency (EPA) as part of the Community Health Environmental Surveillance 

System (CHESS). Subjects with physician-diagnosed, active asthma kept symptom 

diaries in which they were asked to report the presence or absence of an 

asthma attack each day for 34 weeks. Each diary contained information for one 

week; diaries not returned after 16 days were excluded from analysis. The EPA 

data sets used have undergone quality control to ensure accurate coding of 

health responses. There were 16 period- and community-specific panels. In 

selecting panelists, preference was given to prospective subjects reporting 

frequent asthma attacks; local physicians were consulted before final selection. 

'Concentrations of TSP, RSP, SO 4 , and NO3 were measured by EPA in each 

community. Because a large proportion of EPA ozone measurements were missing, 

total oxidant measurements made by the Los Angeles Air Quality Control District 

were used instead. Measurements of NO 2 and S0 2 were not used in data analysis 

because many such measurements were missing. The average distance between 

subjects' homes and monitoring stations was 3 miles (range 1 to 8 miles). The 

aerometric data were arranged into 24-hour periods (midday to midday). Daily 

maximum hourly oxidant levels were used in analysis; panel-specific medians of 

these ranged from 0.03 to, 0.15 ppm. Because RSP, SO 4 , and NO3 were highly 

correlated with TSP, TSP was the oniy particulate pollutant included in analysis. 

Logistic regression analysis was applied to data from 444 person-periods, 

231 male and 213 female. Seventy-two percent of the males' reporting periods 

were supplied by males under 17 years old; the corresponding percentage of 

females'reporting periods was 44 percent. It was possible for an individual's 

data to be analyzed more than once, since some asthmatics participated in more 

than one panel. The dependent variable was the individual's presence or 

absence of an asthma attack on a given day. Independent variables were the 

same day's oxidant and TSP levels, minimum temperature, relative humidity, 

average windspeed, day of study, and day of week, as well as the individual's 

presence or absence of an asthma attack on the previous day (autocorrelation 

variable). 

Present day's attack status was most closely associated with the autocorrelation variable, and was also significantly associated with all pollution 

and weather variables except windspeed. The results suggested high interindividual variability in response to environmental and meteorologic factors. 

11-29 
The model estimated that a panelist having a baseline attack probability of 

0.10 following an attack-free day and a probability of 0.41 on the day after 

an attack day would have these probabilities raised to 0.13 and 0.44, respectively, if the oxidant level increased by 0.2 ppm. The model also estimated 

an increase of less than 0.01 when the oxidant level rose by 0.1 ppm. 

The Whittemore and Korn (1980) analysis suggests an effect of ambient 

oxidants on asthma attack rate. The analysis also offers the major adv,antages 

of adjusting for previous day's status and confining the individual's modelestimated attack probability to the realistic range of zero to one. These 

results cannot, however, be considered quantitative. Oxidant tneasurements, 

not ozone measurements, were used, and some subjects' homes were distant from 

aerometric sites. The independent variable was a subjective measure, subject 

to potential bias. Information on relevant covariates, such as daily medication use, emotional stress, exercise level, acute respiratory infection, and 

other environmental pollutants and pollen counts, was not collected. 

Lebowitz et al. (1982a, 1983, 1985) and Lebowitz (1984) conducted serial 

studies of Tucson, AZ, adults with asthma, with reported chronic symptoms of 

airway obstructive disease (AOD), with reported allergies, and without reported 

symptoms. Subjects were drawn from 117 Anglo-white families from a stratified 

sample of families in three geographic clusters in a community study population. 

Subjects were followed for two years with daily symptom and medication diaries 

and Mini-Wright@ peak flow measurements. A11 families gave information on 

their home structure, heating, cooling, appliances, and smoking in the household. Telephone checks and visits ensured proper use of diaries, and visits 

were made to calibrate peak flow meters. 

Measurements of air pollutants, pollen, bacilli, fungi, and algae were 

made in and directly around a random cluster sample of 41 study households 

(Lebowitz et al., 1984). Pollen and TSP (high-volume samplers) were measured 

simultaneously in the center of each geographic cluster. Air pollutants were 

al,so measured regionally in the Tucson basin (see discussion in previous 

section for details). Indoor pollution was classified according to indoor 

smoking and gas-stove use for homes in which indoor monitoring was not done. 

Indoor particle and pollen concentrations were 100- to 200-fold lower than 

those outdoors. Scanning electron microscopy showed structural differences 

between indoor and outdoor dust. 

A total of 35 asthmatics provided daily peak flows. For each study 

group, a given day was included in analysis only if more than five people had 

11-30 
provided data on that day. There were 353 such days for asthmatics, 544 for 

the AOD group, 494 for the allergy group, and 312 for the asymptomatic group. 

A sex-, age-, and height-specific z-score was computed for each-subject's peak 

flow. Symptom rates per 100 person-days were calculated separately for asthmatics and non-asthmatics. Asthmatics' attack incidence could not be analyzed 

because there were only 75 newly incident asthma attacks in 3820 person-days. 

The data were analyzed by multivariate analysis of variance and regression 

analysis. When appropriate, models were adjusted for differences among individuals' person-days of observation. Of the variables considered, smoking was 

most strongly reiated to peak flow. In the AOD group, 03 and TSP were both 

significantly related to symptoms (p <0.01) after adjustment for gas-stove 

use, smoking, and relative humidity. 

In 23 asthmatics in the geographic cluster where indoor monitoring was 

most complete, 0 3 and temperature had a significant interaction in relation to 

peak flow; high temperature had an effect when 0 3 was low, and 03 had an 

effect only at low temperatures. Ozone aione, however, was not independently 

related to peak fiow after adjustment for other pollutants and covariates. 

There was also a temperature-0 3 interaction on these asthmatics' symptom 

prevalence; 0 3 had an effect (not statisticalTy significant) only in the 

high-temperature range. Ozone was associated with rhinitis in asthmatics 

living in homes with gas stoves (p <0.015). Daily medication correlated 

highly with asthmatics' symptom exacerbations. 

The authors speculated that 0 3 effects in asthmatics were occurring 

mainly at levels of 0.052 ppm or greater, but that 0 3 appeared to be acting as 

a surrogate for other oxidants or in conjunction with other environmental 

factors. These studies included good quality controi of health data and 

unusually extensive environmental monitoring. Like the studies discussed 

previously, they suggest an effect of ozone in persons with pre-existing 

respiratory illness. Their results are not truly quantitative, however, 

largely because sample sizes were often small in relation to the number of 

covariates, and because not all individuals' pollution exposures were known in 

detail. 

Javitz et al. (1983) reanalyzed a study of 286 persons with asthma, 

chronic bronchitis, or pulmonary emphysema in Houston, TX (Johnson et al., 

1979, unpublished report). Over 114 days from May to October 1977, all subjects 

were asked to complete daily symptom diaries, and about one-third of the 

subjects underwent weekly spirometric testing at home. Air pollutants were 

11-31 
measured at nine fixed stations in the Houston area. The symptom data were 

analyzed by logistic regression models, which estimated that the incidence of 

chest discomfort, eye irritation, and malaise would increase as the PAN concentration increased up to 0.012 ppm. The models also estimated that the incidence 

of combined nasal symptoms, combined respiratory symptoms, and medication use 

would increase by 6.0, 3.4, and 5.2 percent, respectively, as the 0 3 level 

increased up to 412 pg/m 3 (0.21 ppm). The models estimated no increase in any 

specific nasal or respiratory symptoms with.increasing 0 3 exposure. 

The spirometric data were analyzed by linear regression models, which 

estimated decreases in FVC and FEV1 of 2.8 percent and 1.6 percent, respectively, as daily maximum 1-hr 03 levels rose 412 pg/m3 (0.21 ppm). These 

models estimated somewhat larger decreases in lung function wi -th rising total 

oxidant (03 and PAN) levels. The model-estimated changes in lung function 

were of questionable statistical significance. 

These results suggest a limited effect of ozone on symptoms and lung 

function in persons with pre-existing lung disease, but substantial limitations 

in data quality render the results inconclusive. Many aerometric data points 

were missing, so that individuals' pollution exposures could not be assessed 

at all confidently. Over one-third of the subjects reported respiratory 

symptoms on 100 or more days, and over two-thirds reported nasal symptoms on 

10 or fewer days. Such skewing of symptom behavior yielded a relatively 

insensitive test for pollution effects in the study group. 

In a preliminary presentation, Holguin et al. (1985) have evaluated the 

association of 03 exposure with the probability of an asthma attack in Houston, 

TX, during May to October 1981. The study population of 51 subjects was 

carefully selected from individuals residing in the neighborhoods of Clear 

Lake and Sunnyside. The subjects were medically diagnosed as probable, uncomplicated extrinsic asthmatics, since all had elevated IgE levels, pulmonary 

function tests consistent with reversible airway disease, and no evidence of 

other chronic cardiopulmonary disease. Baseline pulmonary function status, 

however, was not described in detail. Ages of the subjects ranged from 7 to 

55 yr but the median age was 13 yr and 41 of the subjects were under 20 yr of 

age. A11 subjects completed log forms twice daily providing 12-hr daytime (7 

a. m. to 7 p. m. ) and 12-hr ni ghtti me (7 p. m. to 7 a. m. ) records of hourly 

symptoms, activities, and location. Pulmonary function measurements of peak 

flow were also made during the morning and evening reporting times using a 

Mini-Wright® peak flow meter. Symptoms, medication use, and peak flow data 

11-32 
were examined for patterns that fit the clinical description of asthma and 

that represented deviations from an individuals' baseline profile. Using this 

i nformati on, a speci f i c def i ni ti on of an asthma attack was deri ved for each 

subject. 

Fixed-site monitors within 2.5 miles of the subjects residences in each 

of the two neighborhoods provided: maximum hourly averages for 03 (CHEM), 

NO2 , CO 3 S02 , temperature, and relative humidity (rh); daily 12-hr averages 

for fine (<2.5 pm MMAD) and coarse (2.5-15 pm MMAD) particles, aldehydes, and 

aeroallergens; and daily 24-hr averages for total suspended particulates. 

Mobile monitoring of indoor/outdoor concentrations of the same pollutants was 

collected in 12 residences for 1 week. Detailed measurements of personal 0 3 

exposure were also obtained by means of portable monitors in 30 of 51 study 

subjects. An exposure model that weighted indoor and outdoor location patterns 

as well as fixed-site values was used to estimate individual exposures to 0 3 

and other aerometric variables. Over the 12-hr symptom period, the time-weighted 

1-hr maximum O Z concentrations ranged from 2 to 151 pg/m 3 (0.001 to 0.077 ppm) 

with a mean concentration of 37 pg/m 3 (0.019 ppm). Values for the other 

environmental variables were not reported. 

Logistic regression analysis was applied to 42 subjects, each with more 

than five attacks. The analysis adjusted for autocorrelation of present day's 

attack probability w3th the attack probability on the previous day. Regression 

coefficients were found to be significantly related to a previous attack, to 

increasing 0 3 concentration, and to decreasing ambient temperature. Elevated 

concentrations of pollen in September and October increased the probability of 

an attack in some asthmatics, but this was not statistically significant for 

the group. There was no association between attack probability and NO 2 or rh. 

The utilization of a time-weighted exposure model, employing data from 

fixed-site as well as mobile monitors, provides an unusually good estimate of 

actual exposures. Personal exposure data, however, were used to assess the 

validity of the estimates of individual exposures determined by the model but 

were not used in the development of the exposure estimate model itself. There 

are still some uncertainties associated with this approach since results from 

this comparison indicated that exposure estimates obtained from the model 

underestimated actual personal exposures by approximately 10 ppb (Contant et 

al., 1985). 

The data analysis by Holguin et al. (1985) provides a means of estimating 

the increasing probability of an asthma attack on the basis of a previous 

11-33 
attack, a 40 ppb increase in 03 , an 8° C increase in ambient temperature, and a 

combination of these factors. Although the authors estimate the increased 

attack probabilities associated with incremental 03 increases from given 

baseline probabilities, it would be difficult to quantitate these probabilities 

at any given 0 3 concentration since the magnitude of the effect varies as the 

levels of the other covariates vary. While confounding variables such as NO 2 , 

pollen, and rh were taken into account, other pollutants such as S0 2 , total 

suspended particulates, and inhalable particles (<15 pm MMAD) were not considered in the analysis. The role of other pollutants, particularly the fine 

inhalable particles, in combination with 0 3 , temperature, and pollen needs to 

be evaluated before the results of this study can be used quantitatively. 

11.3.1.5 Incidence of Acute Respiratory Illness. Table 11-6 describes studies 

relating oxidant levels with the incidence of acute respiratory illnesses. 

These studies, however, did not meet the criteria necessary for developing 

quantitative exposure-response relationships for ambient oxidant exposures. 

11.3.1.6 Physician, Emergency Room, and Hospital Visits. Earlier studies 

reviewed in the 1978 EPA criteria document for ozone and other photochemical 

oxidants (U.S. Environmental Protection Agency, 1978) were not able to relate 

oxidant concentrations to hospital admission rates or clearly separate oxidant 

effects from effects of other pollutants (Table 11-7). The effects of social 

factors, which produce day-of-week and weekly cyclical variations, and holiday 

and seasonal variations, were rarely removed (and then with possible loss of 

sensitivity). Relating time of visit to time of exposure was also very difficult. Studies of visits to medical facilities in the United States usually. 

lack appropriate denominators since data on the number of individuals at risk 

are generally not available and the catchment area (total population) is 

unknown. In addition, with the increased use of the emergency room as a 

family practice center, visits are becoming less associated with acute exposure 

or attack than they once were. Also, emergency room data, like hospital 

record data, often lack information on patients' smoking habits, ethnic group, 

social class, occupation, and even other medical conditions. 

Whether changes in hospital use reflect changes in either illness experience or illness perception and behavior is still uncertain. People may behave 

differently according to individual perceptions of environmental challenges. 

The response of the medical-care system is also determined by several factors, 

including insurance and availability of physicians, beds, and services (Bennett, 

11-34 
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1981; Ward and Moschandreas, 1978). Artifacts may arise from changing definitions of classifications and varying diagnostic or coding practices as well. 

Another frequent problem is that repeated admissions or attendance by a small 

number of patients can cause tremendous distortions in the data (Ward and 

Moschandreas, 1978). Furthermore, interpretation of hospital admissions data 

is hindered because hospital statistics often lack reliability and validity 

such that determining disease incidence is difficult; insufficient clinical 

data are available for diagnostic classification and grading of severity'; and 

a number of potential subclassifications of patients may require separation 

and attention in the analysis (Ward and Moschandreas, 1978). 

Namekata et al. (1979) found no significant association between 0 3 levels 

and emergency room visits for cardiac and respiratory diseases in two Chicago 

hospitals during 1977-1978. This study, however, must be considered inadequate 

because information collected from the medical records was insufficient for 

identifying sources of variability in the data and for controlling confounding 

factors of the types noted above. In addition, the 0 3 data were insufficient 

and incomplete and the linear models used could not determine effect levels of 

the pollutant. 

Richards et al. (1981) evaluated the relationship between asthma emergency 

room visits and hospital admissions and indices of air pollution, meteorological conditions, and airborne allergens. Questionnaire data were obtained on 

all children presenting to the Emergency Room of Childrens Hospital of Los 

Angeles for symptoms associated with asthma during a 6-month period (August 

1, 1979 to January 31, 1980), encompassing both high and low periods of air 

pollution. Air pollution and meteorological data were obtained from monitoring 

stations located in the geographical area and weighted according to the density 

of patients residing near the monitoring stations. The weighted averages were 

used to calculate an average exposure representative of the entire geographical 

area. Univariate correlation analyses demonstrated a number of positive and 

negative correlations of asthma with air pollutants; however, when asthma 

morbidity was regressed on the combined factor scores, 30 percent of the total 

variation could be explained by air pollution or meteorological conditions. 

Other variables such as restriction of outdoor activity or exposure to other 

irritants that were not measured could also have affected asthma morbidity. 

In addition, this study suffers from many of the problems enumerated above. 

There was difficulty establishing a definitive diagnosis of as•thma retrospectively in the patients, inadequate exposure assessment, no clear differentiation 

11-38 
of 03 effects from the effects of other pollutants, and the presence of multiple 

confounding variables. 

Goldsmith et al. (1983) studied emergency room visits in four Southern 

California communities (Long Beach, Lennox, Azusa, and Riverside) during 

1974-1975. Logbook data on total admissions were taken from two hospitals in 

each of the first three communities and from three hospitals in the fourth. 

The hospitals were < 8 km from Southern California Air Quality Management 

District stations monitoring TSP, Ox , CO 3 N0, NO2 , 502 , sulfate (SO4 ), and 

coefficient of haze (COH). Catchment areas and air monitoring data for 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 associated with daily admissions in the high-oxidant area 

(Azusa) after correction for other variables using correlation coefficients 

from path analysis (although the more complete path analysis explained less 

variance than the standard regression model). Unfortunately, the lack of population denominators and characteristics, the lack of admission characteristics, 

and poor characterization of exposure seriously limit the use of these findings. 

Bates and Sizto (1983) studied admissions to all 79 acute-care hospitals 

in Southern Ontario, Canada (i.e., the whole catchment area of 5.9 million 

people) for the months of January, February, July, and August in each of 6 

years (1974, 1976-1978, and 1979-1980). Air pollution data for CO 3 NO2 , 03 , 

and particles (COH) were obtained from 15 stations located mostly along the 

prevailing wind direction. Temperature was controlled. In July and August, 

highly significant assocations (Pearson r, 1-tailed, P< 0.001) were found 

between excess (percent deviations from day-of-week and seasonai means) respiratory admissions and average maximum hourly S0 2 and 03 concentrations, and 

temperature (with 24- and 48-hr lags between the variables). Nonrespiratory 

admissions showed no relation to pollution. Temperature was independently 

important (-5.3 ° C average on winter days in study). Admissions, and admission 

correlations with pollutants, were consistent from year to year. Further 

analysis showed that: asthma was the most significant respiratory problem 

driving the admissions.up, especially in younger people. Bronchitis and 

pneumonia admissions were not significantly related to pollutants. The authors 

state that it was difficult to differentiate between the effects of temperature, S02 , and 03 . With data extended through 1980 (Bates, 1985), however, 

there is preliminary information that sulfate levels accounted for a high 

11-39 
percentage of explained variations for all respiratory complaints, but that 

ozone was still independently associated with asthma. Since the number of 

separate people admitted was unknown, a"sensitive" subpopulation could have 

affected the results. In addition, actual exposure information can only be 

approximated in this type of study so that only qualitative associations can 

be drawn between ambient pollutants and morbidity increases in the population. 

11.3.1.7Occupational Studies . Studies of acute effects froin occupational 

exposure are summarized in Table 11-8. These studies did not meet the criteria 

necessary for developing quantitative exposure-response relationships for 

ambient oxidant exposures. 

11.3.2Trends in Mortality 

The possible association between acute exposure to photochemical oxidants 

and increased mortality rates has been investigated a number of times (Table 

11-9) and the results have been reviewed at length in previous documents 

(National Research Council, 1977; U.S. Environmental Protection Agency, 1978; 

World Health Organization, 1978; Ferris, 1978).. As yet, no convincing association has been demonstrated between dai7y mortality and daily oxidant concentrations. High oxidant levels were usually associated with high temperatures 

that were sufficient to account for any excess mortality found in these studies. 

11.4 EPIDEMIOLOGICAL STUDIES OF EFFECTS OF CHRONIC EXPOSURE 

Only a few prospective studies of the chronic effects of 0 3 exposure are 

available. These studies are usually concerned with the association of symptoms, lung function, chromosomal effects, or mortality rates and average 

annual levels of photochemical oxidants; or comparisons of chronic effects in 

populations residing in low- or high-oxidant areas. The inability to relate 

chronic effects with chronic exposure to specific levels of pollutants is a 

major limitation of these studies. In addition, given the long periods of 

time known to be required for the development of chronic diseases, it is 

unlikely that any of these studies can be used to develop quantitative exposureresponse relationships for ambient oxidant exposures. Further study of welldefined populations over long periods of time is required before any relationship between photochemical oxidants and the progression of chronic diseases 

can be conclusively demonstrated from population studies. 

11-40 
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11.4.1 Pulmonary Function and Chronic Lung Disease 

Studies of chronic respiratory morbidity are summarized in Table 11-10. 

While some of these studies (Detels et al., 1979, 1981; Rokaw et al., 1980; 

Hodgkin et al., 1984) suggest an increase in the prevalence of respiratory 

symptoms or possibly impairment of pulmonary function in high-pollutant areas, 

the results do not show any consistent relationship with chronic exposure to 

ozone or other photochemical oxidants. In addition, as discussed above, these 

studies are generally limited by insufficient information about individual 

exposures and by their inability to control for the effects of other environmental factors. They do not provide information useful for quantitative 

exposure-effect assessment. Thus, to date, insufficient information is available in the epidemiological literature on possible exposure-effect relationships 

between 03 or other photochemical oxidants and the preualence of chronic lung 

disease. These relationships will need further study. 

One of the largest investigations of chronic 03 exposure has been the 

series of population studies of chronic obstructive respiratory diseases in 

communities with different air pollutant exposures, reported by Detels and 

colleagues of the University of California at Los Angeles (UCLA) (Detels et 

al., 1979, 1981; Rokaw et al., 1980). The areas studied were characterized by 

high levels of photochemical oxidants (Burbank and Glendora, CA); high levels 

of S4x , 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 the highest-polluted area (Glendora). Lung 

function was generally better among residents of the 1ow-pollution areas, as 

indicated by FEV1 , FVC, maximum expiratory flow rates, closi.ng volume, thoracic 

volume, and airway resistance. Maximal mid-expiratory flow rate, considered 

to be sensitive to changes in small airways, was similar in the residents of 

all three areas, while the mean AN2 was slightly higher among residents of the 

high-pollution areas. Although the results suggest that adverse effects of 

long-term exposure to photochemical oxidant pollutants may occur primarily in 

the larger airways, the usefulness of these studies is limited by a number of 

problems. For example, testing in different communities occurred at different 

times over a 4-year period. Also, the authors presented no information on 

such matters as self-selection and migration in and out of these areas. 

Additional comparisons between mobile laboratory and hospital laboratory 

test results did not always show adequate reproducibility. The study populations had mixed ethnic groups, and completion rates were approximately 70 to 

11-44 
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79 percent in the three areas. Comparisons of participants with census information 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 

residence because of breathing problems. Those with occupations that may have 

involved significant exposure were not necessarily excluded. Analyses were 

often made by smoking status and.compared means or proportions that fell above 

or below certain levels. 

A major difficulty in the analyses is that the exposure data presented 

are not adequate., Control of migration effects on chronic exposure was insufficient, and recent exposure information was provided only by ambient levels 

from only one monitor, located as far as 3 mi away. A further problem is 

that, as in most geographical comparisons, analysis.of results assumes no 

differences by place, date, or season. This assumption is especially important 

since the study periods in each community were different. Furthermore, over 

the 4-year period of the study there were many changes, including amounts and 

types of cigarettes smoked, respiratory infection epidemics, and other 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. 

Interpretation of the UCLA lung function data is complicated by the fact 

that fewer smokers had abnormal lung function than might be expected. Also, 

some of the tests employed, e.g., flow rates at low lung volumes and singlebreath nitrogen tests, require stringent measures to avoid observer bias. It 

is not clear whether such measures were taken in the UCLA studies. 

To test for health effects of air pollution, the investigators often 

compared the lower ends (three to five standard deviations below the means) of 

the distributions of the study communities' health measurements. It is very 

difficult to interpret such comparisons unless the other portions of the 

distributions are also presented. `Also, numbers of cases were sometimes 

relatively small, and some results, e.g., those of the single-breath nitrogen 

test, suggested improving lung function with increasing pollution exposure. 

It is not clear whether covariates were appropriately treated in data analysis. 

Thus, this work is not sufficiently quantitative for air quality standardsetting purposes. 

11-47 
11.4.2 Chromosomal Effects 

The importance of chromosomal damage depends on whether the effect is 

mutagenic or cytogenetic. For example, translocations and trisomies are 

im-portant forms of genetic damage, whereas minor chromosomal breakage (such 

as that associated with caffeine) and chromatid aberrations are of questionable 

significance. Interest in the existence and extent of chromosomal damage in 

populations exposed to 0 3 derives from in vitro cell studies and in vivo 

animal studies (Chapter 9). Findings from in vivo human studies are conflicting, but generally negative (Chapter 10). 

Chromosomal changes in humans exposed to 0 3 have been investigated in 

four epidemiological studies, none of which found any evidence that O B 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, chromosomal changes found were almost entirely of the simple-breakage type and were 

no more numerous than the predicted incidence for a population. 

Magie et al. (1982) studied chromosomal aberrations in peripheral lymphocytes of college students in Los Angeles: 209 nonsmoking freshmen at a campus 

with higher smog levels (>0.08 ppm 0 3 ; >160 pg/m3 ) and 206 freshmen at a 

campus with lower smog levels (<0.08 ppm 0 3 ; <160 pg/m3 ). Students were 

enrolled in the study after completing questionnaires, and were assigned to 

groups on the basis of campus location and previous residence. Blood samples 

and medical histories (obtained at the beginning of the school year, in 

November, in April, and at the beginning of the next school year) were analyzed 

for chromosome and chromatid aberrations, but no significant effects on chromosomal structure were found in peripheral lymphocytes. 

Bloom (1979) studied military recruits before and after welding training. 

No chromosomal aberrations were seen in peripheral lymphocytes (0 3 levels were 

negligible and NO 2 was high). Fredga et al. (1982) studied the incidence of 

chromosomal changes in men occupationally exposed to automobile fuels and 

exhaust gases in groups of drivers, automobile inspectors, and a control group 

matched with respect to age, smoking habits, and length of job employment. 

Chromosome preparations from lymphocytes were made and analyzed by standardized 

routine methods. Analysis of the data gave no evidence of effects from occupational exposure. 

11-48 
11.4.3 Chronic Disease Mortality 

Two studies previously reviewed in the 1978 EPA criteria document for 

ozone and other photochemical oxidants (U.S. Environmental Protection Agency, 

1978) were not able to establish conclusively a relationship between oxidant 

exposure and mortality from chronic respiratory diseases and lung cancer. 

Buell et al. (1967) studied mortality rates among members of the Caiifornia 

Division of the American Legion for the 5-year period from 1958 through 1962. 

Long-term r.esidents of Los Angeles County had slightly lower age- and smokingadjusted lung cancer rates than residents of the San Francisco Bay area and 

San Diego County. Rates of mortality resulting from chronic respi.ratory 

diseases other than iung cancer were higher in Los Angeles than in San 

Francisco or San Diego,,but the rates were highest in the,other less urbanizedcounties. Mahoney (1971) reported higher total respiratory disease mortality 

rates in inland, downwind sections of Los Angeles than in coastal, upwind 

sections; however, variables such as smoking, migration within the city, and 

variation among zones in population density were not considered. In fact, 

socioeconomic, demographic, and behavioral variables were not fully controlled 

in either the Buell et al. (1967) or Mahoney (1971) studies and mortality 

rates were not related to actual pollution measurements. 

11.5 SUMMARY AND CONCLUSIONS 

Field and epidemiological studies offer a unique view of health effects 

research because they involve the real world, i.e., the study of human populations in their natural setting. These studies have attendant limitations, 

however, that must be considered in a critical evaluation of their results. 

One major problem in singling out the effects of one air pollutant in field 

studies of morbidity in populations has been the interference of other environmental variables that are critical. Limitations of epidemiological research 

on the health effects of oxidants include: interference by other air pollutants 

or interactions between oxidants and other pollutants; meteorological factors 

such as temperature and relative humidity; proper exposure assessments, including determination of individual activity patterns and adequacy of number and 

location of pollutant monitors; difficulty in identifying oxidant species 

responsible for observed effects; and characteristics of the populations such 

as smoking habits and socioeconomic status. 

11-49 
The most quantitatively useful information of the effects of acute exposure 

to photochemical oxidants presented in this chapter comes from the field studies 

of symptoms and pulmonary function. These studies offer the advantage of 

studying the effects of naturally-occurring, ambient air on a local subject 

population using the methods and better experimental control typical of 

controlled-exposure studies. In addition, the measured responses in ambient 

air can be compared to clean, filtered air without pollutants or to filtered 

air containing artificial`ly-generated concentrations of 0 3 that are comparable 

to those found in the ambient environment. As shown in Table 11-11, studies 

by Linn et al. (1980, 1983) and Avol et al. (1983, 1984, 1985a,b,c) have 

demonstrated that respiratory effects in Los Angeles area residents are related 

to 03 concentration and level of exercise. Such effects include: pulmonary 

function decrements seen at 03 concentrations of 282 pg/m3 (0.144 ppm) in 

exercising healthy adolescents; and increased respiratory symptoms and pulmonary 

function decrements seen at 0 3 concentrations of 300 pg/m 3 (0.153 ppm) in 

heavily exercising athletes and at 0 3 concentrations of 341 pg/m 3 (0.174 ppm) 

in lightly exercising normal and asthmatic subjects. The light exercise level 

is probably the type most likely to occur in the exposed population of Los 

Angeles. The observed effects are typically mild, and generally no substantial 

differences were seen in asthmatics' versus persons with normal respiratory 

health, although symptoms lasted for a few hours.longer in asthmatics. Many 

of the normal subjects, however, had a history of allergy and appeared to be 

more sensitive to 0 3 than "non-allergic" normal subjects. Concerns raised 

about the relative contribution to untoward effects in these field studies by 

pollutants other than 0 3 have been diminished by direct comparative findings 

in exercising athletes (Avol et al., 1984, 1985c) showing no differences in response between chamber exposures to oxidant-polluted ambient air with a mean 0 3 

concentration of 294 pg/m3 (0.15 ppm) and purified air containing a controlled 

concentration of generated 0 3 at 314 pg/m3 (0.16 ppm). The relative importance 

of exercise level, duration of exposure, and individual variations in sensitivity in producing the observed effects remains to be more fully investigated, 

although the results from field studies relative to those factors are consistent 

with results from controlled human exposure studies (Chapter 10). 

Studies of the effects of both acute and chronic exposures hav'e been 

reported in the epidemiological literature on photochemical oxidants.. Investigative approaches comparing communities with high 03 concentrations and communities with low 03 concentrations have usually been unsuccessful, often because 

11-50 
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11 -51 
actual pollutant levels have not differed enough during the study, or other 

important variables have not been adequately controlled. The terms "oxidant" 

and "ozone" and their respective association with health effects are often 

unclear. Moreover, information about the measurement and calibration methods 

used is often lacking. Also, as epidemiological methods improve, the incorporation of new key variables into the analyses is desirable, such as the use of 

individual exposure data (e.g., from the home and workplace). Analyses employing these variables are lacking for most of the community studies evaluated. 

Studies of effects associated with acute exposure that are considered to 

be qualitatively useful for standard-setting purposes include those on irritative symptoms, pulmonary function, and aggravation of existing respiratory 

disease. Reported effects on the incidence of acute respiratory illness and 

on physician, emergency room, and hospital visits are not clearly related with 

acute exposure to ambient 0 3 or oxidants and, therefore, are not useful for 

deriving health effects criteria for standard-setting purposes. Likewise, no 

convincing association has been demonstrated between daily mortality and daily 

oxidant concentrations; rather, the effect correlates most closely with elevated 

temperature. 

Studies on the irritative effects of 0 3 have been complicated by the 

presence of other photochemical pollutants and their precursors in the ambient 

environment and by the lack of adequate control.for other pollutants, meteorological variables, and non-environmental factors in the analysis. Although 0 3 

does not cause the eye irritation normally associated with smog, several 

studies in the Los Angeles basin have indicated that eye irritation is likely 

to occur in ambient air when oxidant levels are.about 0.10 ppm. Qualitative 

associations between oxidant levels in the ambient air and symptoms such as 

eye and throat irritation, chest discomfort, cough, and headache have been 

reported at >0.10 ppm in both children and young adults (Hammer et al., 1974; 

Makino and Mizoguchi, 1975). Discomfort caused by irritative symptoms may be 

responsible for the impairment of athletic performance reported in high school 

students during cross-country track meets in Los Angeles (Wayne et al., 1967; 

Herman, 1972) and is consistent with the evidence from field studies (Section 

11.2.1) and from controlled human exposure studies (Section 10.4) indicating 

that exercise performance may be limited by exposure to 0 3 . Although several 

additional studies have shown respiratory irritation apparently related to 

exposure to ambient 0 3 or oxidants in community populations, none of these 

11-52 
epidemiological studies provide satisfactory quantitative data on acute 

respiratory i7lnesses. 

Epidemioiogical studies in children and young adults suggest an association of decreased peak flow and increased airway resistance with acute ambient 

air exposures to daily maximum 1-hr 03 concentrations ranging from 20 to 274 

pg/m3 (0.01 to 0.14 ppm) over the entire study period (Lippmann et al., 1983; 

Lebowitz et al., 1982a, 1983, 1985; Lebowitz, 1984; Bock et al., 1985; Lioy et 

al., 1985). None of these studies by themselves can provide satisfactory 

quantitative data on acute effects of 0 3 because of inethodological problems 

along with the confounding influence of other pollutants and environmental 

conditions in the ambient air. The aggregation of individual studies, however, 

provides reasonably good evidence for an association between ambient 0 3 exposure 

and acute pulmonary function effects. This association is strengthened by the 

consistency between the findings from the epidemiological studies and the 

results from the field studies in exercising adolescents (Avol et al., 1985a,b) 

which have shown sma11 decreases in forced expiratory volume and flow at 282 

pg/m3 (0.144 ppm) of 0 3 i n the ambi ent ai r; and wi th the resul ts from the 

controlled human exposure studies in exercising children which have shown 

small decrements in forced expiratory volume at 235 pg/m 3 (0.12 ppm) of 0 3 

(Section 10.2.9.2). 

In studies of exacerbation of asthma and chronic lung diseases, the major 

problems have been the lack of information on the possible effects of inedications, the absence of records for all days on which symptoms could have occurred, 

and the possible concurrence of symptomatic attacks resulting from the presence 

of other environmental conditions in ambient air. For example, Whittemore and 

Korn (1980) and Hoiguin et al. (1985) found small increases in the probability 

of asthma attacks associated with previous attacks, decreased temperature, and 

with incremental increases in oxidant and 0 3 concentrations, respectively. 

Lebowitz et al. (1982a, 1983, 1985) and Lebowitz (1984) showed effects iti 

asthmatics, such as decreased peak expiratory flow and increased respiratory 

symptoms, that were related to the interaction of 0 3 and temperature. A11 of 

these studies have questionable effects from other pollutants, particularly 

inhalable particles. There have been no consistent findings of symptom 

aggravation or changes in lung function in patients with chronic lung diseases 

other than asthma. 

Only a few prospective studies have been reported on morbidity, mortality, 

and chromosomal effects from chronic exposure to 0 3 or other photochemical 

11-53 
oxidants. The lack of quantitative measures of oxidant exposures seriously 

limits the usefulness of many population studies of e morbidity and mortality 

for standards-setting purposes. Most of these long-term studies have employed 

average annual levels of photochemical oxidants or have involved broad ranges 

of pollutants; others have used a simple high-oxidant/low-oxidant dichotomy. 

In addition, these population studies are also limited by their inability to 

control for the effects of other factors that can potentially contr.ibute to 

the development and progression of respiratory disease over long periods of 

time. Thus, insufficient information is available in the epidemiological 

literature on possible exposure-response relationships between ambient 0 3 or 

other photochemical oxidants and the prevalence of chronic lung disease or the 

rates of chronic disease mortality. None of the epidemiological studies 

investigating chromosomal changes have found any evidence that ambient 0 3 or 

oxidants affect the peripheral lymphocytes of the exposed population. 

11-54 
11.6 REFERENCES 

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pollution. J. Air Pollut. Control Assoc. 27: 1125-1126. 

American Thoracic Society. (1978) Epidemiology standardization project. Am. 

Rev. Respir. Dis. 118 (6, pt. 2): 1-20., 

Avol , E. L. ; Wightman, L. H. ; Linn, W. S. ; Hackney, J. D. (1979) A movable 

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Avol, E. L.; Linn, W. S.; Shamoo, D. A.; Venet, T. G. Hackney, J. D. (1983) 

Acute respiratory effects of Los Angeles smog in continuously exercising 

adults. J. Air Pollut. Control Assoc. 33: 1055-1060. 

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Washington, DC. Washington, DC: Government Printing Office; pp. 489-505. 

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Bates, D. V.; Sizto, R. (1983) Relationship between air pollution levels and 

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Bennett, A. E. (1981) Limitations of the use of hospital statistics as an 

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Biersteker, K.; Erendijk, J. E. (1976) Ozone, temperature and mortality in 

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Bloom, A. D. (1979) Chromosomal abnormalities among welder trainees. .Research 

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Bock, N.; Lippmann, M.; Lioy, P.; Munoz, A.; Speizer, F. (1985) The effects of 

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Houston, TX. Pittsburgh, PA: Air Pollution Control Association; pp. 

297-308. (APCA international specialty conference transactions: TR-4). 

Brant, J. W. A. (1965) Human cardiovascular diseases and atmospheric air 

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8: 259-277. 

Broad, W. J. (1979) High anxiety over flights through ozone. Science (Washington, DC) 205: 767-769. 

Buell, P.; Dunn, J. E., Jr.; Breslow, L. (1967) Cancer of the lung and Los 

Angeles-type air pollution: prospective study. Cancer (Philadelphia) 20: 

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11-65 

12. EVALUATION OF HEALTH EFFECTS DATA 

FOR OZONE AND OTHER PHOTOCHEMICAL OXIDANTS 

12.1 INTRODUCTION 

The preceding chapters (Chapters 9, 10, and 11) have documented a wide 

array of toxicological responses elicited by in vivo and in vitro exposures to 

ozone at concentrations of 1 ppm and below and to other photochemical oxidants 

at various concentrations. The extensive body of data on the health effects 

of ozone was reported and discussed in particular detail in those chapters. 

The present chapter examines, in the light of the findings presented in the 

earlier chapters, specific issues and questions that are important for standardsetting. 

Paramount among the issues considered in standard-setting is the identifi cati on of one or more groups of peopl e who need to be protected by the 

regulation; that is, one or more groups of individuals who are at potential 

risk from exposure to ozone and other photochemical oxidants. The identification of such groups presupposes the identification of one or more effects in 

man or animals that are in and of themselves adverse, or that are indicators 

of other effects that are adverse but are not measurable in man because of 

ethical constraints. 

The existing health effects data indicate that ozone can affect structure, 

function, metabolism, and defense against bacterial infection in the pulmonary 

system and can produce extrapulmonary effects, as well. These data are drawn 

from human clinical, field, and epidemiological studies, and from animal 

toxicological studies. Each of these research approaches, however, has inherent 

strengths and weaknesses relative to the assessment of risk. No single approach 

provides an adequate basis for an informed judgment, but together these 

approaches provide a reasonable estimate of the human health effects of ozone. 

In vitro studies on isolated cells and tissues and in vivo studies on 

laboratory animals permit the measurement of effects under circumstances that 

are not permissible in clinical research. Such studies can, therefore, be 

useful for defining concentration-response relationships over a wide range of 

experimental conditions; for studying responses that can only be exainined with 

invasive procedures; for sorting out and testing hypotheses as a prelude to 

clinical investigations; and as an aid in the design of epidemiological studies. 

12-1 
This information can be used to examine possible linkages between acute and 

chronic effects and to correlate biochemical, functional, and structural 

changes with growth, development, and aging of the lung as the result of exposure 

to ozone. The chief weakness of laboratory animal studies lies in the difficulties and associated uncertainties of quantitatively extrapolating their 

results to the healthy human population, and the even greater problems of 

extrapolating such results to diseased human populations. 

Controlled studies on human subjects provide information about sensitive 

populations, concentrati on- response relationships, and responses to a limited 

number of repeated exposures. Subjects can be carefully selected and exposure 

conditions controlled. Such studies, however, are necessarily restricted to 

ethically and legally acceptable pollutant concentrations and exposure regimens, 

as well as to noninvasive techn.iques for measuring effects. Furthermore, only 

reversible effects can ethically be studied. The emphasis in studies of human 

responses to ozone inhalation found in the literature is, therefore, on pulmonary 

function. The chief weaknesses of controlled human exposure studies are found 

in the need to (1) restrict studies to short-term exposures; (2) limit the range 

of pollutant concentrations and type of subjects studied; and (3) use synthetic, 

simplified atmospheres. Some of these weaknesses are, of course, the very 

features that constitute the strengths of controlled studies since they permit 

the determination of concentrati on- response functions relative to a specific 

pollutant and specific endpoint. 

Field and epidemiological studies are designed to associate various 

characteristics of human health and function with ambient air concentrations 

of photochemical oxidants. For the purposes of this document, field studies 

are defined as laboratory experiments in which the postulated cause of an 

effect in the population is tested under conditions similar to those found in 

controlled human studies. Subjects can be carefully selected and exposure 

conditions closely monitored. Exposure-effect relationships, however, are 

measured during exposure to existing ambient conditions rather than to artificially generated pollutants. These studies thus form a bridge between the 

controlled human studies and the more traditional epidemiological studies in 

which human populations are studied in their normal setting. The effects of 

communities acutely and chronically exposed to photochemical oxidants are 

generally assessed by comparing the functional or clinical status of the 

residents during periods of high or low oxidant concentrations. Occasionally, 

12-2 
two or more populations residing in high or low oxidant areas are compared. 

Investigations within the normal setting are not, or course, without their 

drawbacks. Accurate and reliable air exposure data are extremely difficult to 

obtain and often do not include indoor exposure conditions. The information 

gathered on exposure-effect relationships and results may be confounded by 

factors such as variations in the time spend out of doors and indoors, variations in activity levels, cigarette smoking, disease status, socioeconomic 

status, and the coexistence of other pollutants and other environmental conditions. No single epidemiological study can, therefore, provide definitive 

evidence for effects that can be attributed solely to ozone, but can only 

indicate whether ambient air levels of ozone and other photochemical oxidants 

are associated with some measurable outcome of exposure. Although the strength 

of this evidence may vary from study to study, the aggregation of epidemiological 

data and their convergence potentially provide stronger evidence for human 

health effects of ozone. 

The responses to ozone and other photochemical oxidants that can be 

linked most directly to the potential impairment of pubiic health, i.e., 

without extrapolation, are those changes in pulmonary function that have been 

observed in controlled human studies of ozone exposure and in certain field 

studies of human exposure to ambient air containing ozone. Additional, supportive data on related respiratory system effects have been obtained from 

epidemiological studies of acute exposure to ozone and other photochemical 

oxidants in ambient air and from toxicological studies in laboratory animals 

exposed to ozone. 

As discussed in the 1978 criteria document for ozone and other.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 potential impairment of public health for several 

reasons. Alterations in lung function potentially interfere with normal 

activity in the generai popuiation and in population groups, depending upon 

the activity and the population. In the general population, for example, 

ozone exposure during moderate to heavy exercise can produce significant 

decrements in lung function (Chapter 10). In certain individuals in the 

general population, not yet characterized medically except by their response . 

to ozone, significant decrements, larger than those seen in the rest of the 

general population, are elicited by exposure to ozone during either continuous 

12-3 
or intermittent exercise. In individuals who have respiratory diseases such 

as asthma or chronic obstructive lung disease, even small decrements in lung 

function could potentially interfere with normal activity and might be of 

clinical significance. Symptoms usually accompany the observed decrements in 

lung function and impairments in other respiratory indicators, especially 

during exercise. 

Thus, at least when associated with ozone exposure, changes in lung 

function often represent a level of discomfort that, even among 

healthy people, may restrict normal activity or impair the performance of tasks. 

(U.S. Environmental Protection Agency, 1978) 

To evaluate the health effects documented and described in the preceding 

chapters, relevant effects and the identification of potentially-at - risk 

individuals and groups are discussed at length in this chapter. In addition, 

inherent biological characteristics or personal habits and activities that may 

attenuate or potentiate typical responses to ozone and other oxidants are discussed. The environmental factors that determine potential or real exposures 

of populations or groups are presented, as well, including known ambient air 

concentrations of ozone, of other related photochemical oxidants, and of these 

combined oxidants. 

The issues discussed in subsequent sections are enumerated below: 

1. Concentrations and patterns of ozone and other photochemical oxidants, 

including indoor-outdoor gradients, relevant for exposure assessment. 

2. Symptomatic effects of ozone and other photochemical oxidants. 

3. Effects of ozone on pulmonary function in the general population, at 

rest and with exercise and other stresses. 

4. Influence on the effects of ozone of age, sex, smoking status, 

nutritional status, and red-blood-cell enzyme deficiencies. 

5. Effects of repeated exposure to ozone. 

6. Effects of ozone on lung structure and the relationship between 

acute and chronic effects from ozone exposure. 

7. Effects of ozone related to resistance to infections, i.e., host 

defense mechanisms. 

8. Effects of ozone on extrapulmonary tissues, organs, and systems. 

9. Effects of ozone in individuals with preexisting disease. 

12-4 
10. Extrapolation to human populations of ozone/oxidant effects observed 

in animals. 

11. Effects of other photochemical oxidants and the interactions of 

ozone and other pollutants. 

12. Identification of potentially-at-risk groups. 

13. Demographic information on potentially at-risk groups. 

12.2 EXPOSURE ASPECTS 

Certain information about the occurrence of ozone and other photochemical 

oxidants is important for assessing both the potential and the actual exposures 

of individuals and of populations. In this section, air monitoring data are 

summarized as background information for relating the concentrations at which 

effects have been observed in health studies to the occurrence of ozone and 

other oxidants in ambient ai,r; and as background for estimating exposures. 

12.2.1 Potential Exposures to Ozone 

Ozone concentrations exhibit fairly strong diurnal and seasonal cycles. 

In most urban areas, single or multiple peaks of ozone occur during daylight 

hours, usually during midday (e.g., about noon until 3:00 or 4:00 p.m.). The 

formation of ozone and other photochemical oxidants from precursor emissions 

is limited to daylight hours since the chemicai reactions in the atmosphere 

are driven by sunlight. 8ecause of the intensity of sunlight necessary and 

the other meteorological and climatic conditions required, the highest concentrations of ozone and' other photochemical oxidants usually occur during the 

second and third quarters of the year, i.e., April through September. The 

months of highest ozone concentrations depend, however, upon iocal or regional 

weather patterns to a considerable degree, so that the temporal patterns of 

ozone concentrations are location-dependent. In California, for example, 

October is usually a month of higher ozone concentrations than April, and 

therefore the 6-month period of highest average ozone concentrations appears 

typicaily to be May through October in many California cities and conurbations. 

Although most peak ozone concentrations occur during daylight hours in 

nonurban areas, peak concentrations in the eariy evening and at night are not 

uncommon. The occurrence of nighttime peaks appears to be the result of 

combined induction time and transport time for urban plumes, coupled with the 

12-5 
lack of nitric oxide (NO) sources to provide NO for chemical scavenging of 

ozone in the evening and early morning hours. Average ozone concentrations 

are generally lower in nonurban than in urban areas, but peak concentrations 

higher than those found in urban and suburban areas can sometimes occurr. 

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 N0. In nonurban areas, early morning ozone concentrations are 

higher and are near background levels (e.g., about 0.025 to 0.045 ppm), since 

surface scavenging rather than chemical scavenging by NO is the principal 

removal mechanism in nonurban areas. 

Quantitative data on ozone concentrations are briefly summarized here. 

Figure 12-1 shows the frequency distribution of the three highest 1-hour ozone 

concentrations in each year aggregated for 3 years (1979 through 1981) (U.S. 

Environmental Protection Agency, 1980, 1981, 1982). These three curves are 

based on data obtained from predominantly urban monitoring stations. The 

frequency distribution of the highest 1-hour concentrations measured at eight 

rural or remote sites (Evans, 1985) is presented separately in Figure 12-1. 

These 1-hour concentrations, recorded at sites of the National Air Pollution 

Background Network (NAPBN) located in national forests across the country, 

have been aggregated for the same 3-year period, 1979 through 1981. The 

present primary and secondary national ambient air quality standards for ozone 

are expressed as a concentration not to be exceeded on more than one day per 

year. Thus, the second-highest value among daily maximum 1-hour ozone concentrations, rather than the highest, is regarded as a concentration indicative 

of the degree of protection of public health and welfare. As demonstrated by 

Figure 12-1, 50 percent of these values reported at the urban monitoring stations, 

aggregated for 3 years, were — 0.12 ppm; 25 percent were _ 0.15 ppm; and 

10 percent were _ 0.20 ppm. The frequency distribution of the daily maximum 

(i.e., the highest) 1-hour concentrations measured at NAPBN sites shows that 

50 percent of the concentrations were < 0.09 ppm; 25 percent were < 0.08 ppm; 

and 10 percent were < 0.07 ppm. 

As data in Chapter 10 and in Section 12.3.4 show, human controlled-exposure 

studies have demonstrated that attenuation of responses to ozone during repeated, consecutive-day exposures of at least 3 to 4 days occurs in many, 

though not all, of the individuals studied. Thus, the potential for repeated, 

consecutive-day exposures of that duration to ambient air concentrations of 

12-6 
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12-7 
ozotte is of interest. Data records from four cities were.examined in Chapter 5 

for exposures to four different 1-hour concentrations to determine their 

recurrence on 2 or more consecut.ive days in a 3-year period (see Tables 5-6 

through 5-9). Those data are summarized for three cities in Table 12-1. The 

data given in Table 12-1 are descriptive statistics based on aerometric data 

from the respective localities for 1979, 1980, and 1981, and cannot be used to 

predict the number of recurrences of high 1-hour concentrations of ozone for 

any other period or locality. The 1-hour ozone concentration at the Pasadena, 

CA, site reached a 1-hour concentration > 0.18 ppm for 4 consecutive days six 

times and for 8 or more consecutive days seven times in the 3-year period 

examined. A 1-hour concentration > 0.24 ppm was reached on 4 consecutive days 

two times and 8 or more consecutive days one time in the 3 years. Data for 

sites in Dallas, TX, and Washington, DC, show no consecutive-day, recurrences 

of high 1-hour concentrations such as those sustained in Pasadena. Data 

presented in Chapter 5 for a Pomona, CA, site, also in the South Coast Air 

Basin, show a pattern similar to that in Pasadena of consecutive-day recurrences of high 1-hour ozone concentrations. 

Potential exposures of nonurban populations, while not easily ascertained 

in the absence of a suitable aerometric data base, can be estimated from 

measurements made at selected sites known to represent agricultural areas and 

at sites of special-purpose monitoring networks. Data from the eight NAPBN 

national forest (NF) monitoring stations show that arithmetic mean 1-hour 

ozone concentrations at these sites, for the second and third quarters of the 

year, ranged from a 5-year average of 25.8 ppb at Kisatchie NF, LA (1977-1980, 

1982) to a 4-year average of 49.4 ppb at Apache NF, AZ (1980-1983) (Evans, 

1985). (Data are weighted for the number of 1-hour concentrations measured.) 

Data from Sulfate Regional Experiment (SURE) sites showed mean concentrations 

of ozone for August through December 1977 at four "rural" sites of 0.021, 

0.029, 0.026, and 0.035 ppm at Montague, MA, Duncan Falls, OH, Giles County, 

TN, and Lewisburg, WV, respectively. At five "suburban" SURE sites (Scranton, 

PA; Indian River, DE; Rockport, IN; Ft. Wayne, IN; and Research Triangle Park, 

NC), mean concentrations for the"study period were 0.023, 0.030, 0.025, 0.020, 

and 0.025 ppm, respectively. Maximum 1-hour ozone concentrations for the nine 

stations ranged from 0.077 ppm at Scranton, PA, to 0.153 ppm at Montague, MA 

(Martinez and Singh, 1979). 

12-8 
TABLE 12-1. NUMBER OF TIMES THE DAILY MAXIMUM 1-hr OZONE 

CONCENTRATION WAS > 0.06, > 0.12, > 0.18, and > 0.24 ppm 

FOR SPECIFIED CONSECUTIVE DAYS IN PASADENA, DALLAS, AND 

WASHINGTON, APRIL THROUGH SEPTEMBER, 1979 THROUGH 1981 

City and No. of occurrences of daily max. 1-hr 0 3 concns of: no. of 

consecutive days >0.06 ppm > 0.12 ppm > 0.18 ppm > 0.24 ppm 

Pasadena 

2 5a 10 9 13 

3 0 8 10 5 

_ 4 2 4 6 2 

5 2 7 3 2 

6 0 2 4 0 

7 2 0 1 0 

>8 10 14 7 1 

Dallas 

2 10 4 0 0 

3 6 2 0 0 

4 5 0 0 0 

5 8 1 0 0 

6 3 0 0 0 

7 5 0 0 0 

>8 11 0 0 0 

Washington 

2 10 1 0 0 

3 6 0 0 0 

4 2 0 0 0 

5 2 0 0. 0 

6 0 0 0 0 

7 2 0 0 0 

>8 5 0 0 0 

allote: Data are not cumulative by row or by column. This is because an episode in which, for example, a 1-hour concentration of 0.18 ppm is exceeded 

on each of 2 consecutive days is almost always part of a longer episode in 

which a lower 1-hour concentration (.e.g., 0.12 or 0.06 ppm) has been exceeded 

on each day of an even longer consecutive-day period. Thus, the occurrences 

of a 2-day episode at a higher concentration, for example, are a subset of 

the occurrences of an n-day episode (e.g., > 3 days) tabulated under one or 

more lower concentrations. 

Source: SAROAD (1985a,b,c). 

12-9 
Concentrations of ozone indoors, since most people spend most of their 

time indoors, are of value in estimating total exposures. The estimation.of 

total exposures, in turn, is of value for optimal interpretation and use of 

epidemiological studies. Data on concentrations of ozone indoors are few. It 

is known, however, that ozone decays fairly rapidly indoors through reactions 

with surfaces of such materials as wall board, carpeting, and draperies.(Chapter 5). Ozone concentrations indoors depend also on those factors that affect 

both reactive and nonreactive pollutants: concentrations outdoors, temperature, 

humidity, air exchange rates, presence or absence of air conditioning, and 

mode of air conditioning (e.g., 100 percent fresh-air intake versus recirculation of air). Estimates in the literature on indoor-outdoor ratios (I/0, 

expressed as percentage) of ozone concentrations range from just over 0 percent 

to 100 percent for residences (Stock et al., 1983), and from 29 percent 

(Moschandreas et al., 1978) to 80 ± 10 percent (Sabersky et al., 1973) for 

office buildings. Variations in estimated I/0 for buildings are attributable 

to the diversity of structures monitored, their locations, and their heating, 

ventilating, and air-conditioning systems. Measurements made inside automobiles 

show inside ozone concentrations ranging from about 30 percent (Peterson and 

Sabersky, 1975) to about 56 percent (Contant et al., 1985) of outside concentrations. Again, outside concentrations and mode of air conditioning or 

ventilation are among the factors determining the inside concentrations. It 

should be noted that outside concentrations of ozone on well-traveled roadways 

are lower than other outdoor concentrations because nitric oxide emissions 

from automobiles scavenge ozone. 

Along with small-scale spatial variations in ozone concentrations, such 

as indoor-outdoor gradients, large-scale variations exist, such as those that 

occur with latitude and altitude. Latitudinal variations have little effect 

on potential exposures within the contiguous United States, since the contiguous states all fall within latitudes where photochemical oxidant formation 

is favored (Logan et al., 1981; U.S. Environmental Protection Agency, 1978). 

The increases in concentrations of background ozone with increase with altitude 

(Viezee et al., 1979; Seiler and Fishman, 1981) are significant only in the 

free troposphere. When ozone is carried in layers aloft in long-distance 

transport (i.e., mesoscale and synoptic-scale transport), it is conserved 

overnight because of the occurrence of temperature inversions (nocturnal 

inversions) that prevent downward vertical mixing and thus prevent scavenging 

12-10 
at the surface by the nitric oxide present in ground-level emissions. Where 

noctur.nal inversion layers contact mountainsides, ozone concentrations will be 

greater at night at higher elevations than at lower. Daytime concentrations 

may vary slightly but not appreciably with elevation. Daytime peak concentrations 

may occur later in the day at higher elevations because of transport time from 

urban sources , most of whi ch are at 1 ower el evati ons. There appear to be 

fewer implications for human populations than for mountain forests and other 

vegetation, however, since high elevations are usually sparsely populated and 

since the higher concentrations observed at higher elevations occur overnight. 

The altitudinal gradients in the free troposphere could be of possible consequence for certain high-altitude flights, as reported in the field studies 

documented in Chapter 11, except that the air filtration and ventilation 

systems commonly employed on airplanes reduce the on-board concentrations. 

It should be pointed out that the mass of ozone per unit volume decreases 

with elevation (altitude), for given concentrations expressed as volume/volume 

ratios. In addition, data presented in Chapter 5 for Denver, CO 3 for example, 

show that ozone concentrations are lower tfiere than at many lower-elevation 

metropolitan areas of comparable size. 

Even though ozone .is considered to be a regional pollutant, intermediate - 

scale spatial.variations in concentrations occur that are of potential consequence for designing and interpreting epidemiological studies. For example, 

data from a study of ozone formation and transport in the northeast corridor 

(Smith; 1981) showed that in New York City an appreciable gradient existed, at 

least for the study period (summer, 1980), between.ozone concentrations in 

Brooklyn and those in the Bronx. The maximum l-hour ozone concentration 

measured at the Brooklyn monitoring site was 0.174 ppm, while that measured at 

the Bronx monitoring site was 0.080 ppm. 

12.2.2 Potential Exposures to Other Photochemical Oxidants 

12.2.2.1 Concentrations. Concentrations in ambient air of four photochemical 

oxidants other than ozone have been presented.in Chapter 5. Those data are 

drawn upon here to examine the concentrations of these pollutants that might 

be encountered in the United States, including "worst-case" situations, in 

order to determine both the minimum and maximum additive concentrations of 

these pollutants with ozone that could occur in ambient air. The four photochemical oxidants for which concentration data were given in Chapter 5 are 

12-11 
peroxyacetyl nitrate (PAN), peroxypropionyl nitrate (PPN), hydrogen peroxide 

(H2O2 ), and formic acid (HCOOH). 

Although they co-occur to varying degrees with ozone, aldehydes are not 

photochemical oxidants. Since they are not oxidants and are not measured by 

methods that measure oxidants, their role relative to public health and welfare 

is not reported in this document. The reader is referred to a recent comprehensive review by Altshuller (1983) for a treatment of the relationships in 

ambient air between ozone and aldehyde concentrations. 

Few health effects data or aerometric data on formic acid exist. Those 

ambient air concentrations that are given in the literature, however, indicate 

that formic acid occurs at trace concentrations, i.e., <0.015 ppm, even in 

high-oxidant areas such as the South Coast Air Basin of California (Tuazon et 

al., 1981). No data are available for other urban areas or for nonurban 

areas. Given the known atmospheric chemistry of formic acid, concentrations 

in the South Coast Air Basin are expected to be higher than in other urban 

areas of the country (Chapter 3). 

The measurement methods (IR and GC-ECD) for PAN and PPN are specific and 

highly sensitive, and have been in use in air pollution research for nearly 

two decades. Thus, the more recent literature on the concentrations of PAN 

and PPN confirm and extend, but do not contradict, earlier findings reported 

in the two previous criteria documents for ozone and other photochemical 

oxidants (U.S. Department of Health, Education, and Welfare, 1970; U.S. 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, respectively). 

The highest concentrations of PAN measured and reported in the past 

5 years were 42 ppb at Riverside, CA, in 1980 (Temple and Taylor, 1983), and 

47 ppb at Claremont, CA, also in 1980 (Grosjean, 1983). These are clearly the 

maximum concentrations of PAN reported for California and for the entire country 

in this period. Other recently measured PAN concentrations in the Los Angeles 

Basin were in the range of 10 to 20 ppb. Average concentrations of PAN in the 

Los Angeles Basin in the past 5 years ranged from 4 to 13 ppb (Tuazon et al., 

1981; Grosjean, 1983). The only published report covering PAN concentrations 

12-12 
outside California in the past 5 years is that of Lewis et al. (1983) for New 

Brunswick, NJ. The average PAN concentration there was 0.5 ppb and the maximum 

was 11 ppb during a study done from September 1978 through May 1980. Studies 

outside California from the early 1970s through 1978 showed average PAN concentrations ranging from 0.4 ppb in Houston, TX, in 1976 (Westberg et al., 1978) 

to 6.3 ppb i n St. Loui s, M0, i n 1973 ( Lonneman et al ., 1976) . Maxi mum PAN 

concentrations outside California for the same period ranged from 10 ppb in 

Dayton, OH, in 1974 (Spicer et al., 1976) to 25 ppb in St. Louis (Lonneman 

et al., 1976). 

The highest PPN concentration reported in studies from 1963 through the 

present was 6 ppb in Riverside, CA, in the early 1960s (Darley et al., 1963). 

The next highest reported PPN concentration was 5 ppb at St. Louis, MO, in 

1973 (Lonneman et ai., 1976). Among more recent data, maximum PPN concentrations,at respective sites ranged from 0.07 ppb in Pittsburgh, PA (Singh et al., 

1982) to 3.1 ppb at Staten Island, NY, in 1981 (Singh et ai., 1982). California 

concentrations fell within this range. Average PPN concentrations at the 

respective sites for the more recent data ranged from 0.05 ppb at Denver and 

Pittsburgh to 0.7 ppb at Los Angeles in 1979 (Singh et al., 1981). 

Altshuller (1983) has succinctly summarized the nonurban concentrations 

of PAN and PPN by pointing out that they overlap the lower end of the range of 

urban concentrations at sites outside California. At remote locations, PAN 

and PPN concentrations are lower than even the lowest of the urban concentrations (by a factor of three to four). 

Concentrations of H 2O 2 reported in the published literature must be 

regarded as inaccurate, since all wet-chemical methods used to date are now 

thought to be subject to positive interference from ozone. Evidence that 

reported H2O 2 concentrations have been in error is provided not only by recent 

investigations of wet-chemical methods, but by the fact that FTIR measurements 

of ambient air have not demonstrated the presence of H2O 2 even in the highoxidant atmosphere of the Los Angeles area. The limit of detection for a 

1-km-pathlength FTIR system, which can measure H 2O 2 with specificity, is 

around 0.04 ppm (Chapter 4). In urban areas, hydrogen peroxide (H2O2 ) concentrations have been reported to range from < 0.5 ppb in Boulder, CO (Heikes 

et al., 1982) to < 180 ppb in Riverside, CA (Bufalini et al.; 1972). In 

nonurban areas, reported concentrations ranged from 0.2 ppb near Boulder, CO 3 

in 1978 (1Celly et al., 1979) to < 7 ppb 54 km southeast of Tucson, AZ (Farmer 

12-13 
and Dawson, 1982). These nonurban data were obtained by the luminol chemiluminescence technique (see Chapter 4). The urban data were obtained by a variety 

of inethods, including the luminol chemiluminescence, the titanium (IV) sulfate 

8-quinolinol, and other wet chemical methods (see Chapter 4). Thus, these 

reported concentrations have all been measured by methods in which ozone is a 

positive interference. 

12.2.2.2 Patterns. The patterns of formic acid (HCOOH), PAN, PPN, and H 2O2 

can be summarized fairly succinctly. They bear qualitative but not quantitative resemblance to the patterns already summarized for ozone concentrations. 

Qualitatively, diurnal patterns are similar, with peak concentrations of each 

of these occurri ng i n cl ose proxi mi ty to the ti me of the ozone peak. The 

correspondence in time of day is not exact, but is close. As the work of 

Tuazon et al. (1981) at Claremont, CA, demonstrates (see Chapter 5) ozone 

concentrations return to baseline levels faster than the concentrations of 

PAN, HCOOH, or H2O2 (PPN was not measured). 

Seasonally, winter concentrations (first and fourth quarters) of PAN are 

lower than summer concentrations (second and third quarters). The winter 

concentrations of PAN are proportionally higher relative to ozone in winter 

than in summer. Data are not available on the seasonal patterns of the other 

non-ozone oxidants. 

Indoor-outdoor data on PAN are limited to one report (Thompson et al., 

1973), which confirms the pattern to be expected from the known chemistry of 

PAN; that is, it persists longer indoors than ozone. Data are lacking for 

indoor concentrations of the other non-ozone oxidants. 

12.2.3 Potential Combined Exposures and Relationship of Ozone and Other 

Photochemical Oxidants 

Data on concentrations of PAN, PPN, and H2O 2 indicate that in "worst-case" 

situations these non-ozone oxidants together could add as much as about 0.15 

ppm of oxidant to the ozone burden in ambient air. The highest of the "secondhighest" ozone concentration measured in the United States in 1983 was 0.37 

ppm, in the Los Angeles area. (For the definition of the "second-highest" 

1-hour value see Chapter 5). In the presence of that concentration of ozone, 

the addition of "worst-case" concentrations of non-ozone oxidants (0.15 ppm 

total) would bring the total oxidant concentration to around 0.52 ppm, provided 

12-14 
peak concentrations of ozone and non-ozone oxidants were reached at the same 

time. It should be noted that such "worst-case" concentrations are not viewed 

as typical. Data from recent years for the Los Angeles Basin indicate that 

average concentrations of PAN and PPN together would add 0.014 ppm (14 ppb) to 

the average oxidant burden there.(4 to 13 ppb average PAN: Tuazon et al., 

1981; Grosjean, 1983, respectively; and 0.7 ppb PPN: Singh et al., 1981). 

The significance for public health of the imposition of an additional 

oxidant burden from non-ozone oxidants rests not only on average or "worst-case" 

concentrations, however, but on the answers to at least several other questions, 

e. g. . 

1. Do PAN, PPN, or H 2O 2 , 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 synergistically in combination with ozone to elicit adverse or potentially adverse responses in human populations? Do any or all act 

antagonistically with ozone? 

3. What is the relationship between the occurrence of ozone and these 

non-ozone oxidants? Can ozone serve as a surrogate for these other 

oxidants? 

The first two questions are addressed by health effects data presented in 

Chapters 9 through 11 and in Section 12.6 of the present chapter. The third 

question has been addressed in detail by Altshuller (1983). His conclusion is 

that "the ambient air measurements indicate that 0 3 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 0 3 could serve as an abatement surrogate for all 

photochemical products, including those not relevant to effects data examined 

in this document. For example, the products he reviewed relative to ozone 

included aldehydes, aerosols, and nitric acid. Nevertheless, his conclusions 

appear to apply to the subset of photochemical products of concern here: PAN, 

PPN, and H2O 2 . 

The most straightforward evidence of the lack of a quantitative, monotonic 

relationship between ozone and the other photochemical oxidants is the range 

of PAN-to-03 ratios and, indirectly, of PAN-to-PPN ratios presented in the 

review by Altshuller (1983) and summarized in Table 12-2 and in Chapter 5. 

12-15 
TABLE 12-2. RELATIONSHIP OF OZONE AND PEROXYACETYL NITRATE AT URBAN AND= 

SUBURBAN SITES IN THE UNITED STATES IN REPORTS PUBLISHED 1978 OR LATER 

PAN/0 s , % 

Site/year of study Avg. At 0 3 peak Reference 

West Los Angeles, CA, 1978 9 6 Hanst et al. (1982) 

Claremont, CA, 1978 7 6 Tuazon et al. (1981a, 

1981b) 

Claremont, CA, 1979 4 4 Tuazon et al. (1981a) 

Riverside, CA, 1975-1976 9 5 Pitts and Grosjean (1979) 

Riverside, CA, 1976 5 4 Tuazon et al. (1978) 

Riverside, CA, 1977 4 4 Tuazon et al. (1980) 

Riverside, CA, 1977 4 NAa Singh et al. (1979) 

Houston, TX, 1976 3 3 Westberg et al. (1978) 

New Brunswick, NJ, 1978-1980 4 2 Brennan (1980) 

allot available. 

Source: Derived from Altshuller (1983). For primary references, see 

Chapter 5. 

Certain other information presented in Chapter 5 bears out the lack of a 

strictly quantitative relationship between ozone and PAN and its homologues. 

Not only are ozone-PAN relationships not consistent between different urban 

areas (e.g., Singh et al., 1982), but they are not consistent in urban versus 

nonurban areas (e.g., Lonneman et al., 1976), in summer versus winter (e.g., 

Temple and Taylor, 1983), in indoor versus outdoor environments (Thompson et 

al., 1973), or even, as the ratio data show, in location, timing, or magnitude 

of diurnal peak concentrations within the same city (e.g., Jorgen et al., 

1978). In addition, Tuazon et al. (1981) demonstrated that PAN persists in 

ambient air longer than ozone, its persistence paralleling that of HNO 3 , at 

least in some localities. Reactivity data presented in the 1978 criteria 

document for ozone and other photochemical oxidants indicate that all precursors that gi ve ri se to PAN al so gi ve ri se to ozone. Not al l are equal ly 

12-16 
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). 

It must be emphasized that information presented in Chapter 4 clearly 

shows that no one method can quantitatively and reliably measure ali four 

oxidants of potential concern (ozone, PAN, PPN, and hydrogen peroxide), either 

one at a time or in ambient air mixtures. This point was not clearly presented 

in the 1978 criteria document but is given substantial discussion in Chapter 4 

of this document. 

12.3 HEALTH EFFECT.S IN THE GENERAL HUMAN POPULATION 

12.3.1 Clinical Symptoms 

A close association has been observed between the occurrence of respiratory symptoms and changes in pulmonary function in adults acutely exposed in 

environmental chambers to 0 3 (Chapter 10) or to ambient air containing 0 3 as 

the predominant pollutant (Chapter 11). This association holds for both the 

time-course and magnitude of effects. Insofar as cough and chest pain or 

irritation may interfere with the maximal inspiratory or expiratory efforts 

(see Section 12.3.5), such associations between symptoms and function might be 

expected. In a comparison of adults exposed to both oxidant-polluted ambient 

air and purified air containing only 0 3 (Avol et al., 1984, 1985c), no evidence 

was found to suggest that any poilutant other than 0 3 contributed to the symptom 

increases associated with decrements in lung function. Studies on children and 

adolescents exposed to 03 or ambient air containing 0 3 under similar conditions 

have found no significant increases in symptoms despite significant changes in 

pulmonary function (Avol et al., 1985a,b; McDonnell et al., 1985b,c). 

Epidemiological studies have been conducted to compare the incidence of 

acute, irritative symptoms associated with exposure of communities to varying 

concentrations of photochemical oxidants, but to date no studies have been 

designed specifically to test the comparative frequency or magnitude of response 

of symptoms versus functional changes. In addition, epidemiological studies have 

been complicated by (1) the presence of other pollutants, including photochemical 

pollutants and their precursors, in the ambient environment and (2) the lack of 

12-17 
adequate control for other pollutants, meteorological variables, and nonenvironmental factors in the analysis. The symptoms most likely to occur 

within the polluted community are difficult to associate with a specific 

pollutant and are, therefore, of limited use for quantifying exposure-response 

relationships. 

The symptoms found in association with controlled exposure to 0 3 and with 

exposure to photochemical air pollution are similar but not identical. Eye 

irritation, one of the commonest complaints associated with photochemical 

pollution, is not characteristic of controlled exposures to 0 3 alone or to 

ambient air containing predominantly 03 , even at concentrations of the gas 

several times higher than any likely to be encountered in ambient air. Other 

components of photochemical air pollution, such as aldehydes and PAN, are held 

to be chiefly responsible for eye irritation (National Air Pollution Control 

Administration, 1970; Altshuller, 1977; National Research Council, 1977; U.S. 

Environmental Protection Agency, 1978; Okawada et al., 1979). 

There is limited qualitative evidence to suggest that at low concentrations of 03 , symptoms other than eye irritation are more likely to occur in 

populations exposed to ambient air pollution than in subjects exposed in 

chamber studies, especially if 0 3 is the sole pollutant administered in the 

chamber studies. The symptoms may be indicative of either upper or lower 

respiratory tract irritation. For example, in two epidemiological studies, 

qualitative associations between oxidant levels and symptoms such as throat 

irritation, chest discomfort, cough, and headache have been reported at > 0.10 

ppm in both children and young adults (Hammer et al., 1974; Makino and Mizoguchi, 

1975). While some individual subjects have experienced cough, shortness of 

breath, and pain upon deep inspiration at 03 concentrations as low as 0.12 ppm 

during controlled exposure with exercise (McDonnell et al., 1983), the group 

mean symptom response was significant only for cough. It is not clear, however, 

if the symptoms reported in the epidemiological studies cited above could have 

been induced by other pollutants in the ambient air. Above 0.12 ppm 0 3 , a 

variety of both respiratory and non-respiratory symptoms have been reported in 

controlled exposures. They include throat dryness, difficulty or pain when 

inspiring deeply, chest tightness, substernal soreness or pain, cough, wheeze, 

lassitude, malaise, headache, and nausea (DeLucia and Adams, 1977; Kagawa and 

Tsuru, 1979b; McDonnell et al., 1983; Adams and Schelegle, 1983; Avol et al., 

1984, 1985c; Gibbons and Adams, 1984; Folinsbee et al., 1984; Kulle et al., 

12-18 
1985). Most "symptom scores" have been positive at concentrations of 0.2 ppm 

03 and above. Symptoms tend to remit within hours after exposure is ended. 

Relatively few subjects have reported-persistence of symptoms beyond 24 hours. 

Many variables could possibly explain differences in symptomatic effects 

reported in epidemiological and controlled human studies. They inciude different subject populations, pollutant mixtures, and exposure patterns utilized 

in each study, factors affecting the perception of symptoms in one type of 

study compared to the other, or di fferences i n the methods used to assess 

symptoms. Alternatively, the presence of reactive chemical species other than 

03 in polluted ambient air might be chiefly responsible for the symptoms 

observed in epidemiological studies or might interact synergistically with 0 3 

to initiate the symptoms, although recently published data show no excess 

response to oxidant-polluted air containing predominantly 0 3 and particles 

(Avol et al., 1984, 1985c). 

Symptoms have commonly been assessed by the use of recording sheets 

combined with reliance on the subject's recal.l, usualiy right after exposure 

but sometimes several hours or days after exposure (e.g., community studies). 

While it is difficult to score the intensity of symptoms with confidence, the 

types of symptoms obtained immediately after exposure have been noteworthy for 

their general consistency across studies. Moreover, as noted earlier, a good 

association has been observed between changes in symptoms and objective 

functional tests at 0 3 concentrations > 0.15 ppm. Symptoms are therefore considered to be useful adjdncts for assessing the effects of 0 3 and photochemical 

pollution, particularly if combined with objective measurements of pulmonary 

function. 

12.3.2 Pulmonary Function at Rest and with Exercise and Other Stresses 

12.3.2.1 At-Rest Exposures. The great majority of short-term ozone exposure 

studies on resting subjects were published almost a decade ago and were reviewed 

extensively in the previous ozone-oxidants criteria document (U.S. Environmental Protection Agency, 1978). Briefly, resting subjects inhaling ozone at 

concentrations up to 0.75 ppm for 2 hr showed no decrements or only very small 

(< 10 percent) decrements in FVC (Silverman et al., 1976; Folinsbee et al., 

1975; Bates et al., 1972), VC (Silverman et al., 1976; Folinsbee et al., 

1975), FEV1 , and FRC (Siiverman et al., 1976). Other flow-derived variables, 

such as the maximal expiratory flow at 50 percent VC (FEF 50%) and the maximal 

12-19 
expiratory flow at 25 percent VC (FEF25%), were affected to a greater degree, 

showing decreases of up to 30 percent from control in certain individuals at 

0.75 ppm 03 (Bates et al., 1972; Silverman et al., 1976). Small increases in 

airway resistance (Raw < 17 percent) were reported at concentrations greater 

than 0.5 ppm (Bates et al., 1972; Golden et al., 1978). Specific tests of 

lung mechanical properties generally exhibited a lack of significant effects. 

Static compliance (C st) remained virtually unchanged, whereas dynamic compliance 

(Cdyn ) and the maximum static elastic recoil pressure of the lung (Ptp max) 

showed some borderline effects at 0.75 ppm 0 3 (Bates et al., 1972). Ventilatory (VT , fB , VE ) and metabolic (V02 , VE/0 2 ) responses to ozone, even at 0.75 

ppm level, were not significantly altered (Folinsbee et al., 1975). The only 

non-spirometric test reported to be significantly affected by ozone inhalation 

was a bronchial response. Post-ozone (0.6 ppm for 2 hr) challenge with histamine 

showed significant enhancement of airway responsiveness in ever.y subject 

tested. Premedication with atropine blocked only transiently the ozone-induced 

hyperreactivity of airways (SR aw) to histamine (Golden et al., 1978). Breathing 

0.6 to 0.8 ppm 0 3 for 2 hr markedly reduced diffusion capacity (aLco) across 

the alveolar-capillary membrane (Young et al., 1964); however, the mean fractional CO uptake, also an index of diffusion, decreased only marginally under 

similar exposure conditions (Bates et al., 1972). The slope of phase III of 

the single-breath nitrogen closing volume curves, which increases as the 

inhomogeneity in the distribution of ventilation increases, was not significantly altered by 0 3 inhalation (Silverman et al., 1976). 

More recent at-rest ozone exposure studies basically confirmed previously 

reported findings. Decrements in forced expiratory volume and flows have been 

found from exposures to concentrations at and above 0.5 ppm (Folinsbee et al., 

1978; Horvath et al., 1979). Airway resistance was not significantly affected 

at these 0 3 concentrations, and static lung volume changes (increase in RV and 

decrease in TLC) were only suggestive (Shephard et al., 1983). Metabolic and 

cardiopulmonary effects were also minimal (Horvath et al., 1979). At concentrations below 0.5 ppm ozone, the effects assessed by commonly used pulmonary 

function tests were small and inconsistent (Folinsbee et al., 1978; Horvath et 

al., 1979). Reports, however, of ozone-induced symptoms and functional effects 

in some subjects, well exceeding the group mean response, indicate that even 

under resting exposure conditions some subjects are more responsive to ozone 

(Konig et al, 1980; Lategola et al., 1980a,b; Golden et al., 1978). 

12-20 
12.3.2.2 Exposures with Exercise. Minute ventilation (VE ) is considered to be 

one of the principal modulators of the magnitude of response to 0 3 . The most 

convenient physiological procedure for increasing VE is to exercise exposed 

individuals either on a treadmill or bicycle ergometer. Consequent increases 

in frequency and depth of breathing will increase the overall volume of inhaled 

pollutant. Moreover, such a ventilatory pattern also promotes penetration of 

ozone into peripheral lung regions. Thus, a larger amount of ozone will reach 

tissues most sensitive to injury. These processes are further enhanced at 

higher workloads (VE> 35 L/min), since the mode of breathing will change from 

nasal to oronasal or oral only (Niinimaa et al., 1980). As the ventilation 

increases, an increasingly greater portion of the total minute volume is 

inhaled orally, bypassing the scrubbing capacity of the nose and nasopharynx 

(Niinimaa et al., 1981) and further augmenting the ozone dose to the lower 

airways and parenchyma. 

Even in well-controlled experiments on an apparently homogeneous group of 

subjects, physiological responses to the same work and pollutant loads can 

vary widely among individuals (Chapter 10). Under strenuous exposure conditions 

(VE= 45-51 L/min at 0.4 ppm) the least responsive subjects showed FEV1decrements of less than 10 percent, while the most responsive yet apparently healthy 

individuals had severely impaired lung function (FEV 1= 40 percent of control); 

the average decrement was 26 percent (Haak et al., 1984; Silverman et al., 

1976). Some factors, such as the mode of ventilation (oral versus nasal) and 

the pattern of breathing (shallow rapid versus slow deep) contribute to but 

cannot account totally for the commonly observed heterogeneous responses of an 

otherwise homogeneous group of subjects. Implementation of strict subject 

selection criteria including restrictions on age and sex in most of the studies 

narrowed only slightly the distribution of responses. Attempts to determine 

predisposing factors responsible for increased or decreased 0 3responsiveness 

utilizing nonspecific tests were unsuccessful (Hazucha, 1981). Individual 

responsiveness is probably a function of many factors. Previous exposures of 

individuals to other pollutants (Hackney et al., 1976, 1977b), and nutritional 

deficiencies and/or latent infection(s), known to be relevant in animals 

(Chapter 9), might be among contributing factors. Individual responsiveness 

appears to be maintained relatively unchanged for as long as 10 months. 

Generally, within-individual variability in response is considerably smaller 

than the variations reported between subjects (McDonnell et al., 1985a; Gliner 

et al., 1983). 

12-21 
In studies that have described the distribution of individual responses 

to ozone (McDonnell et al., 1983; Kulle et al., 1985), the changes in pulmonary 

function resulting from exposure to clean air or near zero ozone concentrations 

are small and uniformly distributed. As the ozone concentration increases, 

the distribution widens and becomes skewed towards larger decrements in pulmonary 

function, the largest changes respresenting the most responsive subjects. 

Reported retrospective classification of subjects into "responders/sensitives" 

and "nonresponders/nonsensitives" varies from study to study. Some subjects 

were classified as "responders" by medical history and previous exposures or 

test results, or both (Hackney et al., 1975); others had to show more than 10 

percent post-exposure decrements:(Horvath et al., 1981) or decrements exceeding 

two standard deviations of the control (Haak et al., 1984). The term "hyperreactor" or "hyperresponder" has been arbitrarily used to describe the 5 to 20 

percent of the population that is most responsive to ozone exposure. There 

are no clearly established criteria for defining "reactive" or "nonreactive" 

subjects. Nevertheless, it is important to identify criteria to define the 

"reactive" portion of the population since they may represent a subgroup of 

the population which can be considered "at risk". 

Intermittent exercise augments physiological response to 0 3 . Moderate 

exercise (VE= 24-43 L/min) in 0.4 ppm ozone for 2 hr reduced the FEVIof 

healthy subjects by an average of 11 percent. In contrast, rest under the 

same environmental conditions decreased FEV 1by only 3 percent (Haak et al., 

1984), while very heavy exercise (VE> 64 L/min) reduced FEV1by 17 percent on 

the average (5 to 50 percent) (McDonnell et al., 1983). Even low 0 3concentrations (0.12 ppm) induced measurable changes in the lung function of more 

responsive individuals; the average decrements in FVC, FEV1 , and FEF25-75 were 

3, 4.5, and 7.2 percent from control, respectively (McDonnell et al., 1983). 

The maximum changes were observed within 5 to 10 minutes following the end of 

each exercise period (Haak et al., 1984). During subsequent rest periods, 

however, the response does not persist and partial improvement in lung function 

can be observed despitp, continuous inhalation of ozone (Folinsbee et al., 

1977b). Functional recovery from a single exposure with exercise appears to 

progress in two phases: during the initial rapid phase, lasting between 30 

min and 3 hr, improvement in lung function exceeds 50 percent; this is followed 

by a much slower recovery phase usually completed in most.subjects within 24 

hr (Bates and Hazucha, 1973). There are some individuals, however, whose lung 

12-22 
function did not reach the pre-exposure ievel even after 24 hr.s: Despite 

apparent functional recovery of most of the subjects, an enhanced responsiveness to a second 0 3 challenge may persist in some subjects for up to 48 hr 

(Bedi et a1., 1985; Folinsbee and Horvath, 1986). In addition, other regulatory systems may still exhibit abnormal responses when stimulated; e.g.; 

airway hyperreactivity may persist for days (Golden et al., 1978; Kulle et 

al., 1982b). 

The magnitude of functional changes assessed by spirometry is positively 

associated with 0 3 concentration. Exposure of intermittently exercising 

subjects (VE > 63 L/min) for 2 hr to 0.4 ppm reduced significantly (p <0.005) 

FVC by 12 percent, FEVi by 17 percent, and FEF25-75 by 27 percent on the 

average. At lower 03 concentrations (0.18 to 0.24 ppm) the respective decrements (FVC 4 to 11 percent, FEV1 6 to 14 percent, FEF25-75 12 to 23 percent) 

were still statistically significant (McDonnell et al., 1983). The same 

ventilation in a 0.12 or 0.15 ppm 0 3 atmosphere elicited spirometric changes 

(1 to 7 percent) of only questionable significance (McDonnell et al., 1983; 

Kulle et al., 1985). 

Similar positive associations have been reported between lung functlion 

decrements and the level of ventilation. Intermittent exercise (VE > 68 

L/min) in 0.3 ppm 0 3 decreased.FVC, FEV1, and.FEF25-75 by 7, 8, and 10 percent, 

respectively. A lower intensity of exercise (VE — 32 L/min) in the same 0 3 

atmosphere induced proportionally smaller changes; the respective mean decrements were 2, 5, and 8 percent (Folinsbee et al., 1978). 

More recently, the relationship between ventilation, exposure time; 0 3 

concentration, and functional response has been examined in a more general 

way. The response has been evaluated as a function of an "effective rate" 

(Colucci, 1983), an "effective dose" (Colucci, 1983; Folinsbee et al., 1978; 

Silverman et al., 1976), and 0 3 concentration (Kulle et al., 1985). The 

concept of defining ozone exposure in terms of an "effective dose" (the product 

of concentration, ventilation, and time) is relatively simple from a modeling 

point of view. A major weakness of this concept, however, is that the same . 

dose/rate may induce quantitatively different responses, which limits the 

general applicability of the model for standard-setting (Silverman et al., 

1976; Folinsbee et al., 1978). Moreover, the small data base(s) and the 

limited statistical evaluation of almost all of these models further precludes 

their quantitative applications and limits their qualitative application(s) to 

conditions similar to those for which the models were derived. 

12-23 
The effects of intermittent exercise and 0 3concentration on the magnitude 

of average pulmonary function responses (e.g., FEV1 ) during 2-hr exposures are 

illustrated in Figures 12-2 through 12-5. The data sets on which the predictive 

models are based have been limited to studies utilizing intermittent exercise 

and 2-hr exposure protocols. The following types of data were included in the 

analysis: (1) data from single exposures; (2) data obtained on the first day 

of sequential, multiday exposures; and (3) data obtained from repetitive 

exposures of the same cohort to a range of concentrations or to the same 

concentration but with different levels of exercise, provided the reported 

exposures were each separated by at least 7 days. To minimize inhomogeneity 

of data further, studies conducted under unique environmental conditions 

(e.g., high relative humidity and temperature) or on known hyperreactive 

groups of subjects were not included in this analysis. Neither were data from 

resting and continuous exercise studies included in the calculations. 

The selected set of 25 studies represents data obtained on 320 subjects 

studied between 1973 and 1985, in 8 different laboratories (Table 12-3). Since 

minute ventilation is one of the most important determinants of response to 

ozone, the data have been categorized by reference to exercise level, as 

defined by minute ventilation. Based on a distribution pattern of V Eduring 

exercise, four subgroups were identified: light exercise (VE< 23 L/min), 

moderate (VE= 24 to 43 L/min), heavy (VE= 44 to 63 L/min), and very heavy 

exercise group (VE> 64 L/min). Although basic second-order functions were 

considered in modeling the concentration-response relationship, the pure 

quadratic function with no intercept was found to be the simplest and most 

suitable model since this is the only function that passes through a minimum 

(no response) at zero 0 3concentration. The relative contribution of each 

data point was adjusted by weighing it by the number of subjects. Scatter 

plots with superimposed best-fit curves and 95 percent confidence limits for 

FEV1at each exercise level show clearly differentiated response curves with 

high correlation coefficients (r = 0.89 to 0.97). A strong and statistically 

significant (p <0.0001) positive association between decrements in FEVIand 

ozone concentration for all levels of exercise is apparent. From the curves, 

it can be determined with 95 percent confidence that light exercise in a 0.2 

ppm 03atmosphere will decrease FEV1by 1.6 percent, moderate exercise by 2.4 

percent, heavy exercise by 2.8 percent, and very heavy exercise by 4.7 percent 

on the average, respectively. Inversely, a 5 percent decrement in FEV 1can be 

12-24 
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12-33' 
expected with light exercise in 0.36 ppm 0 3 , moderate exercise in 0.29 ppm 0 3 , 

heavy exercise in 0.27 ppm 0 3 , and very heavy exercise in a 0.21-ppm 0 3atmosphere. Since the models are based on a large number of data and show highly 

statistically significant differences of slope with narrow confidence bands, 

they are acceptable for quantitative estimates of response. It is important 

to note, however, that any predictions of average pulmonary function responses 

to 03only apply under, the specific set of exposure conditions at which these 

data were derived. Other pulmonary function variables analyzed in the same 

manner, although not illustrated here, showed the same trend as the FEV 1 , but 

as expected, changes differed in magnitude. For example, the decrements in 

FVC were smaller, while decrements in FEF25-75 were greater, for a given 0 3 

concentration, than decrements in FEV 1 . The Rawshowed a similar concentrationdependent, positively correlated response (r = 0.73). 

Continuous exercise equivalent in duration to the sum of intermittent 

exercise periods at comparable ozone concentrations and minute ventilation (VE 

>60 L/min) elicited greater changes in pulmonary function. The enhancement 

ranged from several percent to more than a twofold augmentation of the effects 

(Folinsbee et al., 1984; Avol et al., 1984, 1985c). Others, on the other hand, 

have reported group mean responses in continuous exercise exposures that were 

similar to those previously observed with comparable levels of intermittent 

exercise (Adams et al., 1981; Adams and Schelegle,, 1984). The lack of sufficient data, however, on comparable levels of exercise in the same subjects 

prevents any quantitative comparison - of the effects induced by continuous 

versus intermittent exercise. 

Exercise not only stresses the respiratory system but other physiological 

systems, as well, particularly the cardiovascular and musculoskeletal systems. 

Various compensatory mechanisms activated within these systems during physical 

activity might facilitate, suppress, or otherwise modify the magnitude and 

persistence of the reaction to ozone. Unfortunately, to date only a few of 

the studies were specifically designed to examine nonpulmonary effects of 

exercise in ozone atmospheres (Gliner et al., 1975, 1979). In one study, 

light intermittent exercise (VE= 20-25 L/min) at a high ozone concentration 

(0.75 ppm) reduced post-exposure maximal exercise capacity by limiting maximal 

oxygen consumption (Folinsbee et al., 1977a); submaximal oxygen consumption 

changes were not significant (Folinsbee et al., 1975). The extent of ventilatory (VT , fR ) and respiratory metabolic changes (V0 2 ) observed during or 

12-34 
following the exposure appears to have been related to the magnitude of pu1- 

monary function impairment. Whether such (metabolic) changes are consequent 

to respiratory discomfort or are the result of changes in lung mechanics, or 

both, is still unclear and needs to be elucidated. 

12.3.2.3Environmentai Stresses . Environmental conditions such as heat and 

relative humidity (rh) may contribute to symptoms and physiological impairment 

during and following 03 exposure. A hot (31 to 40 ° C) and/or humid (85 percent 

rh) environment, combined with exercise in the 0 3 atmosphere, has been shown 

to reduce forced expiratory volume more than similar exposures at normal room 

temperature and humidity (25° C, 50 percent rh) (Folinsbee et al., 1977b; 

Gibbons and Adams, 1984). Modification of the effects of 0 3 by heat or humidity 

stress may be attributed to increased ventilation associated with elevated 

body temperature but there may also be an independent effect of elevated body 

temperature on pulmonary function (e.g., VC). 

12.3.3Other Factors Affecting Pulmonary Response to Ozone 

12.3.3.1 Ace. Although age has been postulated as a factor capable of modifying responsiveness to 03 , studies have not been designed to test specifically 

for the effects of age on responsiveness to 0 3 . Epidemiological studies in 

both children and young adults have suggested an association between decreased 

lung function and exposure to oxidant-polluted ambient air but no comparisons 

were made in these studies between different age groups (Lippmann et al., 

1983; Lebowitz et al., 1982, 1983, 1985; Lebowitz, 1984; Bock et al., 1985; 

Lioy et al., 1985). In addition, it is not clear if the observed effects are 

attributable to 03 alone since these studies have considerable methodological 

problems, including the inability to adjust adequately for the confounding 

influence of other pollutants and environmental conditions in ambient air (see 

Chapter 11). Controlled-exposure studies, however, on children and adolescents 

exposed to 03 or ambient air containing predominantly 03 (Avol et al., 1985a,b; 

McDonnell et al., 1985b,c) have indicated that the effects of 0 3 on lung 

spirometry were very similar to those found in adults exposed under similar 

conditions, except that no significant increases in symptoms were found in 

children. Therefore, based on the limited pulmonary function data available, 

young children and adolescents do not appear to respond any differently to 0 3 

than adults. Further research is needed to confirm these preliminary findings 

in the young and also to determine if older subjects have altered responsiveness 

to 0 3 . 

12-35 
As with human studies to date, the influence of age on responsiveness to 

ozone is also difficult to assess from animal studies. Very few age comparisons have been made within a single study. Raub et al. (1983), Barry et al. 

(1983), and Crapo et al. (1984) studied pulmonary funct,ion and morphometry of 

the proximal alveolar region in neonatal (1-day-old) and young adult (6-week - 

old) rats exposed to 0.08, 0.12, or 0.25 ppm ozone for 12 hr/day, 7 days/week 

for 6 weeks. A few di fferent responses were observed i n the neonates and 

adults, but they were not major. Generally, neonates and young adults were 

about equally responsive, which is consistent with the human studies summarized 

above. 

Animal studies of lung antioxidant metabolism and oxygen consumption 

(Lunan et al., 1977; Tyson et al., 1982; Elsayed et al., 1982) indicate that 

the stage of development at initiation of short-term exposure determines the 

response to 0 3 . Generally, the direction of the effect differs before and 

after weaning. Suckling neonates (5 to 20 days old) exhibited a decrease in 

antioxidant enzyme activities; as the animals grew older (up to 180 days old), 

enzyme activities increased progressively, reached a plateau at 35 days of 

age, and persisted after cessation of exposure. This biochemical response may 

be attributed to morphological changes in the lung that have a similar agerelated pattern in the progression of centriacinar lesions in rats exposed to 

03 before and after weaning (Stephens et al.; 1978). Thus, further research 

is needed to determine if the young differ markedly from adults in their 

response to 03 . 

12.3.3.2 Sex. Sex differences in responsiveness to ozone have not been 

adequately studied. A small number of female subjects have been exposed to' 0 3 

in mixed cohorts in many human controlled studies, but only three reports gave 

enough information for a limited comparative evaluation (Horva -th et al., 1979; 

Gliner et al., 1983; DeLucia et al., 1983). Two additional studies (Gibbons 

and Adams, 1984; Lauritzen and Adams, 1985) compared 0 3 effects in women with 

the results from maie subjects previously studied in the same laboratory. The 

studies reported above suggest that lung function of women, as assessed by 

changes in FEV 1.0 , may have been affected more than that of inen under similar 

exercise and exposure conditions, but the results are not conclusive. Field 

and epidemiological studies of children and adolescents exposed to ambient air 

have also tended to show greater effects in girls, but the differences either 

were not tested statistically (Bock et al., 1985) or were not significant 

12-36 
(Avol et al., 1985a,b). Further research is needed to determine whether 

systematic differences exist between the sexes in their responses to ozone and 

what factors might be responsible for those differences. 

The majority of animal studies have been conducted with male animals. 

Generally, when females have been used they have not been compared to males in 

the same study. This makes comparisons from.animal data of sex-related differences in sensitivity to ozone virtually impossible. The only exception is a 

study of effects of ozone in increasing pentobarbital-induced sleeping time 

(Graham et al., 1981). Since waking from pentobarbital anesthesia is brought 

about by xenobiotic metabolism in the liver, this effect is considered to be 

extrapuimonary. 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 metaboiism, but the other species do 

not. 

12.3.3.3Smoking Status . Differences between smokers and nonsmokers have 

been studied often, but the smoking histories of subjects are not documented 

well. Hazucha et al. (1973) and Bates and Hazucha (1973) appear to have 

demonstrated greater responses (FVC, MMFR) in nonsmokers at 0.37 ppm 0 3 , but 

the responsiveness was reversed at 0.75 ppm (RV, FEV1' Vmax50' and MMFR). 

Kerr et al. (1975) observed greater responses_(FVC, SG aw , R L , FEV3 , and symptoms) 

in nonsmokers at 0.5 ppm 0 3 for 6 hr. DeLucia et al. (1983) also observed 

greater responses in nonsmokers for VC, FEV 1 , MMFR, f B , and V1- at 0.3 ppm 03 

(1 hr). Kagawa and Tsuru (1979a) found greater effects of ozone among nonsmokers at 0.5 ppm than at 0.3 ppm 03 (2 hr); a later study (Kagawa, 1983) 

showed that nonsmokers also had a greater response (SG aw) than smokers to 

0.15 ppm (2 hr). Shephard et al. (1983) found a slower and smaller change in 

spirometric variables in smokers at 0.5 and 0.75 ppm (2 hr). While none of 

these controlled studies examined the effects.of different degrees of smoking, 

the general trend suggests that smokers are less responsive than nonsmokers. 

The reasons for these differences are not known; however, smokers have altered 

lung function and an increase in mucus, both of which could infiuence the 

dosimetry of 0 3 in respective regions of the lung. 

12.3.3.4Nutritional Status . Posin et al. (1979) found that human volunteers 

receiving 800 (about four times the recommended daily units) or 1600 IU of 

12-37 
vitamin E for 9 weeks as a supplement showed no differences in blood biochemistry from unsupplemented volunteers when exposed to 0.5 ppm ozone for 2 hr. 

The biochemical parameters studied included red cell fragility, hematocrit, 

hemoglobin, glutathione concentration, and activities of acetylcholinesterase, 

glucose-6-phosphate dehydrogenase, and lactic acid dehydrogenase. No differences in pulmonary function and symptoms were found between the vitamin 

E-supplemented and placebo groups (Hackney et al., 1981). 

Hamburger et al. (1979) studied the effects of ozone exposure on the 

agglutination of human erythrocytes by the lectin concanavalin A. Pre-incubation with malonaldehyde, an oxidation product of polyunsaturated fatty acids, 

decreased concanavalin A agglutination of red cells exposed in vitro to ozone. 

Red cells obtained from 29 subjects receiving 800 IU of vitamin E or a placebo 

were exposed to 0.5 ppm ozone for 2'hr. Following ozone exposure, a slight 

decrease in agglutination occurred in cells from subjects who did not receive 

vitamin E supplementation, but the results were not statistically significant. 

Increased activity of the glutathione peroxidase system may be one of the 

most sensitive, biochemically measured indices of exposure to < 1 ppm of 03 

because it is involved in antioxidant metabolism. Increases in the activity 

of the glutathione peroxidase system have been reported after exposure of rats 

on a vitamin E-deficient diet to l.evels.as low as 0.1 ppm 0 3 for.7 days (Chow 

et al., 1981; Mustafa, 1975; Mustafa and Lee, 1976). The amount of dietary 

vitamin E fed to the rats influenced the ozone-induced increase irr this system. 

For example, when the diet of rats contained 66 ppm of vitamin E, increased 

glutathione peroxidase activity was observed at 0.2 ppm of 0 3 ; with 11 ppm of 

vitamin E, increases occurred at 0.1 ppm (Mustafa and Lee, 1976). Several 

other investigators have shown that vitamin E deficiency in rats makes them 

more susceptible to these ozone-induced enzymatic changes (Chow et al., 1981; 

Plopper et al., 1979; Chow and Tappel, 1972). 

Studies of ozone-exposed vitamin E-deficient or supplemented rats have 

been undertaken to correlate biochemical findings with morphological alterations. Rats maintained on a basal vitamin E diet had the typical centriacinar 

lesions found as a result of 03 exposure (Stephens et al., 1974; Schwartz et 

al., 1976). Lesions were generally worse, however, in vitamin E-deficient or 

marginally supplemented rats compared to highly supplemented rats (Plopper et 

al., 1979; Chow et al., 1981),.supporting the finding from mortality (Donovan 

et al., 1977) and biochemical studies that vitamin E is protective in rats. 

12-38 
The difference in response between animals and man with regard to the 

protective effects of vitamin E against ozone toxicity may lie in the pharmacokinetics of vitamin E distribution in the body. Redistribution of vitamin E 

from extrapulmonary.stores to the lung is slow. Short exposures to ozone may 

not allow adequate time for redistribution and for a protective effect to be 

observed. Animal exposures in which the striking effects of vitamin E on 

ozone toxicity were observed,were generally conducted over longer exposure 

periods (often,l to 2 weeks). Human subjects were exposed for shorter times 

and lower concentrations because of ethical considerations. Thus, vitamin E 

may have protective effects in man, but if they occur their demonstration 

might require longer exposure times and higher ozone concentrations. In 

animal studies, vitamin E-deficient rats are subject to increased toxicity 

from 03 compared to supplemented groups, while animals on.basal vitamin E 

diets are afforded little if any protection from 0 3 . In human studies, subjects 

were not likely to have had a deficiency substantial enough to show any effect. 

Thus, no evidence indicates that man would benefit from increased vitamin E 

intake relative to ambient ozone exposures, even though the antioxidant role 

of vitamin E in preventing ozone-initiated peroxidation in vitro is well 

demonstrated and the protective effects in vivo are clearly demonstrated in 

rats and mice. Further, vitamin E protection is not absolute and can be 

overcome by continued ozone exposure. The-effects of vitamin E do support the 

general idea, however, that lipid peroxidation is involved in ozone toxicity. 

12..3.3.5 Red Blood Cell Enzyme Deficiencies. The enzyme glucose-6-phosphate 

dehydrogenase (G-6-PD) is essential for the functioning of the glutathione 

peroxi dase . system i n the red bl ood cel l( RBC) , whi ch i s the enzyme system 

proposed as having an integral part in the decomposition of fatty acid peroxides 

or hydrogen peroxide formed by 0 3-initiated polyunsaturated fatty acid peroxidation (see Section 12.5.1). Therefore, Calabrese et al. (1977) have postulated 

that individuals with a hereditary deficiency of G-6-PD could possibly experience 

significant hematological effects from 0 3 exposure. 'There have been too few 

studies performed, however, to reliably document this possibility. Most ozone 

studies have been with red blood cells from rodents, even though differences 

may exist between rodent and human RBCs. Calabrese and Moore (1980)' and Moore 

et al. (1981) have pointed out the lack of ascorbic acid synthesis and the 

relatively l.ow level of glucose-6-phosphate dehydrogenase (G-6-PD) in man 

compared to active ascorbic acid synthesis and high levels of G-6-PD in mice 

12-39 
and rats. Although their species comparisons are based on a very limited data 

base, the authors point out the importance of developing animal models that 

can accurately predict the response of G-6-PD-deficient humans to oxidants 

such as 03 . This group has suggested the use of the C57L/J strain of mice and 

the Dorset sheep as better animal models for hematological studies since these 

species have levels of G-6-PD closer to those in man, especially those levels 

found in G-6-PD-deficient patients. The RBCs of Dorset sheep, however, appear 

to be no more sensitive to ozone than normal human RBCs, even though the 

G-6-PD levels in Dorset sheep are very low. Additional in vitro studies 

(Calabrese et al., 1982, 1983; Williams et al., 1983a,b,c) have demonstrated 

that the responses of sheep and normal human RBCs responded quite similarly 

when separately incubated with potentially toxic 0 3 intermediates, but that 

G-6-PD-deficient human RBCs were considerably more susceptible. Even if 0 3 or 

a reactive product of 0 3-tissue interaction were to penetrate the RBC after in 

yiyo exposure, it is unlikely that decrements in reduced glutathione activity 

woul d be 1 arge enough to 1 ead to chroni c hemolyti c anemi a i n the affected 

individual. 

12.3.4 Effects of Repeated Exposure to Ozone 

12.3.4.1 Introduction. The attenuation of response associated with repeated 

exposure to 03 is generally referred to as "adaptation." Earlier work in 

animals that focused primarily on reductions in pulmonary edema and mortality 

rate to assess this process employed the term "tolerance"; other terms have 

a1so been used to describe this phenomenon (Chapter 9, Section 9.3.5). The 

distinction, if any, among these terms with respect to 0 3 and its effects has 

never been established in a clear, consistent manner. 

The following sections describe the nature of observed alterations in 

responsiveness to 0 3 and discuss possible interrelationships for those observed 

changes in responsiveness. 

12.3.4.2 Development of Altered Responsiveness to Ozone. Successive daily 

brief exposures of human subjects to 03 (< 0.7 ppm for — 2 hrs) induce a 

typical temporal pattern of response (Chapter 10, Section 10.3). Maximum 

functional changes that occur on the first exposure day, as assessed by plethysmographic and bronchial reactivity tests (Farrell et al., 1979; Dimeo et al., 

1981), or on the second exposure day, as assessed by spirometry, become progressively attenuated on each of the subsequent days (Horvath et al., 1981; I(ulle 

12-40 
et al., .1982b; Linn et al., 1982b). By the fourth day of exposure, the average 

effects are not different from those observed following control (air) exposure. 

Individuals need between 3 and 7 days of exposure to develop full attenuation, 

with more sensitive subjects requiring more time (Horvath et al., 1981; Kulle 

et al., 1982b; Linn et al., 1982b; Haak et al., 1984). The magnitude of a 

peak response appears to be directly related to 0 3 concentration (Folinsbee 

et al., 1980; Haak et al., 1984). Whether varying the length or the frequency 

of exposure will modify the time course of this altered responsiveness has not 

been explored. Full attenuation, even in ozone-sensitive subjects, does not 

persist for more than 3 to 7 days after exposure in most individuals (Horvath 

et al., 1981; Kulle et al., 1982b; Linn et al., 1982b), while partial attenuation might persist for up to 2 weeks (Horvath et al., 1981). Although the 

severity of symptoms generally correlates with the magnitude of the functional 

response, partial attenuation of symptoms appears to persist longer, for up to 

4 weeks after exposure (Linn et al., 1982b). Ozone concentrations inducing 

few or no functional effects (< 0.2 ppm) elicited no significant changes in 

pulmonary function with consecutive exposures (Folinsbee et al., 1980). The 

latter findings are consistent with the proposition that functional attenuation 

may not occur in the airways of individuals living in communities where the 

ambient ozone levels do not exceed 0.2 ppm. The difficulty, however, of 

drawing such inferences on the basis of narrowly defined laboratory studies is 

that under ambient conditions a number of uncontrollable factors might modify 

the response. Most notably, other pollutants may interact with ozone during 

more protracted ambient exposures to induce changes at concentrations lower 

than those reported from controlled-laboratory studies. The evidence suggesting that Los Angeles residents exhibit functional attenuation of the 

response to 03 is sparse (Hackney et al., 1976, 1977a,b; Linn et al., 1983a) 

and requires confirmation. 

12.3.4.3 Conclusions Relative to Attenuation with Repeated Exposures. The 

attenuation of acute effects of 0 3 after repeated exposure, such as changes in 

lung function, have been well documented in controlled human exposure studies. 

There are no practical means at present, however, of assessing the role of 

altered responsiveness to 0 3 in human populations chronically exposed to 

ozone. No epidemiological studies have been designed to test whether attenuation of symptoms, pulmonary function, or morbidity occurs in association with 

photochemical air pollution. It might be added that the proposition wouid be 

12-41 
difficult to test epidemiologically. Thus, scientists must rely mainly on 

inferences and qualitative extrapolations from animal experimentation. 

Attenuation of response to 0 3 may be viewed as a process exhibiting some 

concentration-response characteristics. Concentrations of 03 that have little 

or no effect do not appear to influence measurably the response invoked by 

subsequent exposures to higher 03 concentrations. Over some higher range (0.2 

to 0.8 ppm) of exposure, functional recovery after repeated exposure is virtually complete within several days. Insofar as this generalization is valid, 

it suggests that photochemical air pollution may induce altered responses only 

in individuals who previously responded to exposure. Above this range, per- 

--sistent or progressive damage is most likely to accompany repeated exposure. 

The attenuation, however, of the functional changes (and the time course of 

attenuation) following repeated exposure to 03 does not necessarily follow the 

morphological or biochemical pattern of responses nor does it necessarily 

imply that there is attenuation of the'morphological or biochemical responses 

to 03 . 

Responses to 03 , whether functional, biochemical, or morphological, have 

the potential for undergoing changes during repeated or continuous exposure. 

There is an interplay between tissue inflammation, hyperresponsiveness, ensuing 

injury (damage), repair processes, and changes in response. The initial 

response followed by its attenuation may be viewed either as sequential states 

in a continuing process of lung injury and repair or as a physiological adaptation to the irritative stimulus. 

12.3.5 Mechanisms of Responsiveness to Ozone 

The time course, type, and consistency of changes of such indices as 

symptoms, lung volumes, flows, resistances, and bronchial reactiv•ity strongly 

implicate vagal sensory receptors as substantial modulators of responsiveness 

to 03 . 

A growing body of evidence from both animal (Roum and Murlas, 1984; Lee 

et al., 1979; Gertner et al., 1983a,b) and human studies (Golden et al., 1978; 

DiMeo et al., 1981; Beckett et al., 1985) indicates that a post-ozone exposure 

increase in bronchial smooth muscle tone is mediated, at leas -t in part, by 

increased tonic vagal activity consequent to stimulation of muscarini.c receptors. Beckett et al. (1985) demonstrated that pretreatment of subjects with 

atropine (a bronchodilator and muscarinic, cholinergic blocker) prevented an 

12-42 
increase in SRaw and partially blocked a decrease in FEV l ; both tests are used 

clinically as indirect indices of bronchoconstriction. Atropine did not, 

however, prevent the reduction in FVC, increase in frequency of breathing 

(fB ),. or decrease.in tidal volume - (VT). Inhalation of other types of bronchodilators.(e.g., isoproterenol, metaproterenol; adrenergic receptor agonists) 

immediately post-exposure relaxed constricted airways, while elevated R

aw 

 and 

SRaw returned rapidly to baseline values (Golden et al., 1978; Beckett,et al., 

1985). Such a pattern of response strongly suggests the involvement of vagal 

sensory receptors.(irritant, stretch and J-receptors), since stimulation of 

these receptors will generaily elevate bronchomotor tone, increase f B , and 

decrease VT . These findings show that ozone-induced increases in airway 

resistance are caused primarily by a reflex constriction of airway smooth 

muscle. The afferent pathways of this reflex.originate at different receptor 

sites, but the (increased) efferent activity seems to be vagally mediated. 

Besides direct excitation of afferent end-organs (receptors, nerve endings), 

other factors may influence this (afferent) discharge. Enhanced sensitivity 

of receptors (Lee et ai., 1977) and mucosal inflammation (Holtzman et al., 

1983a,b), leading to increased epitheliat permeability of bronchodilators 

(Davis et al., 1980), are some of the proposed mechanisms. Reiative to effectors, sensitization of muscarinic receptors (Roum and Murlas, 1984) and mucosal 

hypersecretion may be contributing factors. 

Under most circumstances, increased R aW may be expected to,reduce FVC and 

increase RV. The lack, however, of a significant association between individual 

changes in Raw and FVC (McDonnell et al., 1983), and the disparate effects of 

bronchodilator agents on airway diameter, indicate the presence of more than 

one mechanism for 0 3-induced changes in pulmonary function. At 0 3 concentrations of 0.5 ppm and less, decrements in.FVC have been related to decreases in 

TLC wi thout changes i n RV or TGV (Hackney et al ., 1975; Fol i nsbee et al ., 

1977b, 1978; Kulle et al., 1985). The consequent decrease in TLC most likely 

results from i.nhibition of maximal inspiration, as indicated by the reduced IC 

reported at higher (0.75 ppm) 03 concentrations (Bates et a1., 1972). Whether 

such an inhibition of maximal inspiration is voluntary (due to discomfort) or 

involuntary (due to reflex pathways or altered lung mechanics) is unclear and 

awaits further experimentation. It is highly probable, however, that most of 

the decrements in lung volume reported to result from exposure to 0 3 at concentrations of greatest relevance to standard-setting (< 0.3 ppm) are caused by 

12-43 
the inhibition of full inspiration rather than by changes in airway diameter. 

The lack of any reported changes in the FEV 1/FVC ratio also supports the 

restrictive nature of this mechanism (Farrell et al., 1979; Kagawa, 1984). 

Among the non-vagal components of the functional response, the release of 

mediators is one of more plausible mechanisms suggested (Lee et al., 1979). 

None of the experimental evidence, however, is definitive. Additional investigation is needed to elucidate, assess the relative importance of, and determine 

the overall contribution of the mechanisms associated with ozone exposure. 

Recent experiments by Gertner et al. (1983a,b,c) may provide additional 

information on possible mechanisms. They demonstrated that even a brief 

exposure of the peripheral airways of dogs to ozone triggered a functional 

response that, depending on 0 3concentration, could be mediated through reflex 

or humoral pathways, or both. The reflex-mediated response was subject to 

attenuation after repeated exposure, whereas the response mediated humorally 

was not. 

Experimental evidence in laboratory animals also suggests a close relationship between the cellular response to 0 3 -induced injury, as measured by 

the appearance of neutrophils in the airway epithelium of dogs exposed to 0 3 , 

and airway hyperresponsiv.eness, as determined with a provocative aerosol 

(Holtzman et al., 1983a,b; Fabbri et al., 1984; Sielczak et al., 1983). When 

mobilization of the neutrophils was prevented by prior treatment with hydroxyurea (0'Byrne et al., 1983), the (neutrophilic) infiltration after ozone 

exposure was depressed (Fabbri et al., 1983), and no increase was seen in 

airway responsiveness. 

Ozone toxicity, in both humans and laboratory animals, may be mitigated 

through altered responses at the cellular or subcellular level, or both. At 

present, the mechanisms underlying altered responses are unclear and the 

effectiveness of such mitigating factors in protecting the long-term health of 

the individual against 0 3is still uncertain (Bromberg and Hazucha, 1982). 

Since cellular mechanisms are difficult if not impossible to investigate in 

humans, animal studies become essential for identifying potential mechanisms 

of effects. Numerous basic metabolic processes in humans and animals appear 

to be similar; mechanisms underlying these processes may indeed provide some 

clues on possible mechanisms in humans (Mustafa and Tierney, 1978; Boushey et 

al., 1980). It has been shown that human and animal leukocytes, alveolar 

macrophages, and neutrophils produce superoxide radicals not only as a product 

12-44 
of a vital biological reduction of molecular oxygen but also as a result of 

stressful stimuli (Pick and Keisari, 1981). Exccessive production of radicals 

without adequate scavenging will injure the supporting tissues, while the 

attenuation of response to successive stimuli suppresses the release of free 

oxygen radicals and depresses the chemotactic responsiveness of the cells 

(Mustafa and Tierney, 1978; Bhatnagar et al., 1983). Accumulation of inflammatory cells at the site of injury and subsequent release of proteases capable 

of degrading connective tissue may upset the protease-antiprotease balance 

critical for controlling the extent of inflammation and injury. Perturbation 

of lung collagen metaboiism, seen in vivo in animals exposed to 0 3 (see 

Section 9.3.3.6), could be involved in the inflammatory response. Furthermore, 

the attenuation of prolyl hydroxylase (a key enzyme in collagen synthesis) 

activity (Hussain et al., 1976a,b), and concurrent changes in the activity of 

superoxide dismutase, the enzyme that catalyzes the dismutation of the superoxide free radical (Bhatnagar et al., 1983), could be another important pathway 

to the development of changes in responsiveness to 0 3 . (However, even though 

the prolyl hydroxylase activity returns to control levels, the collagen produced 

through the original increase in metaboiism remains). The glutathione peroxidase system also increases after 0 3 .exposure, thereby providing another line 

of defense against oxidant toxicity (Chow, 1976; Chow et al., 1976). 

Wi th ti me, there i s a reducti on i n the i ntens i ty and a change i n the 

composition of the inflammatory response. Partial remission occurs with 

continuous or intermittent exposure. There are no data, however, showing how 

important the timing and duration of the 0 3 puisations may be in influencing 

the induction and remission of the inflammatory reaction. The latter issue 

has potential significance for public health, since exposure to ambient air 

pollution is essentially intermittent. The timing and intensity of exposure 

to ozone within the community, and consequently the potential of such exposures 

for inducing altered responses, are likely to be highly variable. Differences 

within the population in patterns of activity and.biological status may be 

expected to contribute to this variability. 

12.3.6 Relationship Between Acute and Chronic Ozone Effects 

Understanding the relationship between acute effects that follow 03 

exposure of man or animals and the effects that follow long-term exposures of 

man or animals is crucial to the evaluation of the full array of possible 

12-45 
human health effects of oxidant pollutants. Most of the acute responses to 0 3 

described in animals and man tend to return toward control (filtered air) 

values with time after the exposure ends. While effects of longer periods of 

exposure have been documented in laboratory animals (Chapter 9), human beings 

have not undergone long-term exposures in laboratory studies because of ethical 

and logistical considerations. In fact, little is known about the long-term 

implications of acute damage or about the chronic effects in man of prolonged 

exposure to 03 . 

With newer techniques, the pulmonary function of experimental animals can 

be more completely evaluated and correlated with biochemical and morphological 

parameters. Long-term exposure of rats to less than 1.0 ppm 0 3 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 3 12 hr/day 

for 42 days, observed significantly lower peak inspiratory flows during spontaneous respiration, in addition to the increased lung volumes noted above. 

While Yokoyama and Ichikawa (1974) did not find changes in lung static pressurevolume curves of rats exposed to 0.45 ppm 0 3 6 hr/day, 6 days/week for 6 to 7 

weeks, Martin et al. (1983) reported increased maximum extensibility of alveolar 

walls and increased fixed lung volumes following exposure of rabbits to 0.4 ppm 

03 7 hr/day, 5 days/week for 6 weeks. 

Wegner (1982) studied pulmonary function in bonnet monkeys exposed to 

0.64 ppm 03 8 hr/day, 7 days/week for up to 1 year. After 6 months of exposure, 

significant increases in pulmonary resistance and in the frequency dependence 

of pulmonary compliance were reported. In the monkeys exposed for 1 year, 

Wegner (1982) reported significantly increased pulmonary resistance and inertance; 

and decreased flows during forced expiratory maneuvers at low lung volumes and 

decreased volume expired in 1 second (FEV1 ). These findings were interpreted 

as indicating narrowing of the peripheral airways. This observation was 

confirmed, using morphometric techniques, by Fujinaka et al. (1985), who 

reported that respiratory bronchioles of the bonnet monkeys exposed for 1 year 

12-46 
had smaller internal diameters and thicker walls. Following a 3-month postexposure period, static lung compliance tended to decrease in both exposed and 

control monkeys, but the decrease in exposed monkeys was significantiy greater 

than that in control monkeys. No other significant differences were measured 

following.the 3-month recovery period, although values for 03-exposed animals 

remained substantially different from those for control animals. Wegner 

(1982) interpreted these differences as an indication that full recovery was 

not complete. 

Morphological alterations in both rats and monkeys tend to decrease in 

magnitude with increasing duration of exposure to 0 3 , but significant alterations in the centriacinar region have still been reported at the end of longterm exposures of rats (Boorman et al., 1980; Moore and Schwartz, 1981; Barry 

et al., 1983; Crapo et al., 1984), monkeys (Eustis et al., 1981; Fujinaka et 

al., 1985), and dogs (Freeman et al., 1973). While repair, as indicated by 

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 0 3 for 42 to 180 days includes damage to 

ciliated cells and centriacinar 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 and intramural inflammatory cells; and in rats, 

but not reported in monkeys, thickening of interalveolar septa (Boorman et al., 

1980; Moore and Schwartz, 1981; Eustis et al., 1981; Barry et al., 1983; Crapo 

et al., 1984). Lungs from the bonnet monkeys studied by Wegner (1982) were 

evaluated morphologically and morphometricaliy by Fujinaka et al. (1985). At 

the end of the 1-year exposure to 0.64 ppm 03 for 8 hr/day, a significant 

increase was found in the total volume of respiratory bronchioles in the lung, 

but their lumens were smaller in diameter because of thickened epithelium and 

other wall components. The reduction in .diameter of the first generation 

respiratory bronchioles correlates with the results of the pulmonary function 

tests performed by Wegner (1982). Cuboidal bronchiolar epithelial cells in 

respiratory bronchioles were hyperplastic. Walls of respiratory bronchioles 

contained significantly more macrophages, lymphocytes, plasma cells, and 

neutrophils. Neither the numbers of fibroblasts nor amount of stainable 

12-47 
collagen was increased significantly, but there was more amorphous intercellular material. There was also a significant increase in arteriolar media and 

i nti ma. 

Lung collagen content was increased after short-term exposures to 0 3 

concentrations ranging from 0.5 to 1.0 ppm 0 3 (Last et al., 1979). This 

change continued during long-term exposure (Last and Greenberg, 1980; Last 

et al., 1984b). Exposure to 0.96 ppm 03 resulted in increased lung collagen 

content in both weanling and adult rats exposed for 6 and 13 weeks, respectively, and in young monkeys exposed to 0.64 ppm 0 3 for l year (Last et al., 

1984b). Some of the weanling rats and their controls were examined after a 

6-week post-exposure period in clean air following the 6-week exposure to 0 3 . 

During this post-exposure period, the differences in lung collagen content between exposed and pair-fed controls increased rather than decreased. Thus, 

with respect to this biochemical alteration, the post-exposure period was one 

of continued damage rather than recovery. 

Continuation of the centriacinar inflammatory process during long-term 0 3 

exposures is especially important, as it appears to be correlated with remodeling of the centriacinar airways (Boorman et al., 1980; Moore and Schwartz, 

1981; Fujinaka et al., 1985). There is morphometric (Fujinaka et al., 1985), 

morphologic (Freeman et al., 1973), and functional evidence (Costa et al., 

1983; Wegner, 1982) of distal airway narrowing. Continuation of the inflammation also appears to be correlated with the increased lung collagen content 

(Last et al., 1979; Boorman et al., 1980; Moore and.Schwartz, 1981; Last 

et al., 1984b) that morphologically appears predominantly in centriacinar 

regions of the lung. 

The distal airway changes described in the above studies of ozone-exposed 

animals have many similarities to those reported in lungs from cigarette 

smokers (Niewoehner et al., 1974; Cosio et al., 1980; Hale et al., 1980; 

Wright et al., 1983). Even though cigarette smoking bas been linked with 

emphysema in humans, however, there is no evidence of emphysema in the lungs 

of animals exposed to 0 3 . The previous criteria document for 0 3 (U.S. Environmental Protection Agency, 1978) cited three studies reporting emphysema in 

laboratory animals after exposure to 0 3 concentrations ranging from 0.4 to 0.88 

ppm for prolonged periods (P'an et al., 1972; Freeman et al., 1974; Stephens 

et al., 1976); but a reevaluation of these findings based on the currently 

accepted definition of emphysema does not find any evidence for such claims 

12-48 
(see Chapter 9; Section 3.1.4.2). Since then, no similar exposures (i.e., 

same species, 03 concentration, and times) have been documented to confirm 

observations of emphysematous changes in the lungs of animals exposed to 0 3 . 

12.3.7Resistance to Infection 

Normally the mammalian respiratory system is protected from bacterial and 

viral infections by the integrated activity of the mucociliary, phagocytic, 

and immunological defense systems. Animal models and isolated cells have been 

used to assess the effects of oxidants on the various components of these lung 

defenses and to measure the ability of these systems to function as an integrated unit in resistance against pulmonary infections. In these studies, 

short-term (3 hr) exposure to 0 3 at concentrations of 0.08 to 0.10 ppm can increase the incidence of mortality from bacterial pneumonia (Coffin et al., 

1967; Ehrlich et al., 1977; Miller et al., 1978a). Subchronic exposure to 0.1 

ppm caused similar effects (Aranyi et al., 1983). Following short-term exposures to 0 3 , a number of alterations in lung defenses have been shown, such as 

(1) impairment in the ability of the lung to inactivate bacteria and viruses 

(Coffin et al., 1968; Coffin and Gardner, 1972; Goldstein et al., 1977; Ehrlich 

et al., 1979); (2) reduced effectiveness of mucociliary ciearance (Phalen et 

al., 1980; Frager et al., 1979; Kenoyer et al., 1981; Abraham et al., 1980); 

(3) immunosuppression (Campbell and Hilsenroth, 1976; Aranyi et al., 1983; 

Thomas et ai., 1981b; Fujimaki et al., 1984); (4) significant reduction in 

number of pulmonary defense cells (Coffin et al., 1968; Alpert et al., 1971); 

and (5) impaired macrophage phagocytic activity, less mobility, more frragility 

and membrane alterations, and reduced lysosomal enzymatic activity (Dowell et 

al ., 1970; Hurst et al ., 1970; Hurst and Coffi n, 1971; Goldstei n et al ., 

1971a,b, 1977; Hadiey et al., 1977; McAllen et al., 1981; Witz et al., 1983; 

Amoruso et al., 1981). Such effects on pulmonary host defense have been 

reported in a variety of species of animals following either short-term or 

subchronic exposure to 0 3 in combination with other airborne chemicals (Gardner 

et al., 1977; Aranyi et al., 1983; Ehrlich, 1980, 1983; Grose et al., 1980, 

1982; Phalen et al., 1980; Goldstein et al., 1974). Studies have also indicated 

that the activity level of the test subject is an important variable that can 

influence the determination of the lowest effective concentration of the 

pollutant (Illing et al., 1980). 

12-49 
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 toxicological response occurring in humans, then the end point for comparison of such 

studies should be morbidity rather than mortality. A better comparison in 

humans would be the increased prevalence of respiratory illness in the community. Such a comparison is proper since both mortality (animals) and morbidity (humans) result from an impairment in pulmonary defenses. Ideally, 

studies of pulmonary host defenses should be performed in.man using epidemiological or volunteer methods of study. Unfortunately, such studies have not 

yet been reported. Therefore, attention must be paid to experiments conducted 

with animals. 

Present knowledge of the physiology, metabolism, and function of host 

defense systems has come primarily from various animal systems, but it is 

generally accepted that the basic host defence mechanisms are similar in 

animals and man. Green (1984) recently delineated the many similarities that 

exist between the rodent and human antibacterial defenses. Both defenses 

consist of the same defense components, which together act to maintain the 

lung free of bacteria. The effects seen in animals represent alterations in 

basic biological systems. An equivalent response (e.g., mortality) may not be 

expected in man, but similar alterations in basic defense mechanisms could 

occur in humans because they possess pulmonary defense systems equi.valent to 

those in laboratory animals. It is understood that different exposure levels 

may be required to produce similar responses in humans. The concentrations of 

03 at which effects become evident can be influenced by a number of factors, 

such as preexisting disease, dietary factors, combinations with other pollutants, 

and the presence of other environmental stresses. Although not confirmed by 

experimental data, it is possible that humans exposed to 0 3 could experience 

decrements in host defenses; but at the present time, the exact concentration 

at which effects might occur in man cannot be predicted, nor can the severity 

of the effect. 

12.3.8 Extrapulmonary Effects of Ozone 

Because of the high degree of reactivity of 03 with biological tissue, it 

is not clear whether 0 3 reaches the circulation. Results from mathematical 

modeling (Miller et al., 1985) suggest that only a small fraction of 03 can 

penetrate the air-blood barrier. Several studies discussed in Chapters 9 and 

12-50 
10 are indicative, however, of either direct or indirect extrapulmonary effects 

of ozone exposure. For example, alterations in red blood cell morphology and 

enzymatic activity, as well as cytogenetic effects in circulating lymphocytes, 

have been reported in man and laboratory animals. Other organ systems of the 

body may also be involved. Exposure to 0 3 may have central nervous system 

effects, since subjective limitations in performance of vigilance tasks have 

been observed in man and laboratory animals. Cardiovascular, reproductive, 

and teratological effects of 0 3 have also been reported in laboratory animals, 

along with changes in endocrine function; but the implications of these findings 

for human heaith are difficult to judge. More recent studies in laboratory 

animals have shown that hepatic metabolism of xenobiotic compounds may be 

impaired by 03 inhalation. While some of these systemic effects, such as 

decrements in exercise and vigiiance performance, may be attributed to odor 

perception or respiratory irritation, the reasons for the others are more 

difficult to conceptualize. These effects may result from direct contact with 

03 or, more likely, from contact with a reactive product of 0 3 that penetrates 

to the blood and is transported to the other organs. 

Cytogenetic and mutational effects of ozone are controversial. Tn human 

cells in culture, a significant increase in the frequency of sister chromatid 

exchanges has been reported to occur after exposure to concentrations of ozone 

as low as 0.25 ppm for 1 hr (Guerrero et al., 1979). Lymphocytes isolated 

from animals were found to have significant increases in the numbers of chromosome .(Zelac et ai., 1971a,b) and chromatid (Tice et al., 1978) aberrations, 

after 4- to 5-hr exposures to 0.2 and 0.43 ppm ozone, respectively. Singlestrand breaks in DNA of mouse peritoneal exudate cells were measurable after a 

24-hr exposure to 1 ppm ozone (Chaney, 1981). Gooch et al. (1976) analyzed 

the bone marrow samples from Chinese hamsters exposed to 0.23 ppm of 0 3 for 

5 hr and the leukocytes and spermatocytes from mice exposed for up to 2 weeks° 

to 0.21 ppm of 0 3 . No effect was found on either the frequency of chromatid 

or chromosome aberrations, nor were there any reciprocal translocations in the 

primary spermatocytes. Small increases observed in chromatid lesions in 

peripheral blood lymphocytes from humans exposed to 0.5 ppm ozone for 6 or 10 

hr were not significant because of the small number (n=6) of subjects studied 

(Merz et al., 1975). Subsequent investigations, however, with more human 

subjects exposed to ozone at various concentrations and for various times have 

failed to show any cytogenetic effect considered to be the result of ozone 

12-51 
exposure (McKenzie et al., 1977; McKenzie, 1982; Guerrero et al., 1979). In 

addition, epidemiological studies have not shown any evidence of chromosome 

changes in peripheral lymphocytes of humans exposed to ozone in the ambient 

environment (Scott and Burkart, 1978; Magie et al., 1982). Clearly, additional 

evaluation of potential chromosomal effects in humans exposed to 03 is needed. 

Evidence now available, however, fails to demonstrate any cytogenetic or. 

mutagenic effects of ozone in humans when exposure schedules are used that are 

representative of exposures that the population at large might actually experience. 

With the exception of peripheral blood lymphocytes, the potential genotoxic 

effects of ozone for all of the other body tissues are unknown. No cytogenetic 

investigations have been conducted on the respiratory tissues of animals 

exposed to ozone, even though these tissues are exposed to the highest concentrations and are also the target of most of the toxic manifestatio.ns of ozone. 

Clearly, ozone-induced genotoxicity data from peripheral blood lymphocytes 

cannot be extrapolated to other organs, such as the lungs or reproductive 

organs. 

Ozone exposure produces a number of hematological and serum chemistry 

changes both in rodents and man, but the physiological significance of these 

effects is unknown. Most of the hematological changes appeared to be linked 

to a decrease in RBC GSH content (Menzel et al., 1975; Buckley et al., 1975; 

Posin et al., 1979; Linn et al., 1978) at concentrations of 0.2 ppm for 30 to 

60 min in man, or 0.5 ppm for 2.75 hr in sheep, or 0.5 ppm continuously for 

5 days in mice and rats. Heinz bodies, disulfide cross-linked methemoglobin 

complexes attached to the inner RBC membrane, were detected in mice exposed to 

ozone (Menzel et al., 1975). Inhibition of RBC acetylcholinesterase was found 

in mouse (Goldstein et al., 1968), human (Buckley et al., 1975), and squirrel 

 monkey RBCs (Clark et al., 1978) at concentrations of 0.4 to 0.75 ppm and 

times as short as 2.75 hr in man or 4 hr/day for 4 days in monkeys.. Loss of 

RBC acetylcholinesterase could either be mediated by membrane peroxidation or 

by loss of acetylcholinesterase thiol groups at the active site. Dorsey 

et al. (1983) observed that the deformability of CD-1 mouse RBCs decreased on 

exposure to 0.7 and 1 ppm for 4 hr. Deformability also decreased at 0.3 ppm, 

but was not statistically significant. These data support the concept of 

membrane damage to circulating RBCs, which appears to be similar in most 

species of animals studied and in normal human RBCs exposed to 0 3 . 

12-52 
12.4 HEALTH EFFECTS IN INDIYIDUALS WITH PREEXISTING DISEASE 

12.4.1 Patients with Chronic Obstructive Lung Disease (COLD) 

Patients with mild COLD have not shown increased responsiveness to 03 in 

controlled human exposure studies. For example, Linn et al. (1982a, 1983b) 

and Hackney et ai. (1983) showed no changes in symptoms or lung function at 

0:12, 0.18, or 0.25 ppm 0 3 (1 hr with intermittent light exercise). Likewise, 

Solic et al. (1982) and Kehrl et al. (1983, 1985) found no significant changes 

in symptoms or function at 0.2 or 0.3 ppm 0 3 (2 hr with intermittent moderate 

exercise). At higher concentrations, however, Kulle et al. (1984) found 

decreased lung function.in a group of 20 smoking chronic bronchitics at 0.4 ppm 

(3 hr with intermittent moderate exercise) on day 1 of exposure and upon 

reexposure at day 9(fourth day following cessation of repeated daily exposures); these subjects were less responsive to 0 3 than healthy nonsmokers. 

There is suggestive evidence that bronchial reactivity is increased in 

some subjects with COLD (two of three) following exposure to 0.1 ppm 0 3 (Konig 

et al., 1980). Small decreases in arterial 0 2 saturation (Sa02 ) have also 

been observed in COLD subjects exercising at 0.12 ppm 0 3 for 1 hr (Linn et 

al., 1982a; Hackney et al., 1983) and at 0.2 ppm 0 3 for 2 hr (Solic et al., 

1982). Decreased Sa0 2 was also-seen at higher 0 3 concentrations but was not 

significant (Linn et al., 1983b; Kehrl et al., 1985). Interpretation of small 

differences in Sa02 or their physiological and c1inical significance is therefore uncertain. In addition, since many of the COLD subjects were smokers, 

the interpretation of small changes in S a0 2 is complicated. Further studies 

are needed to resolve this issue, particularly on COLD subjects exposed to 0 3 

at higher exercise levels. 

One difficulty in attempting to characterize the responsiveness of patients 

with COLD is that they exhibit a wide diversity of clinical and functional 

states. These range from a history of smoking, cough, and minimal functional 

impairment to chronic disability that is usually combined with severe changes 

in blood gases or respiratory mechanical behavior. The chief locus of damage 

may also vary: either the bronchi (chronic bronchitis) or parenchyma (emphysema) may dominate the clinical picture. Finally, the mixture of acute and 

chronic inflammatory processes may vary considerably among patients. Even 

with strict selection criteria, however, it may be very difficult to sort out 

many of these manifestations of COLD in the design of poliutant-exposure 

studies. 

12-53 
12.4.2 Asthmatics 

There is as yet no definitive laboratory evidence demonstrating that mild 

asthmatics are functionally more responsive than healthy.individuals to 0 3 . 

Linn et al. (1978) found no significant changes in lung function, as indicated 

by forced expiratory spirometry or the nitrogen washout test, when a heterogeneous group of adult asthmatics with mild to moderate bronchial obstruction 

was exposed to 0.20 ppm 0 3 for 2 hr with intermittent light exercise; increased 

symptom scores were noted, however. Silverman (1979) found m.inimal changes in 

forced expiratory spirometry following 2-hr exposures of adul -t asthmatics to 

0.25 ppm 03 while at rest. Although group mean changes were not statistically 

significant, one third of the subjects who rested for 2 hr while inhaling 

0.25 ppm 03 demonstrated a greater than 10 percent decrement in lung function. 

Changes of this magnitude have not been reported in normal subjects under 

these conditions. In laboratory field studies with ambient air containing an 

average concentration of 0.17 ppm 0 3 , Linn et a1. (1980) found small but 

statistically significant decrements in forced expiratory measures in both 

healthy and asthmatic adults, following 2-hr exposures with intermittent light 

exercise. The magnitude of functional responses did not differ statistica1ly 

~ between the two groups. Finally, Koenig et.a1. (1985).found no significant 

changes in pulmonary function or symptoms when a group of adolescent subjects 

with atopic, extrinsic asthma were exposed at rest to 0.12 ppm 0 3 for 1 hr. 

The studies reported above are not considered defiinitive since major 

limitations leave open the question of whether the pulmonary function of 

asthmatics is more affected by 0 3 than that of healthy subjects. Intake of 

medication was not controlled in several of the studies, and some subjects 

continued to use oral medication during testing. Adequate characterization of 

subjects is lacking in most studies and, as a result, group mean changes could 

not be detected because of the large variability in responses from such 

heterogeneous groups. For example, some of the subjects in one study (Linn 

et al., 1978) showed evidence of chronic obstructive lung disease in addition 

to asthma. Most of the normal subjects (70 percent) in the Linn et al. (1980) 

study, in which asthmatics were compared to normals, had a history of allergy 

and appeared atypically reactive to the 03 exposure. In addition, the subjects 

in these studies either performed light exercise or rested while exposed. In 

view of the recognized importance of minute ventilation, which increases 

proportionately with the intensity of exercise, in determining the response to 

03 , additional testing at higher levels of exercise should be undertaken. 

12-54 
The specific measurements of pulmonary function and the expo.sure protocols 

employed in the above studies may be inappropriate for ascertaining puimonary 

effects in asthmatic subjects. Asthma is essentially characterized by bronchoconstriction. Compared to airway resistance, some measures of forced expiratory 

spirometry are 'less sensitive tb bronchoconstriction, since fairly severe 

bronchoconstriction must occur in order to affect decrements in these measures. 

McDonnell et al. (1983); reporting on healthy subjects exposed'to levels-of 0 3 

as low as 0.12 ppm with heavy intermittent exercise, attributed small (<5 

percent) decrements in forced expiratory spirometry to a reduced inspiratory 

capacity resulting from stimulation or sensitization of airway receptors by 0 3 

(see Section 12.3.5). They also observed that there was no correlation between 

changes in airway resistance and forced expiratory spirometry for individual 

subjects, which prompted them to postulate two different mechanisms of action. 

It may be that the sensitivity of the mechanism affecting inspiratory capacity 

is the same in asthmatics and normals, while the mechanism affecting airway 

resistance is different. 

Epidemiological findings provide only qualitative evidence of exacerbation 

of asthma at ambient concentrations of 0 3 below those generally associated 

with symptoms or functional,changes in healthy adults. Whittemore and Korn 

(1980) and Holguin et al. (1985) found small increases in the probability of 

asthma attacks associated with previous attacks, decreased temperature, and 

incremental increases in oxidant and 03 concentrations, respectively. Lebowitz 

et al. (1982, 1983, 1985) and Lebowitz (1984) also showed effects in asthmatics, such as decreased peak expiratory flow and increased respiratory symptoms, 

that were related to the interaction of 03 and temperature. A11 of these 

studies have questionable effects from other pollutants, particularly inhalable 

particles. The major problem in epidemiological studies, therefore, has been 

the lack bf definitive information on.the effects of 0 3 alone, since there is 

confounding by the presence of other environmental conditions in ambient air. 

Other factors leading to inconsistencies between epidemiological and controlledlaboratory studies include (1) differences in the pulmonary function tests 

employed, (2) differences in study subjects; since - the general population 

contains individuals with more severe disease than can be studied in controiled 

human exposures, (3) insufficient clinical information in most of these studies, 

or (4) the lack of data on other, unmeasured pollutants and environmental 

conditions in ambient air. 

12-55 
12.4.3 Subjects with Allergy, Atopy, and Ozone-Induced Hyperreactivity 

Allergic or hypersensitivity disorders may be recognized by generalized 

systemic reactions as well as localized reactions in various sites of the 

body. The reactions can be acute, subacute, or chronic; immediate or delayed; 

and may be caused by a variety of physical and chemical stimuli (antigens). 

Although many hypersensitive individuals in the population have a family 

history of allergy, a true allergic reaction is one that is classically elicited 

through an immunological mechanism (i.e., antigen-antibody response), thereby 

distinguishing allergic responses from simple chemical or pharmacologic reactions. There are also some individuals with family histories who develop 

natural or spontaneous allergies, defined generally as atopy. Determination 

of the specific allergens (antigens) responsible for these disorders is often 

difficult, but clinical history, physical examination, skin tests, and selective 

diets are very useful. A more definitive evaluation can be provided by pulmonary function tests (e.g., airway reactivity), serum IgE levels, and nasal 

cytology. The information available on the responsiveness of these individuals 

to ozone, i.e., whether they differ from normal non-allergic, non-atopic 

individuals, is sparse. 

Hackney et al. (1977a) found decreases in spirometric function among 

atopic individuals exposed to 0.5 ppm 0 3 with light intermittent exercise. 

Neither Folinsbee et al. (1978), in a controlled laboratory exposure, nor Linn 

et al. (1980), in a field study in the Los Angeles area, distinguished between 

the responses of normal subjects and allergic non-asthmatic subjects. In the 

latter study, spirometric function was reduced and symptoms were increased in 

association with an average ambient 0 3 concentration of 0.17 ~ ppm. Similarly, 

Lebowitz et al. (1982, 1983) reported, after adjusting for other covariables, 

that 03 and TSP were independently associated with peak flow in adults with 

airway obstructive disease. 

Some healthy subjects with no prior history of respiratory symptoms or 

allergy demonstrate increased nonspecific airway sensitivity resulting from 0 3 

exposure (Golden et al., 1978; Holtzman et al., 1979; Konig et al., 1980; 

Dimeo et al., 1981; Kulle et al., 1982b). Airway responsiveness is typically 

defined by changes in specific airway resistance produced by a provocative 

bronchial challenge to drugs like acetylcholine, methacholine, or histamine, 

administered after 0 3 exposure. In one study (Holtzman et al., 1979), in 

which subjects were classified as atopic or nonatopic based on medical history 

12-56 
and allergen skin testing, the induction and time course of increased bronchial 

reactivity after exposure to 0 3 were unrelated to the presence of atopy. An 

association of 03-induced increases in airway responsiveness with airway 

inflammation has been reported in.dogs at high 0 3 concentrations (l,to 3 ppm) 

(Holtzman et al., 1983a,b; Fabbri et al., 1984); and in sheep at 0.5 ppm 0 3 

(Sieiczak et a1., 1983). Little is known, however, about this relationship in 

animals at lower 03 concentrations (<0.5 ppm), and the possible association 

between 03-induced inflammation and airway hyperresponsiveness in human subjects 

has not been explored systematically. 

12.5 EXTRAPOLATION OF EFFECTS OBSERVED IN ANIMALS TO HUMAN POPULATIONS 

12.5.1 Species Comparisons 

Comparisons of the effects of ozone on different animal species are of 

value in attempting to understand whether man might experience similar effects. 

Two criteria are useful for judging whether effects seen in animals may plausibly be expected to occur in man: (1) the same effects occur in multipie 

animal species; and (2) the mechanisms of toxicity underlying the observed 

effects are common across animal species and between animals and man. Thus, 

if only one of several tested species experienced a given effect of ozone, 

this effect might be species-specific and might not occur in man. Conversely, 

if several animal species, with all their inherent differences, shared a given 

effect of ozone, it would be reasonable to infer that all mammalian species, 

including man, wouid be susceptible to that effect from ozone. A commonality 

of effects across species would be expected, provided the effects were related 

to mechanisms that are shared across species. In the case of ozone, the 

proposed major molecular mechanisms of action are the oxidation of polyunsaturated fatty acids and the oxidation of thiols or amino acids in tissue 

proteins or lower-molecular=weight peptides. Since the affected molecules are 

identical across all species, then any differences in the observed responses 

between species would be a function of species differences in other factors, 

such as delivered doses or subsequent processes of injury and repair. For 

example, a likely target site for 0 3 toxicity is the cellular membrane, such 

as the membrane of cells like the Type 1 and ciliated cells that cover a large 

surface area of the respiratory tract. Since there are no major interspecies 

differences in cell membranes, and membranes are composed of proteins and 

12-57 
lipids, then both proposed molecular mechanisms of 0 3 toxicity could occur at 

the cellular membrane. In fact, the two proposed mechanisms most likely occur 

simultaneously. Although the mechanisms of toxicity would be common across 

species, the consequent toxic impact on the membrane, the cell, and surrounding 

tissue would be influenced by species-specific differences, such as antioxidant 

defenses or repair mechanisms. Even if both criteria cited above are met, it 

does not imply that the concentrations at which man might experience the 

observed effects are the same as those eliciting the effects in experimental 

animals. 

The health data base for ozone includes hundreds of studies in about 

eight species, and even more strains, of laboratory animals., Generally, for a 

given effect, whether it be on lung morphology, physiology, biochemistry, or 

host defenses, all species tested have been responsive to ozone, albeit 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 species have been 

conducted after ozone exposure. In the groups studied; there are significant 

differences in lung structure. Man, nonhuman primates, and dogs have both 

nonrespiratory and respiratory bronchioles, while respiratory bronchioles are 

either absent or poorly developed in mice, rats, and guinea pigs. Additional 

differences exist. Nonetheless, a characteristic ozone lesion occurs at the 

junction of the conducting airways and the gaseous exchange tissues, regardless 

of species differences in structure. The typical effect in all the species 

examined is damage to ciliated and Type 1 cells and hyperplasia of nonciliated 

bronchiolar cells and Type 2 cells. An increase in inflammatory cells is also 

observed. Such changes have been observed after a 7-day intermittent exposure 

of monkeys to 0.2 ppm (Dungworth et al., 1975; Castleman et a1., 1977) and,of 

rats to 0.2 ppm (Schwartz et al., 1976). With different exposure regimens, 

similar effects occur in cats (0.26 ppm, endotracheal tube,, about 6 hr, Boatman 

et al., 1974), mice (0.5 ppm, 35 days, Zitnik et al., 1978), and guinea pigs 

(0.5 ppm, 6 mo, Cavender et al., 1978). For these studies, lower concentrations 

of ozone were not tested. Unfortunately, quantitative comparisons between 

monkey and rat studies is not possible because of inadequate data. Nonetheless, 

responses were roughly equivalent under similar exposure conditions in these 

two species, even though major structural differences exist between them. 

12-58 
~{ 

Pulmonary function of eight species of animals has been studied after 

exposure to ozone. Short-term exposure for 2 hr to 0 3 concentrations as low 

as 0.22 ppm produces rapid, shallow breathing. Similar changes in respiration 

have been observed in man during exposure to comparable ozone concentrations, 

as shown in Table 12-4. The onset of these effects is rapid and appears to be 

related to the ozone concentration. In a literature review, Mauderly (1984) 

compared changes in breathing patterns of humans and guinea pigs during and 

after a 2-hr exposure to 0.7 ppm 0 3 . The respiratory frequency increased and 

tidal volume decreased, with similar patterns in these two species during 

exposure, and returned toward normal in the first 3 hr after exposure. 

Enhanced airway reactivity to inhaled bronchoconstrictive agents has also 

been observed in animals and man after 0 3 exposure (Table 12-5). Short-term 

exposure to 0 3 concentrations as low as 0.32 ppm increases airway responsiveness to provocative aerosols such as acetylcholine, carbachol, methacholine, 

or histamine in sheep, dogs, and humans. However, the time course of this 

response may be species-specific. A maximum response is obtained immediately 

after exposure in man but appears to be delayed by 24 hr in sheep and dogs. 

Mauderly (1984) has also compared the effect of 2-hr 0 3 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 smail number of studies having similar experimental procedures 

and similar exposure levels. Other effects of short- and long-term ozone 

exposure on lung function have been observed (Chapter 9), but there are insufficient points of identity in the experiments to permit direct comparisons 

among animal species or between animals and man. 

Species comparisons of host defense against infection are theoretically 

possible, given the abundance of information describing the effect of.exposure 

to photochemical oxidants in mice and other rodents (see Section 12.3.7). 

Therefore, examination of the similarities between host antibacterial defense 

systems i n rodents and man are i n order. Green (1984) has del i neated the 

similarities as follows. Both defense systems consist of an aerodynamic 

12-59 
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12 MlN 
filtration system; a fluid lining layer covering the respiratory membranes; an 

active transport mechanism for removal and inactivation of viable microorganisms; 

pulmonary cells (alveolar macrophages, polymorphonuclear leukocytes); and 

immune secretions of lymphocytes and plasma cells. These similarities provide 

an ideal basis for qualitative extrapolation, since in man and rodents these 

components act in concert to maintain the lung free of bacteria. On the basis 

of 03 exposure data and the similarities in host antibacterial defense systems, 

Goldstein (1984) has drawn the following conclusions. First, sufficient 

similarity exists between the major defense mechanisms in rodents and humans 

to permit the use of the rat as a human surrogate. Second, the pulmonary 

antibacterial system is a sensitive means of assessing potential toxicity of 

oxidants. Third, pollutant-induced abnormalities in the individual components 

of the host defense system permit bacterial proliferation and disease. Fourth, 

results can be qualitatively extrapolated from rodents to humans. Although 

quantitative relationships may also exist, the detailed information is not yet 

available for such extrapolation. Too few studies of antiviral host defenses 

after 03 exposure exist to form any accurate conclusions regarding viral 

infections. 

Rats and monkeys have been examined for changes in lung biochemistry 

following ozone exposure. In these animals exposed for 7 days (8 hr/day) to 

0.8 ppm ozone (DeLucia et 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 in the monkeys. 

The authors referred to "relatively large variations" in the monkey data. 

Oxygen consumption was measured in rats and monkeys after a 7-day (8 hr/day) 

exposure to several levels of ozone (Mustafa and Lee, 1976). Rhesus monkeys 

may have been slightly less responsive than rats. However, at 0.5 ppm ozone, 

bonnet monkeys and rats had roughly equivalent increases. In all of these' 

reports, there was no mention of statistical comparisons between species or of 

power calculations that would indicate whether, under the experimental conditions of data variability, there was equivalent power for statistically detecting effects in both species. In a few of the reports, the number of 

animals was not given. Mustafa et al. (1982) compared mice to three strains 

of rats exposed to 0.45 ppm ozone continuously for 5 days. Antioxidant 

12-62 
metabolism and oxygen consumption were measured. Generally, increases in 

enzyme activities were observed in both species; in several cases the increase 

in the mice was statistically greater than the increase in the rats. 

For extrapulmonary effects, the only species comparison was made by 

Graham et ai. (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 experimentai conditions used, relative species responsivity cannot 

be assessed. 

An analysis of the animal toxicological data for ozone indicates that the 

rat is the species most often tested. Other species often used include mice, 

rabbits, guinea pigs, and monkeys. A few dog, cat, sheep, and hamster studies 

exi st. As has been noted above, very few speci es compari sons can be made 

because of differences in exposure regimens and measurement techniques. Even 

when direct comparisons are possible, interpretation,is difficult. Statements 

regarding responsiveness can be made, but statements about sensitivity (e.g., 

responses to an equivalent delivered dose) cannot be made untii more dosimetry 

and other types of data are available. Nonetheless, even with the wide variation in techniques and experimental designs, acute and subchronic exposures to 

levels of ozone less than 0.5 ppm produce remarkably similar types of responses 

in many species of animals. Thus, it may be hypothesized that man experiences 

more types of effects from exposure to ozone than can be deduced from human 

studies. Types of effects for which substantial animal data bases exist 

include changes in lung structure, biochemistry, and host defenses. However, 

the risks.toman from breathing ambient levels of ozone cannot fully be determined until quantitative extrapolations of animal results can be made. 

12.5.2 Dosimetry Modejing 

Dosimetry refers to determination of, the amount of ozone that reaches 

specific sites in animals and man, while sensitivity relates to the likelihood 

of equivalency of biological response given the del.ivery, of the same dose of 

ozone to a target site in different species. A coupling of these two elements 

is required to permit quantitative interspecies comparisons of toxicological 

results from different experiments. 

Although additional research is needed on dosimetry and on species sensitivity before quantitative extrapolations can confidently be made between 

species, oniy dosimetry is sufficiently advanced for discussion here. Because 

12-63 
the factors affecting the transport and absorption of 0 3 are general to animals 

and man, dosimetry models can be formulated that use appropriate species 

anatomical and ventilatory parameters to describe 0 3 absorption. Thus far, 

theoretical modeling efforts (McJilton , et al., 1972; Miller et al.,_1978b, 

1985) have focused on the lower respiratory tract. 

Largely because of the technical ease of ineasuring ozone uptake in the 

head, nasopharyngeal removal of ozone has been experimentally studied in the 

dog (Vaughan et al., 1969; Yokoyama and Frank, 1972; Moorman et al., 1973), 

rabbit (Miller et al., 1979), and guinea pig (Miller et al., 1979). To date, 

information on nasopharyngeal removal of 0 3 in man is not available. Since 

nasopharyngeal removal of 03 serves to lessen-the insult to lower respiratory 

tract tissue, an assessment of species differences in this area is critical to 

interspecies comparisons of dosimetry. 

Damage to all respiratory tract regions occurs in animals exposed to 0 3 , 

with location and intensity dependent upon concentration and exposure duration. 

When comparisons are made at the analogous anatomical sites, the morphological 

effects of 0 3 on the lungs of a number of animal species are remarkably similar. 

Despite inherent differences in the anatomy of the respiratory tract between 

various experimental animals and man, the junction between the conducting 

airways and the gas exchange region is the site most severely damaged by 0 3 

exposure in animals (see Section 9.3.1). This finding is consistent with the 

inference that this region is also most likely the principal site affected in 

man. Dosimetry model simulations (Miller et al., 1978b) predict that the 

maximal tissue dose occurs at the region of predominant morphological damage 

in animals. The overall similarity of the predicted 03 dose patterns in 

animal lungs studied thus far (rabbits and guinea pigs) extends to the simulation of 03 uptake in humans (Miller et al., 1985) (see Section 9.2.3.1). 

The consistency and similarity of the human and animal lower respiratory 

tract dose curves lend strong support to the feasibility of extrapolating to 

man the results obtained from animals exposed to 0 3 . In the past, extrapolations have usually been qualitative in nature. With additional research in 

areas that are basic to the formulation of dosimetry models, quantitative 

dosimetric differences among species can be determined. If, in addition, more 

information is obtained on species sensitivity to a given dose, significant 

advances can be made in quantitative extrapolations of effects from exposure 

to 0 3 . Since animal studies are the only available approach for investigating 

12-64 
the full array of potential effects induced by exposure to 0 3 , quantitative 

use of animal data is in the interest of better establishing the 0. 3 levels to 

which man can safely be exposed. 

12.6 HEALTH EFFECTS OF OTHER PHOTOCHEMICAL OXIDANTS AND POLLUTANT MIXTURES 

Ozone is considered to be chiefly responsible for the adverse effects of 

photochemical air pollutants, largely because of its relative abundance compared 

with other photochemical oxidants. Still, the coexistence of other reactive 

oxidants (Section 12.2.2) suggests that the potential effects of other ambient 

oxidants should be examined. Animal and clinical research, however, has 

centered largeiy on 03 ; very limited effort has been devoted to studies of 

peroxyacetyl nitrate (PAN) and hydrogen peroxide (H 2O2 ). Field and epidemiological studies evaluate health effects associated with exposure to the ambient 

environment, making it difficult to single out the oxidant species responsible 

for the observed effects. 

12.6.1Effects of Peroxyacetyl Nitrate 

There have been too few controlled toxicological studies with the other 

oxidants to permit a sound scientific evaluation of their contribution to the 

toxic action of photochemical oxidant mixtures. The few animal toxicology 

studies on PAN indicate that it is less acutely toxic than 0 3 . When the 

effects seen after exposure to 0 3 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 3 to produce a similar effect on lethality, 

behavior modification, morphology, or significant alterations in host pulmonary 

defense system (Campbell et ai., 1967; Dungworth et al., 1969; Thomas et al., 

1979, 1981a). 

A11 of the available controiled human studies with other photochemical 

oxidants have been limited to a series of reports on the effects of PAN on 

healthy young and middle-aged males during intermittent moderate exercise 

(Smith, 1965; Drinkwater et al., 1974; Raven et al., 1974a,b, 1976; Gliner 

et al., 1975). No significant effects were observed at PAN concentrations of 

0.25 to 0.30 ppm, which are higher than the daily maximum.concentrations of 

PAN reported for , relatively high oxidant areas (0.047 ppm). One study 

(Drechsler-Parks et al., 1984) suggested a possible simultaneous effect of PAN 

12-65 
and 03 ; however, there are not enough data to evaluate the significance of 

this effect. 

Field and epidemiological studies have found few specific relationships 

between reported health effects and PAN concentrations. The increased 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 Administration, 1970; Altshuller, 1977; National Research 

Council, 1977; U.S. Environmental Protection Agency, 1978; Okawada et al., 

1979). In one of these studies (Okawada et al., 1979), eye irritation was 

produced experimentally in high school students at concentrations of PAN 

>0.05 ppm. An increased incidence of other health symptoms such as chest 

discomfort was reported along with eye irritation as PAN concentrations in the 

ambient air increased from 0 to 0.012 ppm (Javitz et al., 1983). However, the 

significance of these symptomatic responses is questionable since functional 

changes reported in this study for the subjects exposed to total oxidants (0 3 

and PAN) were similar to those found for 0 3 alone. 

12.6.2Effects of Hydrogen Peroxide 

Toxicological studies on H 2O 2 have been performed at concentrations much 

higher than those reported to occur in the ambient air (see Section 12.2). The 

majority have been mechanistic studies using various in vitrotechniques for 

exposure. Very limited information is available on the health significance of 

inhalation exposure to gaseous H 2O 2 in laboratory animals. No significant 

effects`were observed in rats exposed for 7 days to >95 percent H 2O 2 gas with 

a concentration of 0.5 ppm in the presence of inhalable ammonium sulfate 

particles (Last et al., 1982). Because H 2O 2 is highly soluble, it is generally 

assumed that it does not penetrate into the alveolar regions of the lung but 

is instead deposited on the surface of the upper airways (Last et al., 1982). 

Unfortunately, no studies have been designed to look for possible effects in 

this region of the respiratory tract. 

A fewin vitro studies have reported cytotoxic, genotoxic, and biochemical 

effects of H2O2 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. 

12-66 
12.6.3Interactions with Other Pollutants 

Controlled human exposures have not consistently demonstrated any enhancement of respiratory effects for combined exposures of 0 3with S02 , NO2 , CO 3 

and H2SO4or other particulate aerosols. Ozone alone is considered to be 

responsible for the observed effects of those combinations or with multiple 

mixtures of these pollutants. Studies reviewed in the previous 0 3criteria 

document (U.S. Environmental Protection Agency, 1978) suggested that mixtures 

of S02and 0 3at a concentration of 0.37 ppm are potentially more active than 

would be expected from the behavior of the gases acting separately (Bates and 

Hazucha, 1973; Hazucha and Bates, 1975). High concentrations of inhalable 

aerosols, particularly H2SO4or ammonium sulfate, could have been responsible 

for the results (Bell et al., 1977). Subsequent studies, however, of 0 3 

mixtures with S0 2 , H2SO4 , 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 ai., 1983). 

Combined exposure studies in laboratory animals have produced varied 

results, depending upon the poliutant combination evaluated, the exposure 

design, and the measured variables. Additive or possibly synergistic effects, 

or both, of 03exposure in combination with NO 2have been described for increased 

susceptibility to bacterial infection (Ehrl-ich et al., 1977, 1979; Ehrlich, 

1980, 1983), morphologicai lesions (Freeman et a1., 1974), and increased 

antioxidant metabolism (Mustafa et al., 1984). Additive or possibly synergistic 

effects from exposure to 0 3and H2 SO4have also been reported for host defense 

mechanisms (Gardner et al., 1977; Last and Cross, 1978; Grose et al., 1982), 

pulmonary sensitivity (Osebold et al., 1980), and collagen synthesis (Last et 

al., 1983), but not for morphology (Cavender et al., 1977; Moore and Schwartz, 

1981). Mixtures of 03and (NH4 ) 2 SO4had synergistic effects on collagen 

synthesis and morphometry, including percentage of fibroblasts (Last et al., 

1983 5 1984a). 

Combining 03with other particulate poilutants produces a variety of 

responses in laboratory animals, depending on the endpoint measured". Mixtures 

of 03 , Fe2 (SO4 ) 3 , H2 SO4 , and (NH4 ) 2SO4produced the same effect on clearance 

rate of particles from the lung as exposure to 0 3alone (Phalen et al., 1980). 

However, in studies measuring changes in host defenses, the combination of 0 3 

with NO 2and ZnSO4(Ehrlich, 1983) or 0 3with S0 2and (NH4) 2504(Aranyi et al., 

1983) produced enhanced effects that can not be attributed to 03only. 

12-67 
Early studies in animals exposed to complex mixtures of UV-irradiated 

auto exhaust containing oxidant concentrations of 0.2 to 1.0 ppm demonstrated 

a greater number of effects compared to those reported for nonirradiated 

exhaust (Chapter 9, Section 5.3). No significant differences were found in 

the magnitude of the response either with or without the presence of `sulfur 

oxides in the mixture. Although the effects described in these studies would 

be difficult to associate with any particular oxidant species, they are qualitatively similar to the general effects described for exposure to 0 3 alone. 

One of the major limitations of field and epidemiological studies includes 

the interference of other pollutants or potential interactions between 0 3 and 

other pollutants in the environment, therefore limiting the usefulness of 

these studies for standard-setting. Concerns raised about the relative contribution to : untoward effects by pollutants other than 0 3 have been diminished 

somewhat by direct comparative findings in exercising athletes showing no 

differences in response between chamber exposures to oxidant-polluted ambient 

air or to purified air containing an equivalent concentration of generated 0 3 

(Avol et al., 1984). Nevertheless, there is still concern that combinations 

of oxidant pollutants, including precursors of oxidants, may contribute to the 

decreased function and exacerbation of symptoms reported in asthmatics 

(Whittemore and Korn, 1980; Linn et al., 1980, 1983a; Lebowitz et al., 1982, 

1983, 1985; Lebowitz, 1984; Holguin et al., 1985) and in children and young 

adults (Lippmann et al., 1983; Lebowitz et al., 1982, 1983, 1985; Bock et al., 

1985; Lioy et al., 1985). Possible interactions between 0 3 and total suspended 

particulate matter have been reported with decreased expiratory flow in children 

(Lebowitz et al., 1982, 1983, 1985; Lebowitz, 1984) and adults with symptoms 

of airway obstructive disease (Lebowitz et al., 1982, 1983). 

The effects of interactions between inhaled oxidant gases and other 

environmental pollutants on the lung have not been systematically studied. In 

fact, one of the major problems with the available literature on interaction 

concerns the exposure design. Most of the controlled studies have not used 

concentrations of combined pollutants that are found in the ambient environment. 

In addition, no studies have been reported that.used exposure regimens for 

combined pollutants that are more representative of ambient ratios of peak 

concentrations, frequency, duration, and time intervals between events, or that 

examined sequential exposures to individual pollutants. 

12-68 
12.7 IDENTIFICATION OF POTENTIALLY AT-RISK GROUPS 

12.7.1 Introduction 

The identification of the population or group to be protected by a national 

ambient air quality standard depends upon a number of factors, including 

(1) the identification of one or more specific bioiogicai endpoints (effects) 

that individuals within the population should be protected from; and (2) the 

identification of those individuals in whom those specific pollutant-induced 

endpoints are (a) observed (b) observed at lower concentrations than in other 

individuals, (c) observed with greater frequency than in other individuals, 

(d) have greater consequences than in other individuals, or (e) observed with 

various combinations of "effects levels," frequency, or consequences. In 

addition to identification of effects and of groups susceptible to those 

effects, other factors such as activity patterns and personal habits, as well 

as actual and potential exposures to the pollutant in question, must be taken 

into account when identifying one or more groups potentially at risk from 

exposure to that pollutant. 

In the following sections, biological and other factors that have been 

found to predispose one or more groups to particular risk from exposure to 

photochemical oxidants' are discussed. It should be noted that these factors 

are discussed in reiation to ozone exposure only. There are too few controlled 

studies with the other oxidants to permit a sound scientific evaluation of 

their contribution to the toxic action of photochemical oxidant mixtures. 

Furthermore, all of the controlled studies to date, both in humans and in experimental animais, have utilized-non-ozone oxidants at levels one order of magnitude 

and more above the concentrations measured in ambient air. The health effects 

of most concern, therefore, are those resulting from exposure to ozone. The 

following sections also include estimates of the number of individuals in the 

United States that fall into certain categories of potentially at-risk groups. 

It must be emphasized that the final identification of those effects that 

are considered "adverse" and the final identification of "at-risk" groups are 

both the domain of the Administrator of the U.S. Environmental Protection Agency. 

12.7.2 Potentially At-Risk Individuals 

All studies have shown that there is a wide variation in sensitivity to 

ozone among healthy subjects. The factors suspected of altering sensitivity 

to ozone are numerous, but those actually known to alter sensitivity are few, 

12-69 
largely because few have been examined adequately to determine definitively 

their effects on sensitivity. The discussion below presents information on the 

factors that are thought to have the potential for affecting sensitivity to 

ozone, along with what is actually known from the data regarding t'he importance 

of these factors. The terms "sensitivity" and "susceptibility" have been used 

interchangeably in the Clean Air Act and are also used interchangeably in this 

discussion. 

Sensitivity to a specified dose of an air pollutant may be greater or 

less than normal. Changes in sensitivity may arise from some prior exposure 

or may result from cross-reactivity to chemicals. Individual differences in 

sensitivity or an unusual response upon exposure cannot be explained at the 

present time. Statistical analysis is generally relied upon to establish the 

range of normal responses for a particular biological endpoint, and to distinguish between normal responses and those that are indicative of either increased 

or decreased sensitivity. 

Susceptibility may be conferred by some predisposing host factor, such as 

immunological or biochemical factors; or by some condition, such as preexisting 

disease. Susceptibility may also result from some aspect of the growth or 

decline of lung development (e.g., greater bronchomotor tone in childhood, 

loss of lung function in the elderly), or some previous infectious or immunological process (e.g., childhood respiratory trouble, prior bronchiolitis or 

other lower respiratory tract infections, and prior asthma). In most human 

studies, the complex diagnostic procedures needed to classify study subjects 

properly are not performed, nor is the mechanism of response usually determined 

or even examined (i.e., underlying immunological, biochemical, or structural 

character). In epidemiological studies, often not even baseline pulmonary 

function pulmonary is determined. Furthermore, even diagnostic labels, such 

as COLD, asthma, allergy, and atopy, are not usually based on sufficient 

clinical evaluation nor standardized inclusion/exclusion criteria, so that 

differences in such classifications within and between studies are bound to 

occur. For example, there are few studies in which bronchoconstrictor 

challenges, skin or blood antibody testing, or similar procedures were performed, let alone radiographic studies, to characterize disease status. 

Airway reactivity is affected by a variety of pharmacologic and non-pharmacologic stimuli. The degree to which different stimuli act in a given 

individual is determined by a complex set of inechanisms that may vary from 

subject to subject and from time to time. Unfortunately, little information 

12-70 
on these aspects of the study population is available so that reliance must be 

placed on limited work-ups, non-standardized clinical evaluations and definitions, and theoretical considerations. Thus, estimates of susceptible groups 

are difficult to assess with any precision with presently available data. 

Anthropomorphic and demographic characteristics that have been used to 

attempt to characterize susceptible individuals in the general population 

include gender, age, race, ethnic group, nutritional status, baseline lung 

function, and immunological status. Many of these factors have implications 

for the acquisition or progress of infectious and chronic diseases. For 

example, the very young and very old members of the population, individuals 

with inadequate nutrition, or individuals with depressed baseline lung function 

may all be predisposed to susceptibility or sensitivity to ozone. None of 

these factors, however, has been sufficiently studied in relation to 0 3 exposure 

to give definitive answers. 

The most prominent modifier of response to 0 3 in the general population 

is minute ventilation, which increases proportionately with increases in 

exercise workload. Higher ievels of exercise enhance the likelihood of increased frequency of irritative symptoms and decrements in forced expiratory 

volume and flow. However, even in well-controlled experiments on apparently 

homogeneous groups of healthy subjects, physiological responses to the same 

exercise levels and the same 0 3 concentrations have been found to vary widely 

among individuals. 

Exposure history may determine susceptibility or sensitivity. Smokers, 

for example, are more susceptible to impaired defense against infection, have 

some chronic inflammation in the airways, have cellular damage, and may have 

altered biochemical/cellular responses (e.g., reduced trypsin inhibitory 

capacity, neutrophilia, impaired macrophage activity). Likewise, those with 

"significant" occupational exposures to irritants, sensitizers or allergens 

may have similar predispositions. Furthermore, both groups show differential 

immunological status, atopy, and, in some cases, bronchomotor tone. Despite 

these inferences, there is some evidence to suggest that smokers may be less 

sensitive to 03 , although the available data are not conclusive. 

Social, cultural, and economic factors, especially as they affect nutritional status (e.g., vitamin E intake, anemia), may be important. While 

 animal studies with vitamin E indicate that differential responses may be 

related to nutrition, no evidence exists to indicate that man would benefit 

from increased vitamin E intake in relation to ambient ozone exposures. 

12-71 
Another determinant of sensitivity is preexisting disease. Asthmatics, 

who have variable airflow obstruction or reversible airway reactivity, or 

both, and who may have altered immunological states (e.g., atopy, increased 

immunoglobulin-E, possibly altered prostaglandin function and/or T-cell function) or cellular function (e.g., eosinophilia), may be expected to be potentially more sensitive to 03 . Asthma, however, is not a specific homogeneous 

disease and efforts to define asthma precisely have been unsuccessful. Likewise, allergic individuals, with a predisposing atopy, have altered immunological responses, similar to those in asthmatics, and may have labile bronchomotor 

tone, such that they may also be expected to be potentially more sensitive to 

03 . Patients with COLD may be expected to have a variable sensitivity to 0 3 , 

since they exhibit a wide diversity of clinical and functional states (see 

Section 12.4.1). Although currently available evidence indicates that individuals with preexisting disease respond to 03 exposure to a similar degree as 

rtormal 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 0 3 can be adequately 

determined. Furthermore, it should be noted that ethical constraints have 

precluded the testing in controlled studies of individuals with severe preexisting disease. It is also prudent to consider carefully whether small 

functional change,s in individuals with COLD, asthma, or allergy represent 

equivalent or more severe physiological significance compared to the normal 

sub ject. 

12.7.3Potentially At-Risk Groups 

As the precedi ng di scussi on and di scussi ons i n Secti ons 12.3 and 12.4 

indicate, only small samples of the population, either of healthy individuals 

or those with preexisting disease, have been tested. Definitive data on the 

relative susceptibilities to ozone of various kinds of individual subjects are 

therefore lacking, both in epidemiological and controlled-exposure studies. 

Notwithstanding the uncertainties that exist in the data, it is possible to 

identify the groups that might be at potential risk from ozone-induced effects 

if exposed under certain conditions. The following discussion deals with 

potential risk only, not actual risk. Actual risk must be estimated (1) in 

conjunction with actual exposure to ozone, as opposed to potential exposure; ` 

(2) in conjunction with any factors known to modify the effects of ozone, such 

12-72 
as exercise; and (3) in conjunction with the existing uncertainties in the 

data on the effects of ozone from controlled, field, or epidemiologic studies. 

In the legislative history of Section 109 of the Clean Air Act (U.S. 

Senate, 1970), the definition of a"sensitive population" excludes "individuals 

who are otherwise dependent on a controiled internal environment" but includes 

"particularly sensitive citizens ... who in the normal course of daily 

activity are exposed to the ambient environment." Early research demonstrated 

that the respiratory system is affected by exposure to certain air pollutants, 

including ozone, nitrogen dioxide, and other oxidants. As a consequence, 

Congress took note of pollutant effects on the respiratory system and gave 

bronchial asthmatics and emphysematics as examples of "particularly sensitive" 

individuals. With regard to research on health effects, Congress has noted 

that attention should go beyond "normal segments of the population to effects 

on the very young, the aged, the infirm, and other susceptible individuals." 

Concern should be given to the "contribution of age, ethnic, social, 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 group that appears to be at potential risk from exposure 

to ozone is that group of the general population characterized as having 

preexisting respiratory disease. In the case of asthmatics, in particular, 

emerging data from controlled studies indicate no greater responsiveness.to 

ozone in mild asthmatics than in the normal,'healthy population. Data from 

epidemiological studies continue to introduce an element of uncertainty 

regarding the potential risk from exposure to ambient air in asthmatics. The 

epidemiological studies, however, lack definitive information on the effects 

of ozone aione, since there is confounding by the presence of other pollutants 

(e.g., inhalable particles) and environmental conditions (e.g., temperature) 

in ambient air (see Section 12.4.2). Furthermore, it must be emphasized that 

neither controlled nor epidemiological or field studies give any indication 

that asthmatics are less responsive to ozone exposure than healthy individuais. 

In the case of individuals with COLD, clinical and functional states vary 

widely, and responsiveness to ozone exposure may also vary accordingly (see 

Section 12.4.1). 

Nevertheless, several important considerations place individuals with 

preexisting respiratory disease among groups at potential risk from exposure 

to ozone. First, it must be noted that concern with triggering untoward 

reactions has necessitated the use of low concentrations and low exercise 

12-73 
levels in most studies on subjects with preexisting disease as well as the 

involvement only of subjects clinically diagnosed as having mild-to-moderate, 

but not severe, disease. As a result, few or no data on responses at higher 

concentrations, at higher exercise levels, or in subjects with more severe 

disease states are available for comparison with responses in normal subjects. 

Second, subjects in controlled studies may not have been adequately characterized 

in all instances regarding disease state. Thus, definitive data on the modification by preexisting disease of responses to ozone are not available. Third, 

the effects that ozone may have on groups with preexisting disease may not be 

measured by traditional tests of lung function and the identification of such 

effects may require the use of different tests or may have to await new 

technological developments. Finally, it must be emphasized that in individuals 

with already compromised pulmonary function, the decrements in function produced 

by exposure to ozone, while similar to or even the same as those experienced 

by normal subjects, represent a further decline in volumes and flows that are 

already diminished. It is possible that such declines may impair further the 

ability to perform normal activities involving exercise. Although many individuals with preexisting disease would not be expected to exercise 'at the levels 

at which healthy individuals exercise, any increase in activity level would 

bring about a commensurate increase in minute ventilation, which is a potentiator 

of ozone-induced effects. In individuals with preexisting diseases such as 

asthma or allergies, increases in symptoms upon exposure to ozone, above and 

beyond symptoms seen in the general population, may also impair or further 

curtail the ability to function normally. 

The second group at potential risk from exposure to ozone consists of the 

general population of normal, healthy individuals (i.e., not diagnosed as 

having preexisting respiratory disease). Data presented in Chapter 10 and 

discussed in preceding sections of this chapter indicate that two factors 

place members of the general population at potential risk from exposure to 

ozone: (1) unusual responsiveness to ozone in some members of the general 

population; and (2) potentiation by exercise of the effects induced by ozone 

at any given concentration. 

Unusual responsiveness to ozone has been observed in some individuals 

("responders"), not yet characterized medically except by their response to 

ozone, who experience greater decrements in lung function from exposure to 

ozone than the average response of the groups studied. It is not known if 

12-74 
"responders" are a specific population subgroup or simply represent the upper 

5 to 20 percent of the ozone response distribution. As yet no means of determining in advance those members of the general population who are "responders" 

has been devised. It is important to note here what has been discussed previously in.this chapter and in Chapter 10; that is, the group means presented in 

Chapter 10 (and the references therein) and in Figures 12-2 through 12-5 (and 

Table 12-3) include values for the "responders" in the respective study cohorts 

of otherwise healthy, normal subjects; and reflect the sometimes dramatic 

decrements seen in those individuals. 

Data presented in Chapter 10 and in this chapter underscore the importance 

of exercise in the potentiation of effects from exposure to ozone. Thus, the 

general population potentially at risk from exposure to ozone includes those 

individuals whose.activities out of doors, whether vocational or avocational, 

result in increases in minute ventilation. As stated in section 12.7.2, "the 

most prominent modifier of response to 0 3 in the general population is minute 

ventilation, which increases proportionateiy with increases in exercise workload." 

As pointed out in this chapter, other biologicai and nonbiological factors 

are suspected of influencing responses to ozone.. Data remain inconclusive at 

the present, however,, regarding the importance of age, gender, and other 

factors in influencing response to ozone. Thus, at the present t.ime, no 

groups are thought to be at potential risk from exposure to ozone in ambient 

air through biological predisposition or activity patterns other than those 

identified in this section. 

12.7,4 Demographic Distribution of the General Population 

The U.S. Bureau of the Census periodically provides an updated statistical 

summary of the U.S. population by conducting a decennial survey, supplemented 

by monthly surveys of representative population samples. The complete census 

represents a total count of the population since an attempt is made to.account 

for. the sociai, economic, and housing characteristics of every residence. . In 

determining residence, the census counts,the place where eating and sleeping 

usually take place rather than counting a person's legal or voting residence. 

Each residence is, in- turn, grouped according to the official standard 

metropolitan statistical areas (SMSA's) and standard consolidated statistical 

areas (SCSA's) as defined by the Office of Management and Budget. Briefly, 

12-75 
SMSA's represent a large population nucleus together with adjacent communities 

which have a high degree of social and economic i.ntegration; SCSA's are large 

metropolitan complexes consisting of groups of closely related adjacent SMSA's. 

Table 12-6 gives the geographical distribution of the resident population of 

the United States for 1980 (U.S. Bureau of the Census, 1982). The entire 

territory of the United States is classified as metropolitan (inside SMSA's) 

or nonmetropolitan (outside SMSA's). According to the 1980 census, the urban 

population comprises all persons living in cities, villages, boroughs, and 

towns of 2500 or more inhabitants. Additional data on age, sex, and race 

obtained from the 1980 census are shown in Table 12-7. Evaluation of previous 

census data indicated a total net underenumeration rate of about 2.2 percent 

in 1970 and 2.7 percent in 1960. Although estimates for 1980 have not been 

published, preliminary results indicated that overall coverage improved in the 

1980 census. Census data presented in Tables 12-6 and 12-7 have not been 

adjusted for underenumeration. 

12.7.5 Demographic Distribution of Individuals with Chronic Respiratory 

Conditions 

Certain subpopulations have been identified as potentially-at-risk to 

ozone or photochemical oxidant exposure by virtue of preexisting respiratory 

conditions like chronic obstructive lung disease (COLD) and asthma. Each year 

the National Health Interview Survey (HIS) conducted by the National Center 

for Health Statistics (NCHS) reports the prevalence of chronic respiratory 

conditions in the United States. These conditions are classified by type, 

according to the Ninth Revision of the International Classification of Diseases 

adopted for use in the United States (World Health Organization, 1977). 

According to NCHS, a condition was considered to be chronic if it had been 

documented by a physician more than three months before the interview was 

conducted. In the HIS for 1979 (U.S. Department of Health and Human Services, 

1981) COLD was not listed as a specific medical condition since it is a clinical 

term and not generally recognized by the general public. However, this term 

has been used with increasing frequency by physicians rather than the more 

common terms chronic bronchitis and emphysema in classifying chronic airways 

obstruction. As a result, there may be an underestimation by the HIS of the 

true prevalence of this disorder. 

12-76 
TABLE 12-6. GEOGRAPHICAL DISTRIBUTION OF THE RESIDENT POPULATION 

OF THE UNITED STATES, 1980 a . 

Population, Population, 

Residence millions percent 

Total 226.5 100.0 

Northeast 49.1 21.7 

North Central 58.9 26.0 

South 75.4 33.3 

West 43.2 19.0 

Metropolitan areas b 169.4 74.8 

Central cities 68.0 30.0 

Outside central cities 101.5 44.8 

Nonmetropolitan areas 57.1 25.2 

Urbanc 167.1 73.7 

Rural 59.5 26.3 

aU.S. Bureau of the Census (1982). 

b 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. 

The estimated prevalence of chronic bronchitis, emphysema, and asthma in 

the United States is shown in Table 12-8 for the year 1979 (U.S. Department of 

Health and Human Services, 1981). A11 three respiratory conditions combined 

accounted for over 16 miilion individuals in 1979, representing 7.5 percent of 

the population. Approximately one-third of the individuals with chronic 

bronchitis and asthma were under 17 years of age. An additional 15 to 16 

million persons reported having hay fever and other upper respiratory allergies. 

Accounting for an underestimation by the HIS, the total number of individuals 

with documented and undocumented respiratory conditions in the United States 

may be as high as 47 million, which is approximately 20 percent of the population. 

12-77 
TABLE 12-7. TOTAL POPULATION OF THE UNITED STATES 

BY AGE, SEX, AND RACE, 1980 a 

Population, Population, 

Age, sex, race millions percent 

Total 226.5 100.0 

Under 5 years 16.3 7.2 

5-17 years 47.1 20.8 

18-44 years 93.3 41.2 

45-64 years 44.4 19.6 

65 years and over 25.5 11.3 

Male 110.0 48.6 

Female 116.5 51.4 

Whiteb 194.8 86.0 

Black 26.6 11.7 

Otherb 5.1 2.3 

aU.S. Bureau of the Census (1982). 

bData represent self-classification according to 15 groups listed on the 1980 

census questionnaire: White, Black, American, Indian, -Eskimo, Aleut, 

Chinese, Filipino, Japanese, Asian Indian, Korean, Vietnamese, Hawaiian, 

Samoan, Guamanian, and Other. 

12.8 SUMMARY AND CONCLUSIONS 

12.8.1Health Effects in the General Human Population 

Controlled human studies of at-rest exposures to 0 3 lasting 2 to 4 hr 

have demonstrated decrements in forced expiratory volume and flow occurring at 

and above 0.5 ppm of 0 3 (Chapter 10). Airway resistance was not significantly 

changed at these 0 3 concentrations. Breathing 0 3 at rest at concentrations 

< 0.5 ppm did not significantly impair pulmonary function although the occurrence of some 0 3-related pulmonary symptoms has been suggested in a number of 

studies. 

One of the principal modifiers of the magnitude of response to 0 3 is 

minute ventilation (VE ), 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 VE not only increase the overall.. volume of inhaled pollutant, but 

the increased tidal volume may lead to a higher concentration of ozone in the 

12-78 
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high work loads (VE > 35 L/min), since the mode of breathing changes at that 

1/E from nasal to oronasal. 

Statistically significant decrements in forced expiratory volume and flow 

are generally observed in healthy adult subjects (18 to 45 yr old) after 1 to 

3 hr of exposure as a function of the level of exercise performed and the 

ozone concentration inhaled during the exposure. Group mean data pooled from 

numerous controlled human exposure (Chapter 10) and field (Chapter 11) studies 

indicate that, on average, pulmonary function decrements occur: 

1. At >0.37 ppm 0 3 with light exercise (VE < 23 L/min); 

2. At >0.30 ppm 0 3 with moderate exercise (VE = 24-43 L/min); 

3. At >0.24 ppm 03 with heavy exercise (VE = 44-63 L/min); and 

4. At >0.18 ppm 0 3 with very heavy exercise (VE > 64 L/min). 

Note, however, that data from specific individual`studies indicate that pulmonary 

function decrements occur with very heavy exercise in healthy adults at 0.15 

to 0.16 ppm 0 3 (Avol et al., 1984) and suggest that such effects may occur 

in healthy adults at levels as low as 0.12 ppm 0 3 (McDonnell et al., 1983). 

Also, pulmonary function decrements have been observed in children and adolescents at concentrations of 0.12 and 0.14 ppm 03 with heavy exercise (McDonnell 

et al., 1985b; Avol et al., 1985a). At the lower 0 3 concentrations (0.12 to 

0.15 ppm), the average changes in lung function are generally small (<5 percent) 

and are a matter of controversy in regard to their medical significance. 

In the majority of the studies reported, 15-min intermittent exercise 

alternated with 15-min rest was employed for the duration of the exposure. 

Figure 12-6 uses the pulmonary function measurement FEV 1 to illustrate the 

effects of intermittent exercise and 0 3 concentration during 2-hr exposures. 

As noted above, larger decrements in lung function occur at higher exercise 

levels and at higher 03 concentrations. The maximum response to 0 3 exposure 

can be observed within 5 to 10 min following the end of each exercise period. 

Other measures of spirometric pulmonary function (e.g., FVC arnd FEF25-75./) are 

consistent with FEV1 and, therefore, are not depicted here. It is important 

to note, however, that any predictions of average pulmonary function responses 

to 03 only apply under the specific set of exposure conditions at which these 

data were derived. 

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12-81 
Continuous exercise equivalent in duration to the sum of intermittent 

exercise periods at comparable ozone concentrations (0.2 to 0.4 ppm) and 

minute ventilation (60 to 80 L/min) seems to elicit greater changes in pulmonary 

function (Folinsbee et al., 1984; Avol et al., 1984, 1985c) but the differences 

between intermittent and continuous exercise are not clearly established. 

More experimental data are needed to make any quantitative evaluation of the 

differences in effects induced by these two modes of exercise. 

Functional recovery, at least from a single exposure with exercise, 

•appears to progress in two phases: during the initial rapid phase, lasting 

between 1 and 3 hr, pulmonary function improves more than 50 percent; this is 

followed by a much slower recovery that is usually completed in most subjects 

within 24 hr. In some individuals, an enhanced responsiveness to a second 0 3 

challenge may persist for up to 48 hr (Bedi et al., 1985; Folinsbee and Horvath, 

1986). In addition, despite apparent functional recovery, other regulatory 

systems may still exhibit abnormal responses when stimulated; e.g., airway 

hyperreactivity may persist for days. 

Group mean changes may be useful for making statistical inferences about 

homogeneous populations, but they are not adequate for describing differences , 

in ,responsiveness to 03 among individuals. Even in well-controlled experiments 

on an apparently homogeneous group of healthy subjects, physiological responses 

to the same work and pollutant loads will vary widely among individuals (Horvath 

et al., 1981; Gliner et al., 1983; McDonnell et al., 1983; Kulle et al., 1985).' 

Despite large intersubject variability, individual responsiveness to a given 

03 concentration is quite reproducible (Gliner et al., 1983; McDonnell et al., 

1985a). Some individuals, therefore, are consistently more responsive to 0 3 

than are others. The term "responders" has been used to describe the 5 to 20 

percent of the studied population that is most responsive to 0 3 exposure. 

There are no clearly established criteria to define this group of subjects. 

Likewise, there are no known specific factors responsible for increased or 

decreased responsiveness to 0 3 . Characterization of individual responses to 

03 , however, is pertinent since it permits the assessment of a segment of the 

general population that is potentially at-risk to 0 3 exposure (see Section 

12.7.3) although statistical treatment of these data is still rudimentary and 

their validity is open to question. 

12-82 
A ciose association has been observed between the occurrence of respiratory 

symptoms and changes in pulmonary function in adults acutely exposed in environmental chambers to 03 (Chapter 10) or to ambi ent ai r contai ni ng 03 as the 

predominant pollutant (Chapter 11). This association holds for both the 

time-course and magnitude of effects. Studies on children and adolescents 

exposed to 0 3 or ambient air containing 0 3 under similar conditions have found 

no significant increases in symptoms despite significant changes in pulmonary 

function (Avol et al., 1985a,b; McDonnell et al., 1985b,c). Epidemiological 

studies of exposure to ambient photochemical pollution are of limited use for 

quantifying exposure-response relationships for 03 because they have not 

adequately controlled for other pollutants, meteorological variables, and 

non-environmental factors in the data analysis. Eye irritation, for example, 

one of the most common complai.nts associated with photochemical pollution, is 

not characteristic of clinical exposures to 0 3 , even at concentrations several 

times higher than any likely to be encountered in ambient air. There is 

limited qualitative evidence to suggest that at low concentrations of 0 3 , 

other respiratory and nonrespiratory symptoms, as well, are more likeiy to 

occur in populations exposed to ambient air pollution than in subjects exposed 

in chamber studies (Chapter 11). 

Discomfort caused by irritative symptoms may be responsible for the 

impairment of athletic performance reported in high school students during 

cross-country track meets in Los Angeles (Chapter 11). Only a few controlledexposure studies, however, have been designed to examine the effects of 0 3 on 

exercise performance (Chapter 10). In one study, light intermittent exercise 

(VE = 20-25 L/min) at a high 0 3 concentration (0.75 ppm) reduced postexposure 

maximal exercise capacity by limiting maximal oxygen consumption; submaximal 

oxygen consumption changes were not significant. The extent of ventilatory 

and respiratory metabolic changes observed during or following the exposure 

appears to have been related to the magnitude of pulmonary function impairment. 

Whether such changes are consequent to respiratory discomfort (i.e., symptomatic 

effects) or are the result of changes in iung mechanics or both is still 

unclear and needs to be elucidated. 

Environmental conditions such as heat and relative humidity may alter 

subjective symptoms and physiological impairment associated with 0 3 exposure. 

Modification of the effects of 0 3 by these factors may be attributed to increased ventilation.associated with elevated body temperature but there may 

12-83 
also be an independent effect of elevated body temperature on-pulmonary function 

(VC)• 

Numerous additional factors have the potential for altering responsiveness 

to ozone. For example, children and older individuals may be more responsive 

than young adults. Other factors such as gender differences (at any age), 

personal habits such as smoking, nutritional deficiencies, or differences in 

immunologic status may predispose individuals to susceptibility to ozone. In 

addition, social, cultural, or economic factors may be involved. Those actually 

known to alter sensitivity, however, are few, largely because they have not 

been examined adequately to determine definitively their effects on sensitivity 

to 03 . The following briefly summarizes what is actually known from the data 

regarding the importance of these factors (see Section 12.3.3 for details): 

1. Age. Although changes in growth and development of the lung with 

age have been postulated as one of many factors capable of modifying responsiveness to 03 , sufficient numbers of studies have not been performed to provide 

any sound conclusions for effects of different age groups on responsiveness 

to 03 . 

2. Sex. Sex differences in responsiveness to ozone have not been 

adequately studied. Lung function of women, as assessed by changes in FEV1.0' 

might be affected more than that of inen under similar exercise and exposure 

conditions, but the possible differences have not been tested systematically. 

3. Smoking Status. Differences between smokers and nonsmokers have 

been studied often, but the smoking histories of subjects are not documented 

well. There is some evidence, however, to suggest that smo,kers may be less 

responsive to 03 than nonsmokers. 

4. Nutritional Status. Antioxidant properties of vitamin E in preventing 

ozone-initiated peroxidation in vitro are well demonstrated and their protective 

effects in yiyo 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. 

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 3 exposure. Even if 03 or a reactive product of 0 3-tissue 

12-84 
interaction were to penetrate the red blood cell after in vivo exposure, it is 

unlikely that any depletion of glutathione or other reducing compounds would 

be of functionai significance for the affected individual. 

Successive daily brief exposures of healthy human subjects to 0 3 (<0.7 ppm 

for approximately 2 hr) induce a typical temporal pattern of response (Chapter 10, Section 10.3). Maximum functional changes that occur after'the first 

or second exposure day become progressively attenuated on each of the subsequent 

days. By the fourth day of exposure, the average effects are not different 

from those observed following control (air) exposure. Individuals need between 

3 and 7 days of exposure to develop full attenuation, with more sensitive 

subjects requiring more time. The magnitude of a peak response to 0 3 appears 

to be directly related to 0 3 concentration. It is not known how variations in 

the length or frequency of exposure will modify the time course of this altered 

responsiveness. In addition, concentrations of 03 that have no detectable 

effect appear not to invoke changes in response to subsequent exposures at 

higher 03 concentrations. Fuil attenuation, even in ozone-sensitive subjects, 

does not persist for more than 3 to 7 days after exposure in most individuals, 

whiie partial attenuation might persist for up to 2 weeks. Although the 

severity of symptoms 'is generally related to the magnitude of the functional 

response, partial attenuation of symptoms appears to persist longer, for up to 

4 weeks after exposure. 

Whether populations exposed to photochemical air poliution develop at 

least partial attenuation is unknown. No epidemiological studies have been 

designed to test this hypothesis and additional information is required from 

controlled laboratory studies before any sound conclusions can be made. 

Ozone toxicity, in both humans and laboratory animals, may be mitigated 

through altered responses at the cellular and/or subcellular level. At present, 

the mechanisms underlying altered responses are unclear and the effectiveness 

of such mitigating factors in protecting the iong-term health of the individual against ozone is still uncertain. A growing body of experimental evidence 

suggests the involvement of vagal sensory receptors in modulating the acute 

responsiveness to ozone. It is highly probable that most of the decrements in 

lung volume reported to result from exposures of greatest relevance to standardsetting (<0.3 ppm 0 3 ) are caused by the inhibition of maximal inspiration rather 

than by changes in airway diameter. None of the experimental evidence, however, 

12-85 
is definitive and additional research is needed to elucidate the precise 

mechanism(s) associated with ozone exposure. 

12.8.2 Health Effects in Individuals with Preexisting Disease 

Currently available evidence indicates that individuals with preexisting 

disease respond to 0 3 exposure to a similar degree as normal, healthy subjects. 

Patients with chronic obstructive lung disease and/or asthma have not shown 

increased responsiveness to 03 in controlled human exposure studies, but there 

is some indication from epidemiological studies that asthmatics may be symptomatically and possibly functionally more responsive than healthy individuals 

to ambient air exposures. Appropriate inclusion and exclusion criteria for 

selection of these subjects, however, especially better clinical diagnoses 

validated by pulmonary function, must be considered before their responsiveness 

to 0 3 can be adequately determined. None of these factors has been sufficiently 

studied in relation to 0 3 exposures to give definitive answers. 

12.8.3 Extrapolation of Effects Observed in Animals to Human Populations 

Animal experiments on a variety of species have demonstrated increased 

susceptibility to bacterial respiratory infections following 0 3 exposure. 

Thus, it could be hypothesized that humans exposed to 0 3 could experience 

decrements in their host defenses against infection. At the present. time, 

however, these effects have not been studied in humans exposed to 0 3 . 

Animal studies have also reported a number of extrapulmonary responses to 

03 , including cardiovascular, reproductive, and teratological effects, along 

with changes in endocrine and metabolic function. The implications of these 

findings for human health are difficult to judge at the present time. In 

addition, central nervous system effects, alterations in red blood cell morphology and enzymatic activity, as well as cytogenetic effects on circulating 

lymphocytes, have been observed in laboratory animals following exposure to 

03 . While similar effects have been described in circulating cells from human 

subjects exposed to high concentrations of 03 , the results were either inconsistent or of questionable physiological significance (Section 12.3.8). It'is 

not known, therefore, if extrapulmonary responses would be likely to occur in 

humans when exposure schedules are used that are representative of exposures 

that the population at large might actually experience. 

12-86 
Despite wide variations in study techniques and experimental designs, 

acute and subchronic exposures of animals to levels of ozone < 0.5 ppm produce 

remarkably similar types of responses in all species examined. A characteristic 

ozone lesion occurs at the junction of the conducting airways and the gasexchange regions of the lung after acute 03 exposure. Dosimetry model simulations predict that the maximal tissue dose of 0 3 occurs in this region of the 

iung. Continuation of the inflammatory process during longer 0 3 exposures is 

especially important since it appears to be correlated with increased airway 

resistance, increased lung collagen content, and remodeling of the centriacinar 

airways, suggesting the development of distal airway narrowing. No convincing 

evidence of emphysema in animals chronically exposed to 0 3 has yet been published, but centriacinar inflammation has been shown to occur. 

Since substantial animal data exist for 0 3-induced changes in lung structure and function, biochemistry, and host defenses, it is conceivable that man 

may experience more types of effects from exposure to ozone than have been 

established in human clinical studies. It is important to note, however, that 

the risks to man from breathing ambient leveis of ozone cannot fully be determined until quantitative extrapolations of animal results can be made. 

12.8.4Health Effects of Other Photochemical`Oxidants and Pollutant Mixtures 

Controlled human studies have not consistently demonstrated any modification of respiratory effects for combined exposures of 0 3 with S02, NO2 , CO, or 

H2SO4 and other particulate aerosols. Ozone alone is considered to be responsible for the observed effects of those combinations or of multiple mixtures 

of these poilutants. Combined exposure studies i'n laboratory animals have 

produced varied results, depending upon the pollutant combination evaluated, 

the exposure design, and the measured variables (Section 12.6.3). Thus, no 

definitive conclusions can be drawn from animal studies of pollutant interactions. There have been far too few controlled toxicological studies with 

other oxidants, such as peroxyacetyl nitrate or hydrogen peroxide, to permit a 

sound scientific evaluation of their contribution to the toxic action of 

photochemical oxidant mixtures. There is still some concern, however, that 

combinations of oxidant pollutants with other pollutants may contribute to the 

symptom aggravation and decreased lung function described in epidemiological 

studies on individuals with asthma and in children and young adults. For this 

reason, the effects of interaction between inhaled oxidant gases and other 

12-87 
environmental pollutants on the lung need to be systematically studied using 

exposure regimens that are more closely representative of ambient air ratios 

of peak concentrations, frequency, duration, and time intervals between events. 

12.8.5 Identification of Potentially At-Risk Groups 

Despite uncertainties that may exist in the data, it is possible to 

identify the groups that may be at potential risk from exposure to ozone, 

based on known health effects, activity patterns, personal habits, and actual 

or potential exposures to ozone. 

The first group that appears to be at potential risk from exposure to 

ozone is that group of the general population characterized as having preexisting respiratory disease. Available data on actual differences in responsiveness between these and healthy members of the general population indicate 

that, under the exposure conditions studied to date, individuals with preexisting disease are as responsive to ozone as healthy individuals. Nevertheless, two primary considerations place individuals with preexisting respiratory 

disease among groups at potential risk from exposure to ozone. First, it must 

be noted that concern with triggering untoward reactions has necessitated the 

use of low concentrations and low exercise levels in most studies on subjects 

with mild, but not severe, preexisting disease. Therefore, few or no.data on 

responses at higher concentrations, at higher exercise levels, and in subjects 

with more severe disease states are available for comparison with responses in 

healthy subjects. Thus, definitive data on the modification by preexisting 

disease of responses to ozone are not available. Second, however, it must be 

emphasized that in individuals with already compromised pulmonary function, 

the decrements in function produced by exposure to ozone, while similar to or 

even the same as those experienced by normal subjects, represent a further 

decline in volumes and flows that are already diminished. It is possible that 

such declines may impair further the ability to perform normal activities. In 

individuals with preexisting diseases such as asthma or allergies, increases 

in symptoms upon exposure to ozone, above and beyond symptoms seen in the 

general population, may also impair or further curtail the ability to function 

normally. 

The second group at potential risk from exposure to ozone consists of the 

general population of normal, healthy individuals. Two specific factors place 

members of the general population at potential risk from exposure to ozone. 

First, unusual responsiveness to ozone has been observed in some individuals 

Hum 
("responders"), not yet characterized medically except by their response to 

ozone, who experience greater decrements in lung function from exposure to 

ozone than the average response of the groups studied. It is not known if 

"responders" are a specific population subgroup or simply represent the upper 

5 to 20 percent of the ozone response distribution. As yet no means of determining in advance those members of the general.population who are "responders" 

has been devised. Second, data presented in this chapter underscore the 

importance of exercise in the potentiation of effects from exposure to ozone. 

Thus, the general population potentially at risk from exposure to ozone includes 

those individuals whose activities out of doors, whether vocational or avocational, 

result in increases in minute ventilation, which is the most prominent modifier 

of response to ozone. 

Other biological and nonbiological factors have the potential for influencing responses to ozone. Data remain inconclusive at the present, however, 

regarding the importance of age, gender, and other factors. in influencing 

response to ozone. Thus, at the present time, no other groups are thought to 

be biologically predisposed to increased sensitivity to ozone. It must be 

emphasized, however, that the final identification of those effects that are 

considered "adverse" and the final identification of "at-risk" groups are both 

the domain of the Administrator of the U.S. Environmental Protection.Agency. 

12-89 
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Wright, J. L.; Lawson, L. M.; Pare, P. D.; Wiggs, B. J.; Kennedy, S.; Hogg, J. 

C. (1983) Morphology of peripheral airways in current smokers and exsmokers. Am. Rev. Respir. Dis. 127: 474-477. 

12-114 
Yokoyama, E. (1969) A comparison of the effects of S02i NO2 and 03 on the 

pulmonary ventilation: guinea pig exposure experiments. Sangyo Igaku 11: 

563-568. 

Yokoyama, E.; Frank, R. (1972) Respiratory uptake of ozone in dogs. Arch. 

Environ. Health 25: 132-138. 

Yokoyama, E.; Ichikawa, I. (1974) Study on the biological effects of atmospheric pollutants (FY 1972-1975). In: Research report for funds of the 

Environmental Agency in 1974. Tokyo, Japan: Institute"of Public Health, 

Department of Industrial Health; pp. 16-1 - 16-6. 

Young, W. A.; Shaw, D. B.; Bates, D. V. (1964) Effect of low concentrations of 

ozone on pulmonai^y function in man. J. Appl. Physiol. 19: 765-768. 

Zeiac, R. E.; Cromroy; H. L.; Boich, W. E., Jr.; Dunavant, B. G.; Bevis, H. A. 

(1971a) Inhaied ozone as a mutagen. I. Chromosome aberrations induced in 

Chinese hamster lymphocytes. Environ. Res. 4: 262-282. 

Zelac, R. E.; Cromroy, H. L.; Bolch, W. E., Jr.; Dunavant, B. G.; Bevis, H. A. 

(1971b) Inhaled ozone as a mutagen. II. Effect on the frequency of chromosome aberrations observed in irradiated Chinese hamsters. Environ. Res. 

4: 325-342. 

Zitnik, L. A.; Schwartz, L. W.; McQuillen, N. K.; Zee, Y. C.; Osebold, J. W. 

(1978) Pulmonary changes induced by low-level ozone: morphological observations. J. Environ. Pathol. Toxicol. 1: 365-376. 

12-115 

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 drapiets ~hat are dispersed or suspended 

in a gas, ranging in size from 10 to 10 micrometers (pm). 

Air spaces: A11 alveolar ducts, alveolar sacs, and alveoli. To be contrasted 

with AIRWAYS. 

Airway conductance (Gaw): Reciprocal of airway resistance. Gaw =(1IRaw). 

Airway resistance (Raw): The (frictional) resistance to airflow afforded by 

the airways between the airway opening at the mouth and the alveoli. 

Airways: A11 passageways of the respiratory tract from mouth or nares down to 

and including respiratory bronchioles. To be contrasted with AIR SPACES. 

Aliergen: 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 jP(A-a)02 ]: The difference in 

partial pressure of 0 in the alveolar gas spaces and that in the systemic 

arterial blood, measu;ed in torr. 

Alveolar-capiliary membrane: A fine membrane (0.2 to 0.4 pm) separating 

alveolus from capiliary; composed of epithelial cells lining the alveolus, 

a thin layer of connective tissue, and a layer of capillary endothelial 

cells. 

Aiveolar carbon dioxide pressure (P CO Partiai pressure of carbon dioxide 

in the air contained in the lA Aveoli. 

Alveolar oxygen partial pressure (P 0): Partial pressure of oxygen in the 

air contained in the alveoli ofA t~ e lungs. 

Alveolar septum (pl. 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. 

f:ID 
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 alveol=i. 

An alveolus is an ultimate respiratory unit where t°he gas exchange takes 

pl ace. 

Anatomical dead space (V): Volume of the conductiyng airways down to the 

level where, durinT a~tbreathing, gas exchange with blood can occur, a 

region probably situated at the entrance of the alveolar ducts. 

Arterial oxygen saturation (Sa0 2): Percent saturation of dissolved oxygen in 

arterial blood. - 

Arterial partial pressure of carbon dioxide (PaCO 2 ): 'Partial pressure of 

dissolved carbon dioxide in arterial blood. - 

Arterial partial pressure of oxygen (Pa02 ): Partial pressure of dissolved 

oxygen in arterial blood. 

Asthma: A disease characterized by an increased responsiveness of the airways 

to various stimuli and manifested by slowing of forced expiration which 

changes in severity either spontaneously or as a result of therapy. The 

term asthma may be modified by words or phrases indicating its etiology, 

factors provoking attacks, or its duration. 

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

phase. 

ATPS condition (ATPS): Ambient temperature and pressure, saturated with water 

vapor. These are the conditions existing in a water spirometer. 

Atropine: A poisonous white crystalline alkaloid, C 1 HNO~ , from belladonna 

and related plants, used to relieve spasms of s

~ 

oo uscles. It is an 

anticholinergic agent. 

Breathing pattern: A general term designating the characteristics of the 

ventilatory activity, e.g., tidal volume, frequency of breathing, and 

shape of the volume time curve. 

Breuer-Hering reflexes (Hering-Breuer reflexes): Ventilatory reflexes originating in the lungs. The reflex ares are formed by the pulmonary mechanoreceptors, the vagal afferent fibers, the respiratory centers, the medullospinal pathway, the motor neurons, and the respiratory muscles. The afferent 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 reflexes 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 disregarded by Breuer and Hering, in which sudden inflation may stimulate 

inspiratory muscles. 

A-2 
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 iumens 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 etiology, its chronicity, the presence of associated airways dysfunction, or 

type of anatomic change. The term chronic bronchitis, when unqualified, 

refers to a condition associated with prolonged exposure to nonspecific 

bronchial irritants and accompanied by mucous hypersecretion and certain 

structural alterations in the bronchi. Anatomic changes may include 

hypertrophy of the mucous-secreting apparatus and epithelial metaplasia, 

as well as more classic evidences of inflammation. In epidemiologic 

studies, the presence of cough or sputum production on most days for at 

least three months of the year has sometimes been accepted as a criterion 

for the diagnosis. 

Bronchoconstrictor: An agent that causes a reduction in the caliber (diameter) 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 le"ft 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 partiai pressure of water vapor as 47 

torr. 

Carbacfioi: A parasympathetic stimulant (carbamoylcholine chloride, C 6H

15 C1N20 2 ) 

that produces constriction of the bronchial smooth muscles. 

Carbon dioxide production (VCO 2 ): Rate of carbon dioxide production by organisms, tissues, or cells. Common units: ml CO 2 (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 2 . 

A-3 
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 alveoiar 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 VENT>~L°AHION and RESISTANCE. 

Collateral ventilation: Ventilation of air spaces via indirect pathways, 

e.g., through pores in alveolar septa, or anastomosing respiratory bronchioles. 

Compliance (CL ,C t): A measure of distensibility. Pulmonary compliance is 

given by thi slope of a static volume-pressure curve at a point, or the 

linear approximation of a nearly straight portion of such a curve, expressed in liters/cm H 0 or ml/cm H 0. Since the static volume-pressure 

characteristics of lunis are nonlin ar (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 ineasurement 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 0, D CO , D CO): Amount of gas (0 

CO 3CO ) commonly expressed is m~' das {~STf~D) c'iffusing between alveol?a

,

r 

gas ang 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 d n ): The ratio of the tidal volume to the change in 

intrapleural press~ure between the points of zero flow at the extremes of 

tidal volume in liters/cm H 0 or ml/cm H2O. Since at the points of zero 

airflow at the extremes of 2tidal volume, volume acceleration is usually 

other than zero, and since, particularly in abnormal states, flow may 

still be taking place within lungs between regions which are exchanging 

volume, dynamic compliance may differ from static compliance, the latter 

pertaining to condition of zero volume acceleration and zero gas flow 

throughout the lungs. In normal lungs at ordinary volumes and respiratory 

frequencies, static and dynamic compliance are the same. 

A-4 
Elastance (E): TheFreciprocal of COMPLIANCE; expressed in cm H 20/liter or cm 

H 20/ml. 

Electrocardiogram (ECG, EKG): The graphic record of the eiectricai currents 

that are associated with the heart's contraction and relaxation. 

Emphysema: A condition of the iung characterized by abnormal, permanent 

enlargement of airspaces distal to the terminal bronchiole, accompanied 

by the destruction of their walls, and without obvious fibrosis. 

Expiratory reserve volume (ERV): The maximal volume of air exhaled from the 

end-expiratory.,level. 

FEVt/FVC: A ratio of timed (t = 0.5, l, 2, 3 s) forced expiratory volume 

(FEVt) to forced vital capacity (FVC). The ratio is often expressed in 

percent 100 x FEV t/FVC. It is an index of airway obstruction. 

Fiow 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 measurement is made. For example: 

FEF75%. = instantaneous forced expiratory flow after 75% 

of`the FVC has been exhaled. 

FEF200-1200 — mean forced expiratory flow between 200 ml 

and 1200 ml of the FVC (formeriy called the 

maximum expiratory flow rate (MEFR). 

FEF25-75% = mean forced expiratory flow during the middie 

half of the FVC [formerly called the maximum 

mid-expiratory flow rate (MMFR)]. 

FEFinax — the maximal forced expiratory flow achieved during 

an FVC. 

Forced expiratory volume (FEV): Denotes the volume of gas which is exhaled in 

a given time interval during the execution of a forced vital capacity. 

Conventionally, the times used are 0.5, 0.75, or 1 sec, symbolized FEVO 5' 

FEV~ 51 FEVl ~ . These values are often expressed as a percent of the 

for e~ vital c pacity, e.g. (FEVI 0/VC) X 100. 

Forced inspiratory vital capacity (FIVC): The maximal volume of air inspired 

with a maximally forced effort from a position of maximal expiration. 

Forced vitai,capacity (FVC): Vital capacity performed with a maximally forced 

expiratory effort. 

A-5 
Functional residual capacity (FRC): .The sum of RV and, ERV (the volume of air 

remaining in the lungs at the end-expiratory position). The method of 

measurement should be indicated as with RV. 

Gas exchange: Movement of oxygen from the alveoli into the pulmonary capillary 

blood as carbon dioxide enters the alveoli from the blood. In broader 

terms, the exchange of gases between alveoli and lung capillaries. 

Gas exchange ratio (R): See RESPIRATORY QUOTIENT. 

Gas trapping: Trapping of gas behind small airways that were opened during 

inspiration but closed during forceful expiration: It is a volume difference between FVC and VC. 

~ 

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

bl ood. 

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 hemy+ 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 amino 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 0/100 ml arterial blood; in mixed venous blood 

at rest it is 13-18 ml 0 2/160 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 P is low in the environment, whether because of 

decreased barometric 0~_essure or decreased fractional concentration of 

0, the condition is termed environmental hypoxia. Hypoxia when referring 

tg the blood is termed hypoxemia. Tissues are said to be hypoxic when 

their P is low, even if there is no arterial hypoxemia, as in "stagnant 

hypoxiaQ2 which occurs when the local circulation is low compared to the 

local metabolism. 

Inspiratory capacity (IC): 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. 

A-6 
Kiiogram-meter/min (kg-m/min): The work performed each min to move a mass of 1 

kg through a" vertical distance of 1 m against the force of gravity. 

Synonymous with kiiopond-meter/min. 

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

conductin~ airways. 

Maximal aerobic capacity (max VO): The rate of oxygen uptake by the body 

during repetitive maximal r ~spiratory 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 orm&xactual volume of the lung at which the measurement is made. ::Modifiers refer to the amount of lung volume remaining 

when the measur,ement is made: For example: 

V = instantaneous forced expiratory flow when the max 75/ lung is at 75% of its TLC. 

V — `instantaneous forced expiratory flow when the 

max 3.0 + lung volume is 3.0 liters 

Maximum expiratory flow rate (MEFR): Synonymous with FEF200-1200' 

Maximum mid-expiratory flow rate (MMFR or MMEF): Synonymous with FEF25-75%' 

Maximum ventilation (max V): The volume of air breathed in one minute during 

repetitive maximal resEpiratory 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 transport. Methemoglobins are formed by various drugs and occur under pathological conditions. Many methods for hemoglobin measurements utilize 

methemoglobin (chlorhemiglobin, cyanhemiglobin). 

Minute ventilation (V ): Volume of air breathed in one minute.It is a 

product of tidal Fbolume (VT ) and breathing frequency (fB ). 

I

See VENTILATION. 

Minute volume: Synonymous with minute ventilation. 

Mucociliary transport: The process by which mucus is transported, by ciliary 

action, from the lungs. 

A-7 
Mucus: The clear, viscid secretion of mucous membranes°; consisting of mucin, 

epithelial cells, leukocytes, and various inorganic salts suspended in 

water. . 

Nasopharyngeal: Relating to the nose or the nasal cavity and the pharynx 

(throat). 

Nitrogen oxides: Compounds of N and 0 in ambient air; ti.e., nitric oxide (NO) 

and others with a higher oxidation state of N, of,,which NO 2 is the most 

important toxicologically. 

Nitrogen washout (AN, dN )• The curve obtained by plotting the fractional 

concentration o ~f N ~'n expired alveolar gas vs. time, for a subject 

switched from breat~ ing ambient air to an inspired mixture of pure 0. A 

progressive decrease of N concentration ensues which may be analy ~ ed 

into two or more exponentqal components. Normally, after 4 min of pure 

0 breathing the fractional N2 concentration in expired alveolar gas is 

dgwn to less than 29o. 

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 2 , QO): Rate of oxygen uptakedof organisms, tissues, 

or cells. Common units~: ml 02 (STPD)/(kg•min) or ml 0(STPD)/(kg•hr). 

For whole organisms the oxygen consumption is commonly &pressed per unit 

surface area or some power of the body weight. For tissue samples or 

isolated cells Q 02 = pl 0 2/hr per mg dry weight. 

Oxygen saturation (SO )• The amount of oxygen combined with hemoglobin, 

expressed as a pA^centage of the oxygen capacity,of that hemoglobin. In 

arterial blood, Sa0 2 . 

Oxygen uptake (V02 ): Amount of oxygen taken up by the body from the environment, 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 2 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 x in the air; an ingredient of photochemical smog. 

. • 
Physiologicai dead space (V ): Calculated volume which accounts for the 

difference betwe~en the $ressures of CO in expired and alveolar gas (or 

arterial blood). Physiological dead s ~ace reflects the combination of 

anatomical dead space and alveolar dead space, the volume of the iatter 

increasing with. the importance of the nonuniformity of the 

ventilation/perfusion ratio in the lung. 

Plethysmograph: A r`igid chamber placed around a iiving structure for the 

purpose of ineasuring changes in the voiume of the structure. In respiratory measurements, the entire body is ordinarily enclosed ("body plethysmograph") 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 th&.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) p.ressure-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 aiveoli 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 fiuid in the lung 

extravascular tissue and air spaces. 

Pulmonary emphysema: An abnormal, permanent enlargement of the air spaces 

distal to the terminal nonrespiratory bronchiole, accompanied by destructive 

changes of the alveolar walls and without obvious fibrosis. The term 

emphysema may be modified by words or phrases to indicate its etiology, 

its anatomic subtype, or any associated airways dysfunction. 

Residual volume (RV): That volume of air remaining in the lungs after maximal 

exhalation. The method of ineasurement should be indicated in the text 

or, when necessary, by appropriate qualifying symbols. 

A-9 
Resistance flow (R): The ratio of the flow-resistive`components of pressure 

to simultaneous flow, in cm H 0/liter per sec. Flow-resistive components 

of pressure are obtained by sgbtracting any elastic or inertial components, 

proportional respectively to volume and volume acceleration. Most flow 

resistances in the respiratory system are nonlinear, varying with the 

magnitude and direction of flow, with lung volume and lung volume history, 

and possibly with volume acceleration. Accordingly, careful specification 

of the conditions of ineasurement is necessary; see AIRWAY RES•ISTANCE, 

TISSUE RESISTANCE, TOTAL PULMONARY RESISTANCE, COLLATERAL RESISTANCE. 

Respiratory cycle: A respiratory cycle is constituted by the inspiration 

followed by the expiration of a given volume of gas, called tidal volume. 

The duration of the respiratory cycle is the respiratory or ventilatory 

period, whose reciprocal is the ventilatory frequency. 

Respiratory exchange ratio: See RESPIRATORY QUOTIENT. 

Respiratory frequency (f): The number of breathing cycles per unit of time. 

Synonymous with bre~thing frequency (f 6 ). ~ 

Respiratory quotient (RQ, R): Quotient of the volume of CO 2 produced divided 

by the volume of 0 consumed by an organism, an organ, or a tissue during 

a given period of 2time. 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 CO output to the 0 uptake by the lungs, "respiratory 

quotient" being 2i^estricted to the2 actual metabolic CO output and 0 

uptake by the tissues. With this definition, respira&ry quotient a~ d 

respiratory exchange ratio are identical in the steady state, a condition 

which implies constancy of the 0 2 and CO2 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-toleft 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 facility. 

A-10 
Static lung compliance (C L ): Lung compliance measured at zero flow (breathholding) over linear }~~ rtion of the volume-pressure curve above FRC. See 

COMPLIANCE. 

Static transpulmonary pressure (P t): Transpulmonary pressure measured at a 

specified lung volume; e.g., ~ stTLC is static recoil pressure measured at 

TLC (maximum recoil pressure). 

Sulfur dioxide (SO ): Colorless gas with pungent odor, released primarily from 

burning of fo2ssii fuels, such as coal, containing sulfur. 

STPD conditions (STPD): Standard temperature and pressure, dry. These are 

the condi ti ons of a vol ume of gas at 0 °C, at 760 torr, wi thout 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 possibie 

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 vo1ume (TGV): Vo1ume of communicating and trapped gas in the 

lungs measured by body plethysmography at specific 1ung 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 VTshould be used. 

Tissue resistance (Rti ): Frictional resistance of the pulmonary and thoracic 

tissues. 

Torr: A unit of pressure equal to 1,333.22 dynes/cm 2or 1.33322 millibars. 

The torr is equal to the pressure required to support a column of inercury 

1 mm high when the mercury is of standard density and subjected to standard 

acceleration. These standard conditions are met 2t 0°C and 45 0latitude, 

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 ineasurement 

should be indicated, as with RV. 

A-11 
Total pulmonary resistance (R ): Resistance measured by relating flow-dependent 

transpulmonary pressure Yo airflow at the mouth. Represents the total 

(frictional) resistance of the lung tissue (Rti ) and the airways (Raw). 

R L= Raw+ 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. 

Transpulmonary pressure (P ): Pressure difference between airway opening 

(mouth, nares, or cankula opening) and the visceral pledral surface, in 

cm H 0. Transpulmonary in the sense used includes extra kpulmonary structurW 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 ventilatory minute volume) which is the product of the tidal volume by the 

ventilatory frequency. Conditions are usually indicated as modifiers; 

i.e., 

VE = Expired volume per minute (BTPS), 

and 

VI = 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 A): 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 tida1 volume minus the volume of the dead space. This truly complete 

expiration volume times the ventilatory frequency constitutes the alveolar 

ventilation. _ 

Ventilation, dead-space (V ): Ventilation per minute of the physiologic dead 

space (wasted ventilRion), BTPS, defined by the following equation: 

Vp = VE (PaCO 2 - P ECO2 )/(PaCO 2 - P I CO2 ) 

Ventilation/perfusion ratio (V /Q): Ratio of the alveolar ventilation to the 

blood perfusion volume f16% through the pulmonary parenchyma. This ratio 

is a fundamental determinant of the 0 2 and CO pressure of the alveolar 

gas and of the end-capillary blood. Through~ ut 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. 

{rU.B. QOVERNMENT PRINTINO'OFFICEI 9 8 6--6 4 6 - 1 1 6/ 4 0 6 4 0' 

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