x-xEPA
United States
Environmental Protection
Agency
Office of Research and
Development
Washington, DC 20460
EPA/600/AP-93/004d
February 1994
External Review Draft
Air Quality
Criteria for
Ozone and
Related
Photochemical
Oxidants
Review
Draft
(Do Not
Cite or
Quote)
Chapter 1.
Executive Summary
and
Chapter 9.
Integrative Summary of
Ozone Health Effects
Notice
This document is a preliminary draft. It has not been formally
released by EPA and should not at this stage be construed to
represent Agency policy. It is being circulated for comment on its
technical accuracy and policy implications.
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DRAFT-DO NOT QUOTE OR CITE EPA/6007AP-93/004c
February 1994
External Review Draf
Air Quality Criteria for Ozone
and Related Photochemical Oxidants
Chapter 1. Executive Summary
and
Chapter 9. Integrative Summary of
Ozone Health Effects
NOTICE
This document is a preliminary draft. It has not been formally
released by EPA and should not at this stage be construed to
represent Agency policy. It is being circulated for comment on
its technical accuracy and policy implications.
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
^ZA) Printed on Recycled Paper
U.S. Environmental Protection Agency
Region 5, Library (PL-12J)
77 West Jackson Boulevard, 12th floor
Chicago, IL 60604-3590
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DISCLAIMER
This document is an external draft for review purposes only and does not constitute
U.S. Environmental Protection Agency policy. Mention of trade names or commercial
products does not constitute endorsement or recommendation for use.
February 1994 IV-ii DRAFT-DO NOT QUOTE OR CITE
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PREFACE
In 1971, the U.S. Environmental Protection Agency (EPA) promulgated National
Ambient Air Quality Standards (NAAQS) to protect the public health and welfare from
adverse effects of photochemical oxidants. In 1979, the chemical designation of the
standards was changed from photochemical oxidants to ozone (O3). This document,
therefore, focuses primarily on the scientific air quality criteria for O3 and, to a lesser extent,
for other photochemical oxidants like hydrogen peroxide and the peroxyacyl nitrates.
The EPA promulgates the NAAQS on the basis of scientific information contained in
air quality criteria documents. The previous O3 criteria document, Air Quality Criteria for
Ozone and Other Photochemical Oxidants, was released in August 1986 and a supplement,
Summary of Selected New Information on Effects of Ozone on Health and Vegetation, was
released in January 1992. These documents were used as the basis for a March 1993
decision by EPA not to revise the existing 1-h NAAQS for O3. That decision, however, did
not take into account some of the newer scientific data that became available after the 1986
criteria document. This revised air quality criteria document for O3 and related
photochemical oxidants critically evaluates and assesses the latest scientific data associated
with exposure to concentrations of these pollutants found in ambient air. Emphasis is placed
on presentation of health and environmental effects data; however, other scientific data are
presented and evaluated in order to provide a better understanding of the nature, sources,
distribution, measurement, and concentrations of O3 and related photochemical oxidants and
their precursors in the environment. The document is not an exhaustive literature review;
rather it assesses the most pertinent literature available through 1993.
The chapters in this volume summarize and interpret key information drawn from the
other, more detailed chapters (Chapters 2 through 8) of the present document, which were
prepared and peer reviewed by experts from various Federal and State governmental offices,
academia, and private industry for use by EPA to support decision making regarding
potential risks to public health and welfare. The Environmental Criteria and Assessment
Office of EPA's Office of Health and Environmental Assessment acknowledges with
appreciation the contributions provided by these authors and reviewers as well as the
diligence of its staff and contractors in the preparation of this document at the request of the
Office of Air Quality Planning and Standards.
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TABLE OF CONTENTS
Page
LIST OF TABLES IV-vii
LIST OF FIGURES IV-viii
AUTHORS, CONTRIBUTORS, AND REVIEWERS IV-ix
U.S. ENVIRONMENTAL PROTECTION AGENCY PROJECT TEAM
FOR DEVELOPMENT OF AIR QUALITY CRITERIA FOR OZONE
AND RELATED PHOTOCHEMICAL OXIDANTS IV-xi
1. EXECUTIVE SUMMARY 1-1
1.1 INTRODUCTION 1-1
1.2 LEGISLATIVE AND REGULATORY BACKGROUND 1-1
1.3 TROPOSPHERIC OZONE AND ITS PRECURSORS 1-1
1.4 ENVIRONMENTAL CONCENTRATIONS, PATTERNS, AND
EXPOSURE ESTIMATES 1-9
1.5 ENVIRONMENTAL EFFECTS OF OZONE AND RELATED
PHOTOCHEMICAL OXIDANTS 1-13
1.6 TOXICOLOGICAL EFFECTS OF OZONE 1-21
1.7 HUMAN HEALTH EFFECTS OF OZONE AND RELATED
PHOTOCHEMICAL OXIDANTS 1-26
1.8 EXTRAPOLATION OF ANIMAL TOXICOLOGICAL DATA
TO HUMANS 1-31
1.9 INTEGRATIVE SUMMARY OF OZONE HEALTH
EFFECTS 1-32
9. INTEGRATIVE SUMMARY OF OZONE HEALTH EFFECTS 9-1
9.1 INTRODUCTION 9-1
9.2 HEALTH EFFECTS OF SHORT-TERM EXPOSURES 9-2
9.2.1 Exposure-Dose Relationships 9-2
9.2.2 Physiological Responses to Ozone Exposure 9-4
9.2.2.1 Respiratory Symptom Responses 9-5
9.2.2.2 Changes in Lung Volume 9-6
9.2.2.3 Responses to Ambient Ozone Exposures 9-7
9.2.2.4 Changes in Airway Resistance 9-7
9.2.2.5 Changes in Breathing Pattern 9-8
9.2.2.6 Changes in Airway Responsiveness 9-8
9.2.2.7 Small Airways Responses 9-8
9.2.2.8 Effects on Exercise Performance 9-9
9.2.3 Exacerbation of Existing Disease 9-9
9.2.3.1 Responses of Asthmatics to Controlled
Ozone Exposure 9-9
9.2.3.2 Increased Hospital Admissions and
Asthma Attacks 9-10
9.2.4 Cellular-Biochemical Responses 9-10
9.2.4.1 Inflammation and Cell Damage 9-10
9.2.4.2 Host Defense 9-14
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TABLE OF CONTENTS (cont'd)
Page
9.2.5 Ozone Exposure-Response Relationships 9-16
9.2.5.1 Prediction and Summary of Mean
Responses 9-20
9.2.5.2 Prediction and Summary of Individual
Responses 9-25
9.3 HEALTH EFFECTS OF LONG-TERM EXPOSURES 9-30
9.3.1 Repeated Exposures 9-30
9.3.2 Prolonged Exposures 9-31
9.3.3 Genotoxicity and Carcinogenicity of Ozone 9-35
9.4 COMBINED POLLUTANT EXPOSURES 9-36
9.5 CONCLUSIONS 9-37
REFERENCES 9-43
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LIST OF TABLES
Number Page
9-1 Gradation of Physiological Responses to Short-Term Ozone
Exposure 9-29
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LIST OF FIGURES
Number Page
9-1 Mean predicted postexposure to preexposure changes in forced
expiratory volume in one second following two-hour exposures
to ozone with intermittent exercise 9-20
9-2 Predicted mean decrements in forced expiratory volume in one
second for one- and two-hour exposures to ozone with
intermittent heavy exercise and 6.6-hour exposures with
moderate prolonged exercise 9-21
9-3 Derived means of bronchoalveolar lavage protein and the
exponential model as tune varies from two to eight hours 9-22
9-4 Predicted mean forced vital capacity for rats exposed to ozone
while undergoing intermittent carbon dioxide-induced hyperpnea . . 9-22
9-5 Predicted mean decrements in forced expiratory volume in one
second following two-hour exposures to ozone while undergoing
heavy intermittent exercise for three age groups 9-25
9-6 The distribution of response for 87 subjects exposed to clean
air and at least one of 0.08, 0.10, or 0.12 ppm ozone is
shown here 9-26
9-7 Proportion of heavily exercising individuals predicted to
experience a 10% decrement in forced expiratory volume in one
second following a one- or two-hour exposure to ozone 9-27
9-8 Proportion of heavily exercising individuals predicted to
experience mild cough following a two-hour ozone exposure .... 9-28
9-9 Proportion of moderately exercising individuals exposed to ozone
for 6.6 hours predicted to experience 5, 10, or 15% decrements
in forced expiratory volume in one second as a function of
concentration times time at 24 years of age 9-28
9-10 Schematic comparison of the duration-response profiles for
epithelial hyperplasia, bronchioloalveolar exudation, and
interstitial fibrosis in the centriacinar region of lung exposed
to a constant low concentration of ozone 9-33
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHAPTER 1. EXECUTIVE SUMMARY
Principal Authors
Mr. James A. Raub—Environmental Criteria and Assessment Office (MD-52),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Mr. William G. Ewald—Environmental Criteria and Assessment Office (MD-52),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. J.H.B. Garner—Environmental Criteria and Assessment Office (MD-52),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Judith A. Graham—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
CHAPTER 9. INTEGRATIVE SUMMARY OF OZONE HEALTH EFFECTS
Principal Authors
Dr. Daniel L. Costa—Health Effects Research Laboratory (MD-82), U.S. Environmental
Protection Agency, Research Triangle Park, NC 27711
Dr. Robert B. Devlin—Health Effects Research Laboratory (MD-58), U.S. Environmental
Protection Agency, Research Triangle Park, NC 27711
Dr. Lawrence J. Folinsbee—Health Effects Research Laboratory (MD-58),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Timothy R. Gerrity—Health Effects Research Laboratory (MD-58), U.S. Environmental
Protection Agency, Research Triangle Park, NC 27711
Dr. Judith A. Graham—Environmental Criteria and Assessment Office (MD-52),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. William F. McDonnell—Health Effects Research Laboratory (MD-58),
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
February 1994 IV-ix DRAFT-DO NOT QUOTE OR CITE
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AUTHORS, CONTRIBUTORS, AND REVIEWERS (cont'd)
Contributors and Reviewers
Dr. Frederick J. Miller—Chemical Industry Institute of Toxicology, P.O. Box 12137,
Research Triangle Park, NC 27709
Dr. Edward S. Schelegle—Department of Human Physiology, School of Medicine,
Building 1-A, Room 4140, University of California, Davis, CA 95616
Dr. Walter S. Tyler—Department of Anatomy, School of Veterinary Medicine, University of
California, Davis, CA 95616
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U.S. ENVIRONMENTAL PROTECTION AGENCY
PROJECT TEAM FOR DEVELOPMENT OF AIR QUALITY CRITERIA
FOR OZONE AND RELATED PHOTOCHEMICAL OXIDANTS
Scientific Staff
Mr. James A. Raub—Health Scientist, Environmental Criteria and Assessment Office
(MD-52), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. A. Paul Altshuller—Physical Scientist, Environmental Criteria and Assessment Office
(MD-52), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Mr. William G. Ewald—Health Scientist, Environmental Criteria and Assessment Office
(MD-52), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. J.H.B. Garner—Ecologist, Environmental Criteria and Assessment Office (MD-52),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Dr. Judith A. Graham—Associate Director, Environmental Criteria and Assessment Office
(MD-52), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Ms. Ellie R. Speh—Secretary, Environmental Criteria and Assessment Office (MD-52),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Ms. Beverly E. Tilton—Physical Scientist, Environmental Criteria and Assessment Office
(MD-52), U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
Technical Support Staff
Mr. Douglas B. Fennell—Technical Information Specialist, Environmental Criteria and
Assessment Office (MD-52), U.S. Environmental Protection Agency, Research Triangle Park,
NC 27711
Mr. Allen G. Hoyt—Technical Editor and Graphic Artist, Environmental Criteria and
Assessment Office (MD-52), U.S. Environmental Protection Agency, Research Triangle Park,
NC 27711
Ms. Diane H. Ray—Technical Information Manager (Public Comments), Environmental
Criteria and Assessment Office (MD-52), U.S. Environmental Protection Agency, Research
Triangle Park, NC 27711
Mr. Richard N. Wilson—Clerk, Environmental Criteria and Assessment Office (MD-52),
U.S. Environmental Protection Agency, Research Triangle Park, NC 27711
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U.S. ENVIRONMENTAL PROTECTION AGENCY
PROJECT TEAM FOR DEVELOPMENT OF AIR QUALITY CRITERIA
FOR OZONE AND RELATED PHOTOCHEMICAL OXIDANTS
(cont'd)
Document Production Staff
Ms. Marianne Barrier—Graphic Artist, ManTech Environmental, P.O. Box 12313,
Research Triangle Park, NC 27709
Mr. John R. Barton—Document Production Coordinator, ManTech Environmental
Technology, Inc., P.O. Box 12313, Research Triangle Park, NC 27709
Ms. Lynette D. Cradle—Lead Word Processor, ManTech Environmental Technology, Inc.,
P.O. Box 12313, Research Triangle Park, NC 27709
Ms. Jorja R. Followill—Word Processor, ManTech Environmental Technology, Inc.,
P.O. Box 12313, Research Triangle Park, NC 27709
Ms. Wendy B. Lloyd—Word Processor, ManTech Environmental Technology, Inc.,
P.O. Box 12313, Research Triangle Park, NC 27709
Mr. Peter J. Winz—Technical Editor, Mantech Environmental Technology, Inc.,
P.O. Box 12313, Research Triangle Park, NC 27709
Technical Reference Staff
Mr. John A. Bennett—Bibliographic Editor, ManTech Environmental Technology, Inc.,
P.O. Box 12313, Research Triangle Park, NC 27709
Ms. S. Blythe Hatcher—Bibliographic Editor, Information Organizers, Inc., P.O. Box 14391,
Research Triangle Park, NC 27709
Ms. Susan L. McDonald—Bibliographic Editor, Information Organizers, Inc.,
P.O. Box 14391, Research Triangle Park, NC 27709
Ms. Carol J. Rankin—Bibliographic Editor, Information Organizers, Inc., P.O. Box 14391,
Research Triangle Park, NC 27709
Ms. Deborah L. Staves—Bibliographic Editor, Information Organizers, Inc.,
P.O. Box 14391, Research Triangle Park, NC 27709
Ms. Patricia R. Tierney—Bibliographic Editor, ManTech Environmental Technology, Inc.,
P.O. Box 12313, Research Triangle Park, NC 27709
February 1994 IV-xii DRAFT-DO NOT QUOTE OR CITE
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i 1. EXECUTIVE SUMMARY
2
3 1.1 INTRODUCTION
4 The external review draft document Air Quality Criteria for Ozone and Related
5 Photochemical Oxidants evaluates the latest scientific information useful in deriving criteria
6 that form the scientific basis for U.S. Environmental Protection Agency (EPA) decisions
7 regarding the National Ambient Air Quality Standards (NAAQS) for ozone (O3). This
8 Executive Summary concisely summarizes key conclusions from the document, which
9 comprises nine chapters. Following this Executive Summary is a brief Introduction
10 (Chapter 2) containing information on the legislative and regulatory background for review of
11 the O3 NAAQS. Chapter 3 provides information on the chemistry, sources, emissions,
12 measurement, and transport of O3 and related photochemical oxidants and their precursors,
13 whereas Chapter 4 covers environmental concentrations, patterns, and exposure estimates of
14 O3 and oxidants. This is followed by Chapter 5, dealing with the environmental effects;
15 Chapters 6, 7, and 8 discuss, respectively, animal lexicological studies, human health effects,
16 and the extrapolation of animal lexicological data to humans. The last chapter, Chapter 9,
17 provides an integrative, interpretative evaluation of heallh effecls associated with exposure to
18 O3. The following subsections follow the chapter organization of the external review draft.
19
20
21 1.2 LEGISLATIVE AND REGULATORY BACKGROUND
22
23 The EPA is required under Sections 108 and 109 of the Clean Air Act to periodically
24 evaluate Ihe air quality criteria thai reflect the latesl scientific information relevant to review
25 of the O3 NAAQS. These air qualily criteria, contained in Ihe criteria document, are useful
26 for indicating the land and extent of all identifiable effects on public health or welfare lhat
27 may be expected from Ihe presence of O3 and related photochemical oxidanls in ambienl air.
28 The lasl criteria documenl was released in 1986, and a supplement was released in 1992.
29 These documents were used as Ihe basis for a March 1993 decision by EPA lo nol revise Ihe
30 existing 1-h NAAQS for O3 al lhal tune. That decision, however, did not take into
31 consideration more recent scientific information that has been published since the last
32 literature review in early 1989. The purpose of this revised criteria documenl, Iherefore, is
33 lo summarize Ihe pertinenl information conlained hi Ihe previous O3 criteria documenl and to
34 critically evaluate and assess Ihe more recenl scientific dala associaled wilh exposure to the
35 concentrations of O3 and related photochemical oxidants that are found hi ambient air.
36
37
38 1.3 TROPOSPHERIC OZONE AND ITS PRECURSORS
39
40 Tropospheric Ozone Chemistry
41
42 Ozone is found in the slratosphere, the "free" troposphere, and the planelary boundary
43 layer (PEL) of the earth's almosphere. Ozone occurs in the stratosphere as Ihe result of
44 chemical reactions initialed by short-wavelength radiation from the sun. In the "free"
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1 troposphere, O3 occurs as the result of incursions from the stratosphere; upward venting
2 from the PEL (the layer next to the earth's surface) through certain cloud processes; and
3 photochemical formation from precursors, notably methane (CF^), carbon monoxide (CO),
4 and nitrogen oxides (NOX). In the PEL, O3 occurs as the result of downward mixing from
5 the stratosphere and free troposphere and as the result of photochemical processes occurring
6 within the PEL.
7
8 The photochemical production of O3 and other oxidants found at the earth's surface
9 (in the PEL, troposphere, or ambient air, used interchangeably in this summary) is the result
10 of atmospheric physical processes and complex, nonlinear chemical processes involving two
11 classes of precursor pollutants, reactive volatile organic compounds (VOCs) and NOX. The
12 only significant initiator of the photochemical production of O3 in the polluted troposphere is
13 the photolysis of nitrogen dioxide (NO2), yielding nitric oxide (NO) and a ground-state
14 oxygen atom that reacts with molecular oxygen to form O3. The O3 thus formed reacts with
15 NO, yielding O2 and NO2. These cyclic reactions attain equilibrium in the absence of
16 VOCs. In the presence, however, of VOCs, which are abundant in polluted ambient air, the
17 equilibrium is upset, resulting in a net increase in O3. Methane is the chief VOC found in
18 the free troposphere and in relatively "clean" areas of the PEL. The VOCs found in polluted
19 ambient air are more complex and more reactive than CH^ but, as with CH4, their
20 atmospheric oxidative degradation is initiated through attack on the VOCs by hydroxyl (OH)
21 radicals. As in the CH4 oxidation cycle, the conversion of NO to NO2 during the oxidation
22 of VOCs is accompanied by the production of O3 and the efficient regeneration of the OH
23 radical. The O3 and peroxyacyl nitrates (PANs) formed in polluted atmospheres increase
24 with the NO2/NO concentration ratio.
25
26 At night, in the absence of photolysis of reactants, the simultaneous presence of 03 and
27 NO2 results in the formation of the nitrate radical, NO3. Reactions with NO3 radicals appear
28 to constitute major sinks for alkenes, cresols, and some other compounds, although alkyl
29 nitrate chemistry is not well characterized.
30
31 Most inorganic gas-phase processes, that is, the nitrogen cycle and its interrelationships
32 with O3 production, are well understood. The chemistry of the VOCs in ambient air is not
33 as well understood. It is well-known, however, that the chemical loss processes of gas-phase
34 VOCs, with concomitant production of O3, include reaction with OH and NO3 radicals and
35 O3, and photolysis. Reaction with the OH radical is the only important atmospheric reaction
36 (loss process) for alkanes, aromatic hydrocarbons, and the higher aldehydes and ketones that
37 lack >C=C< bonds; and the only atmospheric reaction of alcohols and ethers. Photolysis
38 is the major loss process for formaldehyde and acetone. Reactions with OH and NO3
39 radicals and with O3 are all important loss processes for alkenes and for carbonyls containing
40 >C=C< bonds.
41
42 Uncertainties in the atmospheric chemistry of the VOCs can affect quantification of the
43 NO-to-NO2 conversion and of O3 yields; and can present difficulties in representation of
44 mechanisms, products, and product yields in O3 air quality models. Major uncertainties in
45 current understanding of the atmospheric chemistry of the VOCs include (1) chemistry of
46 alkyl nitrate formation, (2) products and reaction rates for > C4 alkanes and for branched
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1 alkanes, (3) mechanisms and products of alkene-O3 reactions, and (4) products of aromatic
2 hydrocarbons in both urban and rural atmospheres.
3
4 It should be noted that the atmospheric chemical processes involved in the
5 photooxidation of VOCs and the formation of O3 and other photochemical oxidants can lead
6 also to the formation of OH radicals and of particulate-phase organic compounds. The OH
7 radicals produced can not only oxidize VOCs but can also react with NO2 and sulfur dioxide
8 (SO2) to form nitric and sulfuric acids, respectively, which become incorporated into aerosols
9 as paniculate nitrate and sulfate.
10
11 Meteorological Influences on Ozone Formation and Transport
12
13 The surface energy (radiation) budget of the earth strongly influences the dynamics of
14 the PEL. The redistribution of energy through the PEL creates thermodynamic conditions
15 that influence vertical mixing. Growing evidence indicates that the strict use of mixing
16 heights in modeling is an oversimplification of the complex processes by which pollutants are
17 redistributed within urban areas; and that it is necessary to treat the turbulent structure of the
18 atmosphere directly and acknowledge the vertical variations in mixing. Energy balances
19 therefore require study so that more realistic simulations can be made of the structure of the
20 PEL.
21
22 Day-to-day variability in O3 concentrations depends heavily on day-to-day variations in
23 meteorological conditions, such as the degree of mixing that occurs between release of a
24 pollutant or its precursors and their arrival at a receptor; the occurrence of inversion layers
25 (layers in which temperature increases with height above ground level); and the transport of
26 O3 left overnight in layers aloft and subsequent downward mixing of that O3 to the surface.
27
28 The transport of O3 and its precursors beyond the urban scale (< 50 km) to neighboring
29 rural and urban areas has been well documented and was described in the 1986 EPA criteria
30 document for O3. Episodes of high O3 concentrations in urban areas are often associated
31 with high concentrations of O3 in the surroundings. Areas of O3 accumulation are
32 characterized by (1) synoptic-scale subsidence of air in the free troposphere, resulting in
33 development of an elevated inversion layer; (2) relatively low wind speeds associated with
34 the weak horizontal pressure gradient around a surface high pressure system; (3) a lack of
35 cloudiness; and (4) high temperatures.
36
37 Ultraviolet (UV) radiation from the sun plays a key role in initiating the photochemical
38 processes leading to O3 formation and affects individual photolytic reaction steps. Still, there
39 is little empirical evidence in the literature linking day-to-day variations in observed UV
40 radiation levels with variations in O3 levels. An association, however, between tropospheric
41 O3 concentrations and tropospheric temperature has been demonstrated. Empirical data from
42 four urban areas, for example, show an apparent upper bound on O3 concentrations that
43 increases with temperature. A similar qualitative relationship exists at a number of rural
44 locations.
45
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1 The relationship between wind speed and O3 buildup varies from one part of the
2 country to another.
3
4 Statistical techniques (e.g., regression techniques) can be used to help identify real
5 trends in O3 concentrations, both intra- and interannual, by normalizing meteorological
6 variability. In the Southern Oxidant Study, for example, regression techniques were
7 successfully used to forecast O3 levels to ensure that specialized measurements were made on
8 appropriate days.
9
10 Precursors
11
12 Nitrogen Oxides Emissions
13
14 Anthropogenic NOX is associated with combustion processes. The primary pollutant
15 emitted is NO formed at high combustion temperatures from the nitrogen and oxygen in air
16 and from nitrogen in the combustion fuel. Emissions of NOX in 1991 in the United States
17 totaled 21.39 Tg. The two largest single NOX emission sources are electric power generation
18 and highway vehicles. Because a large proportion of anthropogenic NOX emissions come
19 from distinct point sources, published annual estimates are thought to be very reliable.
20
21 Natural NOX sources include stratospheric intrusion, oceans, lightning, soils, and
22 wildfires. Lightning and soil emissions are the only two significant natural sources of NOX
23 in the United States. Combined natural sources contribute about 2.2 Tg of NOX to the
24 troposphere over the continental United States. Uncertainties in natural NOX inventories are
25 much larger, however, than for anthropogenic NOX emissions.
26
27 Volatile Organic Compound Emissions
28
29 Hundreds of VOCs, commonly containing from 2 to about 12 carbon atoms, are
30 emitted by evaporative and combustion processes from a large number of source types.
31 Total U.S. VOC emissions in 1991 were estimated at 21.0 Tg. The two largest source
32 categories were industrial processes (10.0 Tg) and transportation (7.9 Tg). Emissions of
33 VOCs from highway vehicles accounted for almost 75 % of the transportation-related
34 emissions; studies have shown that the majority of these VOC emissions come from about
35 20% of the automobiles in service, many, perhaps most, of which are older cars that are
36 poorly maintained. The accuracy of VOC emission estimates is difficult to determine, both
37 for stationary and mobile sources.
38
39 Vegetation emits significant quantities of VOCs into the atmosphere, chiefly
40 monoterpenes and isoprene, but also oxygenated VOCs, according to recent studies. The
41 most recent biogenic VOC emissions estimate for the United States showed annual emissions
42 of 29.1 Tg/year.
43
44 Uncertainties in both biogenic and anthropogenic VOC emission inventories prevent
45 establishing the relative contributions of these two categories.
46
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1 Concentrations of Volatile Organic Compounds in Ambient Air
2
3 The VOCs most frequently analyzed in ambient air are the nonmethane hydrocarbons
4 (NMHCs). Morning concentrations (6:00 a.m. to 9:00 a.m.) have been measured most often
5 because of the use of morning data in the Empirical Kinetics Modeling Approach (EKMA)
6 and in air quality simulation models. Measurements made in 22 cities in 1984 and 19 cities
7 in 1985 showed median NMHC concentrations ranging from 0.39 ppm C to 1.27 ppm C for
8 1984; and from 0.38 ppm C to 1.63 ppm C in 1985. Overall median values from all urban
9 sites were about 0.72 ppm C in 1984 and 0.60 ppm C in 1985.
10
11 Concurrent measurements of anthropogenic and biogenic NMHCs have shown that
12 biogenic NMHCs usually constituted much less than 10% of the total NMHCs. For
13 example, average isoprene concentrations ranged from 0.001 to 0.020 ppm C and terpenes
14 from 0.001 to 0.030 ppm C.
15
16 Concentrations of Nitrogen Oxides in Ambient Air
17
18 Measurements of NOX made in 22 and 19 U.S. cities hi 1984 and 1985, respectively,
19 showed median 6:00-to-9:00 a.m. NOX concentrations ranging from 0.02 to 0.08 ppm hi
20 most of these cities. Nonurban NOX concentrations, reported as average seasonal or annual
21 NOX, range from <0.005 to 0.015 ppm.
22
23 Ratios of 6:00-to-9:00 a.m. nonmethane organic compounds (NMOC) to NOX are
24 higher in southeastern and southwestern U.S. cities than hi northeastern and midwestern U.S.
25 cities, according to data from EPA's multicity studies conducted hi 1984 and 1985. Median
26 ratios ranged from 9.1 to 37.7 hi 1984; hi 1985, median ratios ranged from 6.5 to 53.2 hi
27 the cities studied. Rural NMOC/NOX ratios tend to be higher than urban ratios. Morning
28 (6:00-to-9:00 a.m.) NMOC/NOX ratios are used in the EKMA type of trajectory model. The
29 correlation of NMOC/NOX ratios with maximum 1-h O3 concentrations, however, was weak
30 hi a recent analysis.
31
32 Source Apportionment and Reconciliation
33
34 Source apportionment (now regarded as synonymous with receptor modeling) refers to
35 determining the quantitative contributions of various sources of VOCs to ambient air
36 pollutant concentrations. Source reconciliation refers to the comparison of measured ambient
37 VOC concentrations with emissions inventory estimates of VOC source emission rates for the
38 purpose of validating the inventories.
39
40 Recent findings showed that vehicle exhaust was the dominant contributor to ambient
41 VOCs in seven of eight U.S. cities studied. Whole gasoline contributions have been
42 estimated to be equal to vehicle exhaust in one study and 20 % of vehicle exhaust in a second
43 study.
44
45 Estimates of biogenic VOCs at a downtown site in Atlanta hi 1990 indicated a lower
46 limit of 2 % (24-h average) for the biogenic percentage of total ambient VOCs at that location
47 (isoprene was used as the biogenic indicator species). The percentage varies during the 24-h
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1 period because of the diurnal (e.g., temperature, light intensity) dependence of isoprene
2 concentrations.
3
4 Source reconciliation data have shown disparities between emission inventory estimates
5 and receptor-estimated contributions. For biogenics, emission estimates are greater than
6 receptor-estimated contributions. The reverse has been true for natural gas contributions
7 estimated for Los Angeles, Columbus, and Atlanta; and for refinery emissions in Chicago.
8
9 Analytical Methods for Oxidants and Their Precursors
10
11 Oxidants
12
13 Current methods used to measure O3 are chemiluminescence (CL); UV absorption
14 spectrometry; and newly developed spectroscopic and chemical approaches, including
15 chemical approaches applied to passive sampling devices (PSDs) for O3.
16
17 The CL method has been designated as the reference method by EPA. Detection limits
18 of 0.005 ppm and a response time of < 30 s are typical of currently available commercial
19 instruments. A positive interference from atmospheric water vapor was reported in the
20 1970s and has recently been confirmed. Proper calibration can minimize this source of
21 error.
22
23 Commercial UV photometers for measuring O3 have detection limits of about
24 0.005 ppm and a response time of < 1 min. Because the measurement is absolute, UV
25 photometry is also used to calibrate O3 methods. A potential disadvantage of UV photometry
26 is that atmospheric constituents that absorb 254 nm radiation, the wavelength at which 63 is
27 measured, will cause a positive interference in O3 measurements. Interferences have been
28 reported in two recent studies, but assessment of the potential importance of such
29 interferences (e.g., toluene, styrene, cresols, nitrocresols) is hindered by lack of absorption
30 spectra data in the 250 nm range and by lack of aerometric data for the potentially interfering
31 species.
32
33 Calibration of O3 measurement methods (other than PSDs) is done by UV spectrometry
34 or by gas-phase titration (GPT) of O3 with NO. Ultraviolet photometry is the reference
35 calibration method approved by EPA. Ozone is unstable and must be generated in situ at
36 time of use to produce calibration mixtures.
37
38 Peroxyacetyl nitrate and the higher PANs are normally measured by gas
39 chromatography using an electron capture detector (GC-ECD). Detection limits have now
40 been extended to 1 to 5 ppt. The preparation of reliable calibration standards is difficult
41 because PAN is unstable (explosive and subject to surface-related decomposition), but several
42 methods are available.
43
44
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1 Volatile Organic Compounds
2
3 Traditionally, NMHCs and other NMOCs have been measured by methods that employ
4 a flame ionization detector (FID) as the sensing element that measures a change in ion
5 intensity resulting from the combustion of air containing organic compounds. The method
6 recommended by EPA for total NMOC measurement involves the cryogenic preconcentration
7 of NMOCs and the measurement of the revolatilized NMOCs using FID. The main
8 technique for speciated NMOC/NMHC measurements is cryogenic preconcentration followed
9 by GC-FID. Systems for sampling and analysis of VOCs have now been developed that
10 require no liquid cryogen for operation, yet provide sufficient resolution of species.
11
12 Stainless steel canisters have become the containers of choice for collection of whole-air
13 samples for NMHC/NMOC data. Calibration procedures for NMOC instrumentation require
14 the generation, by static or dynamic systems, of dilute mixtures at concentrations expected to
15 occur in ambient air.
16
17 Preferred methods for measuring carbonyl species (aldehydes and ketones) in ambient
18 air are spectroscopic methods; on-line colorimetric methods; and the most common method
19 in current use for measuring gas-phase carbonyl compounds in ambient air, which is the
20 high-performance liquid chromatography (HPLC) method employing
21 2,4-dinitrophenylhydrazine (DNPH) derivatization in a silica gel cartridge. Use of an
22 O3 scrubber has been recommended to prevent interference in this method by O3 in ambient
23 air. Several methods are available for preparing stable calibration mixtures.
24
25 Oxides of Nitrogen
26
27 Nitric oxide and NO2 comprise the NOX compounds involved as precursors to O3 and
28 other photochemical oxidants.
29
30 The most common method of NO measurement is the gas-phase CL reaction with O3,
31 which is essentially specific for NO. Commercial NO monitors have detection limits of a
32 few parts per billion by volume (ppbv) in ambient air but may not have sensitivity sufficient
33 for surface measurements in rural or remote areas, or for airborne measurements. Direct
34 spectroscopic methods for NO exist that have very high sensitivity and selectivity for NO,
35 but their complexity, size, and cost restrict these methods to research applications. No PSDs
36 presently exist for measurement of NO.
37
38 Chemiluminescence analyzers are the method of choice for NO2 measurement, even
39 though they do not measure NO2 directly. Minimum detection levels for NO2 have been
40 reported to be 5 to 13 ppb, but more recent evaluations have indicated detection limits of
41 0.5 to 1 ppbv. Reduction of NO2 to NO is required for measurement. In practice, selective
42 measurement of NOX by this approach has proved difficult, and the NO2 value inferred from
43 such measurements may be significantly in error.
44
45 Several spectroscopic approaches to NO2 detection have been developed but share the
46 drawbacks of spectroscopic NO methods. Passive samplers for NO2 exist, but are still in the
47 developmental stage for ambient air monitoring.
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1 Calibration of methods for NO measurement is done using standard cylinders of NO in
2 nitrogen. Calibration of methods for NO2 measurement include use of cylinders of NO2 in
3 nitrogen or air, use of permeation tubes, and GPT.
4
5 Ozone Air Quality Models
6
7 Models and Their Components
8
9 Photochemical air quality models are used to predict how O3 concentrations change in
10 response to prescribed changes in source emissions of NOX and VOCs. They operate on sets
11 of input data that characterize the emissions, topography, and meteorology of a region and
12 produce outputs that describe air quality in that region.
13
14 Two kinds of photochemical models are recommended in guidelines issued by EPA:
15 (1) the use of EKMA is acceptable under certain circumstances, and (2) the grid-based Urban
16 Airshed Model (UAM) is recommended for modeling O3 over urban areas. The 1990 Clean
17 Air Act Amendments mandate the use of three-dimensional (grid-based) air quality models
18 such as UAM in developing State Implementation Plans for areas designated as extreme,
19 severe, serious, or multistate moderate. General descriptions of EKMA and of grid-based
20 models were given in the 1986 EPA criteria document for O3.
21
22 The EKMA-based method for determining O3 control strategies has some limitations,
23 the most serious of which is that predicted emissions reductions are critically dependent on
24 the initial NMHC/NOX ratio used in the calculations. This ratio cannot be determined with
25 any certainty and is expected to be quite variable in an urban area.
26
27 Grid-based, photochemical air quality models have their limitations as well. These are
28 pointed out subsequently.
29
30 Spatial and temporal characteristics of VOC and NOX emissions are major inputs to a
31 grid-based photochemical air quality model. Greater accuracy in emissions inventories is
32 needed for biogenics and for both mobile and stationary source components. Grid-based air
33 quality models also require as input the three-dimensional wind field for the photochemical
34 episode being simulated.
35
36 A chemical kinetic mechanism (a set of chemical reactions), representing the important
37 reactions that occur in the atmosphere, is used in an air quality model to estimate the net rate
38 of formation of each pollutant simulated as a function of time.
39
40 Dry deposition is an important removal process for O3 on both urban and regional
41 scales and is included in all urban- and regional-scale models. Wet deposition is generally
42 not included in urban-scale photochemical models, since Oj episodes do not occur during
43 periods of significant clouds or rain.
44
45 Concentration fields of all species computed by the model must be specified at the
46 beginning of the simulation ("initial conditions"). These initial conditions are determined
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1 mainly with ambient measurements, either from routinely collected data or from special
2 studies; but interpolation can be used to distribute the surface ambient measurements.
3
4 Use of Ozone Air Quality Models
5
6 Photochemical air quality models are used for control strategy evaluation by first
7 demonstrating that a past episode, or episodes, can be adequately simulated and then
8 reducing hydrocarbon or NOX emissions or both in the model inputs and assessing the effects
9 of these reductions on O3 in the region. The adequacy of control strategies based on grid-
10 based models depends in part on the nature of input data for simulations and model
11 validation, on input emissions inventory data, and on the mismatch between model output
12 and the current form of the NAAQS for O3. Uncertainties in models can obviously affect
13 their outputs. Uncertainties exist in all components of grid-based O3 air quality models:
14 emissions, meteorological modules, chemical mechanisms, deposition rates, and
15 determination of initial conditions.
16
17 Grid-based models that have been widely used to evaluate control strategies for O3 or
18 acid deposition, or both, are (1) the Urban Airshed Model (UAM), (2) the California
19 Institute of Technology/Carnegie Institute of Technology (CIT) model, (3) the Regional
20 Oxidant Model (ROM), (4) the Acid Deposition and Oxidant Model (ADOM), and (5) the
21 Regional Acid Deposition Model (RADM).
22
23 Conclusions
24
25 Urban air quality models are becoming readily available for application and have been
26 applied in recent years in several urban areas. Significant progress has also been made in the
27 development of regional models and the integration of state-of-the-art prognostic
28 meteorological models as drivers.
29
30 Although there are still many uncertainties in photochemical air quality modeling, prime
31 among which are emission inventories, models are nevertheless essential for regulatory
32 analysis and constitute one of the major tools for attacking the O3 problem. Grid-based
33 O3 air quality modeling is superior to the available alternatives for O3 control planning, but
34 the chances of its incorrect use must be minimized.
35
36
37 1.4 ENVIRONMENTAL CONCENTRATIONS, PATTERNS, AND
38 EXPOSURE ESTIMATES
39
40 Ozone is measured at concentrations above the minimum detectable level at all
41 monitoring locations in the world. In this section of the document, hourly average
42 concentration and exposure information was summarized for urban, rural forested, and rural
43 agricultural areas in the United States.
44
45 Because O3 produced from urban area emissions is transported to more rural downwind
46 locations, elevated O3 concentrations can occur at considerable distances from urban centers.
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1 Urban O3 concentration values are often depressed because of titration by NO. Because of
2 the absence of chemical scavenging, O3 tends to persist longer in nonurban than in urban
3 areas and exposures may be higher than hi urban locations.
4
5 Trends
6
7 Ozone hourly average concentrations have been recorded for many years by the state
8 and local air pollution agencies who report their data to the EPA. The 10-year (1983 to
9 1992) composite average trend for the second highest daily maximum hourly average
10 concentration during the O3 season shows that the 1992 composite average for the trend sites
11 is 21 % lower than the 1983 average. The 1992 value is the lowest composite average of the
12 past 10 years. The 1992 composite average is significantly less than all the previous nine
13 years, 1983 to 1991. The relatively high O3 concentrations in 1983 and 1988 were likely
14 attributable in part to hot, dry stagnant conditions in some areas of the country that were
15 especially conducive to O3 formation.
16
17 Between 1991 and 1992, the composite mean of the second highest daily maximum
18 1-h O3 concentrations decreased 7% and the composite average of the number of estimated
19 exceedances of the O3 standard decreased by 23%. Nationwide VOC emissions decreased
20 3% between 1991 and 1992. The composite average of the second daily maximum
21 concentrations decreased in 8 of the 10 EPA Regions between 1991 and 1992, and remained
22 unchanged in Region VII. Except for Region Vn, the 1992 regional composite means are
23 lower than the corresponding 1990 levels.
24
25 Surface Concentrations
26
27 Published data provides evidence showing the occurrence, at some sites, of multihour
28 periods within a day of O3 at levels of potential health effects. Although most of these
29 analyses were made using monitoring data collected from sites in or near nonattainment
30 areas, in one analysis of five sites (two in New York state, two in rural California, and one
31 in rural Oklahoma), none of which was in or near a nonattainment area, O3 concentrations
32 showed only moderate peaks but showed multihour levels above 0.10 ppm.
33
34 On the basis of O3 data from isolated monitoring sites, the EPA has indicated that a
35 reasonable estimate of natural O3 background concentration near sea level in the United
36 States today, for an annual average, is from 0.020 to 0.035 ppm. This estimate included a
37 0.010- to 0.015-ppm contribution from the stratosphere and a 0.01-ppm contribution from
38 photochemically affected biogenic NMHCs. An additional 0.010 ppm is possible from the
39 photochemical reaction of biogenic methane. The EPA concluded that a reasonable estimate
40 of natural O3 background concentration for a 1-h daily maximum at sea level in the United
41 States during the summer is on the order of 0.03 to 0.05 ppm. This estimate may be low,
42 however, because available data from sites appearing to be isolated from anthropogenic
43 sources in the western United States indicate that maximum hourly concentrations can reach
44 0.06 and 0.075 ppm with infrequent occurrences below 0.02 ppm (i.e., lack of scavenging).
45
46
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1 Diurnal Variations
2
3 Diurnal patterns of O3 may be expected to vary with location, depending on the balance
4 among the many factors affecting O3 formation, transport, and destruction. Although they
5 vary with locality, diurnal patterns for O3 typically show a rise in concentration from low or
6 levels near minimum detectable amounts to an early afternoon peak. The diurnal pattern of
7 concentrations can be ascribed to three simultaneous processes: (1) downward transport of
8 O3 from layers aloft, (2) destruction of O3 through contact with surfaces and through
9 reaction with NO at ground level, and (3) in situ photochemical production of O3.
10
11 Seasonal Patterns
12
13 Seasonal variations in O3 concentrations in urban areas usually show the pattern of high
14 O3 in late spring or in summer and low levels in the winter; however, weather conditions in
15 a given year may be more favorable for the formation of O3 and other oxidants than during
16 the prior or following year.
17
18 Average O3 concentrations tend to be higher in the second versus the third quarter of
19 the year for many isolated rural sites. This observation has been attributed to either
20 stratospheric intrusions or an increasing frequency of slow-moving, high-pressure systems
21 that promote the formation of O3. However, for several clean rural sites, the highest
22 exposures have occurred in the third quarter rather than in the second. For rural O3 sites in
23 the southeastern United States, the daily maximum 1-h average concentration was found to
24 peak during the summer months.
25
26 Spatial Variations
27
28 Concentrations of O3 vary with altitude and with latitude. There appears to be no
29 consistent conclusion concerning the relationship between O3 exposure and elevation.
30
31 Indoor Ozone
32
33 Until the early 1970s, very little was known about the O3 concentrations experienced
34 inside buildings, and to date, the database on this subject is not large and a wide range of
35 indoor/outdoor O3 concentration relationships can be found in the literature; reported
36 indoor/outdoor values for O3 are highly variable. Indoor/outdoor O3 concentration ratios
37 generally fall in the range from 0.1 to 0.7 and indoor concentrations of O3 will almost
38 invariably be less than outdoors.
39
40 Estimating Exposure
41
42 Both fixed-site monitoring information and human exposure models are used to
43 estimate risks associated with O3 exposure. Because, for most cases, it is not possible to
44 estimate population exposure solely from fixed-station data, several human exposure models
45 have been developed. Some of these models include information on human activity patterns
46 (i.e., the microenvironments people visit and the times they spend there). These models also
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1 contain submodels depicting the sources and concentrations likely to be found in each
2 microenvinonment, including indoor, outdoor, and in-transit settings.
3
4 Few data are available for individuals using personal exposure monitors. Results from
5 a pilot study demonstrated that fixed-site ambient measurements may not adequately represent
6 individual exposures. Models based on time-weighted indoor and outdoor concentrations
7 explained only 40% of the variability in personal exposures.
8
9 Two distinct types of O3 exposure models exist: those that focus narrowly on predicting
10 indoor O3 levels and those that focus on predicting O3 exposures on a community-wide basis.
11
12 Peroxyacyl Nitrates
13
14 Peroxyacetyl nitrate and peroxypropionyl nitrate (PPN) are the most abundant of the
15 non-O3 oxidants in ambient air in the United States, other than the inorganic nitrogenous
16 oxidants such as NO2, and possibly nitric acid (HNO3). The concentrations of PAN that are
17 of most concern are those to which vegetation could potentially be exposed, especially during
18 daylight hours in agricultural areas. Most of the available data on concentrations of PAN
19 and PPN in ambient air are from urban areas. The levels to be found in nonurban areas will
20 be highly dependent upon the transport of PAN and PPN or their precursors from urban
21 areas because the concentrations of the NOX precursors to these compounds are considerably
22 lower in nonurban than in urban areas.
23
24 Co-occurrence
25
26 Studies of the joint occurrence of gaseous NO2/O3 and SO2/O3 at rural sites have
27 concluded that the periods of co-occurrence represent a small portion of the potential plant
28 growing period. For human ambient exposure considerations, in most cases, the
29 simultaneous co-occurrence of NO2/O3 and SO2/O3 was infrequent. Some researchers have
30 reported the joint occurrence of O3, nitrogen, and sulfur in forested areas, combining
31 cumulative exposures of O3 with data on dry deposition of sulfur and nitrogen. One study
32 reported that several forest landscapes with the highest dry deposition loadings of sulfur and
33 nitrogen tended to experience the highest average O3 concentrations and largest cumulative
34 exposure. Although the authors concluded that the joint concentrations of multiple pollutants
35 in forest landscapes were important, nothing was mentioned about the hourly co-occurrences
36 of O3 and SO2 or O3 and NO2. Acid sulfates, which are usually composed of sulfuric acid,
37 ammonium bisulfate, and ammonium sulfate, have been measured at a number of locations in
38 North America. The potential for O3 and acidic sulfate aerosols to co-occur at some
39 locations in some form (i.e., simultaneously, sequentially, or complex-sequentially) is real
40 and requires further characterization. For human ambient exposures, the simultaneous
41 co-occurrence of NO2 and O3 was infrequent.
42
43 In one study, the relationship between O3 and hydrogen ions in precipitation was
44 explored using data from sites that monitored both O3 and wet deposition simultaneously and
45 within one minute latitude and longitude of each other. It was reported that individual sites
46 experienced years in which both hydrogen ion deposition and total O3 exposure were at least
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1 moderately high. With data compiled from all sites, it was found that relatively acidic
2 precipitation occurred together with relatively high O3 levels approximately 20% of the time,
3 and highly acidic precipitation occurred together with a high O3 level approximately 6% of
4 the time. Sites most subject to relatively high levels of both hydrogen ions and O3 were
5 located in the eastern portion of the United States, often in mountainous areas.
6
7 The co-occurrence of O3 and acidic cloudwater in high-elevation forests has been
8 characterized. The frequent O3-only and pH-only single-pollutant episodes, as well as the
9 simultaneous and sequential co-occurrences of O3 and acidic cloudwater, have been reported.
10 Both simultaneous and sequential co-occurrences were observed a few times each month
11 above cloud base.
12
13
14 1.5 ENVIRONMENTAL EFFECTS OF OZONE AND RELATED
15 PHOTOCHEMICAL OXIDANTS
16
17 Ozone is the gaseous pollutant most injurious to agricultural crops, trees, and native
18 vegetation. Exposure of vegetation to O3 can inhibit photosynthesis, alter carbon
19 (carbohydrate) allocation, and interfere with mycorrhizal formation in tree roots. Disruption
20 of these important physiological processes can suppress the growth of crops, trees, shrubs,
21 and herbaceous vegetation by decreasing their capacity to form the carbon (energy)
22 compounds needed for growth and maintenance and their ability to absorb the water and
23 mineral nutrients they require from the soil. In addition, loss of vigor increases
24 susceptibility of trees and crops to insects and pathogens and impairs their ability to
25 reproduce. The following section summarizes key environmental effects associated with
26 O3 exposure.
27
28 Effects on Agroecosystems
29
30 Methodologies Used in Vegetation Research
31
32 Most of the knowledge concerning the effects of O3 on vegetation comes from the
33 exposure-response studies of important agricultural crop plants and some selected forest and
34 urban tree species, mostly as seedlings. A variety of methodologies have been used, ranging
35 from field exposures without chambers to open-top chambers and to exposures conducted in
36 chambers under highly controlled climates. In general, the more controlled conditions are
37 most appropriate for investigating specific responses and for providing the scientific basis for
38 interpreting and extrapolating results.
39
40 Mode of Action
41
42 Photosynthesis provides plants with the energy and structural building blocks necessary
43 for their existence. The photosynthetic capacity of a plant (i.e., carbohydrate production) is
44 an important aspect of plant response to stresses in natural environments and is strongly
45 associated with leaf nitrogen content and with water movement. Continued acquisition of
46 nitrogen and water uptake are necessary, if photosynthesis is to occur, and involves the
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1 allocation of carbohydrates from the leaves to the roots. Leaf photosynthetic capacity is age
2 dependent. As the plant grows, the canopy structure changes, altering the amount and angle
3 of light hitting a leaf. Allocation of carbohydrates and nutrients to new leaves is especially
4 important in stimulating growth production.
5
6 Ozone exposure results in a leaf-mediated plant response. Leaves are important
7 regulators of plant stress response and function. As the major regulators of anatomical and
8 morphological development of the shoot, they control the allocation of carbohydrates to the
9 whole plant. The many regulatory systems contained in leaves change both as a function of
10 leaf development and in response to different environmental stresses.
11
12 Only O3 that enters the plant through stomata (openings in the leaves) can impair plant
13 processes. In addition, an effect will occur only if sufficient O3 reaches sensitive sites within
14 leaf cells. Ozone injury will not be detected if (1) the rate of uptake is small enough for the
15 plant to detoxify or metabolize O3 or its derivatives, or (2) the plant is able to repair or
16 compensate for its impacts at a rate equal to or greater than the rate of uptake. (If the rate
17 of repair is very slow, there may be an effect.)
18
19 The uptake and movement of O3 to sensitive cellular sites are subject to various
20 biochemical and physiological controls. The magnitude of O3-induced effects depends upon
21 the physical environment of the plant, including both macro-and microclimatic factors, and
22 the chemical environment of the plant, including other gaseous pollutants and biological
23 factors. Visible foliar injury is usually the first indication of cellular plant response. Once
24 sufficient O3 enters the leaf, the plant can experience reduced photosynthesis, altered
25 carbohydrate production and allocation, reduced plant vigor, reduced growth or yield or
26 both, and sometimes death. The alterations in the biochemical and physiological processes
27 mentioned above may occur with or without visible injury to the plant.
28
29 Reductions in photosynthesis caused by O3 are likely to be accompanied by a shift in
30 growth pattern that favors shoots. Plants compensate for differences in resource imbalances
31 by allocating energy, water, and minerals to maintain optimal growth. Allocation of these
32 resources to leaf repair or to new leaf formation and an overall reduction in carbohydrate
33 formation decrease the availability of carbohydrates for both stem and root growth.
34 Alteration of the normal allocation pattern affects all aspects of plant growth and
35 reproduction.
36
37 Factors That Modify Plant Response
38
39 Plant response to O3 may be modified by a variety of biological, chemical, and physical
40 factors. Both the impact of environmental factors on plant response to O3 and the effects of
41 O3 on the responses of plants to environmental factors have to be considered when
42 determining the impact of oxidants on vegetation in the field.
43
44 Biological factors include those both within and external to the plant. Within the plant,
45 its genetic composition and stage of development play critical roles in plant response to O3 as
46 well as other stresses. Different varieties or cultivars, as well as different individuals of a
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1 species, due to differences in their genetic composition, are known to differ greatly in their
2 responses to a given O3 exposure.
3
4 The magnitude of the response of a particular species or variety depends on such
5 environmental factors as temperature and humidity, soil moisture and nutrition, exposure to
6 other pollutants or agricultural spray chemicals, and interaction with plant pests and
7 pathogens. In other words, the plant's present and past environmental mileu, which includes
8 the temporal exposure pattern and stage of development, dictates the plant response. The
9 corollary is also true: exposure to O3 can modify plant response to other environmental
10 variables. For example, exposure to O3 reduces the ability of trees to withstand winter
11 injury caused by freezing temperatures and influences the success of pest and fungal
12 infections by decreasing tree vigor.
13
14 Effects Based Air Quality Exposure Indices
15
16 Environmental scientists for many years have attempted to characterize and
17 mathematically represent plant exposures to O3. A variety of averaging times have been
18 used to characterize exposure-response in plants. Though most studies have characterized
19 exposure by using mean concentrations such as seasonal, monthly, weekly, daily, or peak
20 hourly means, other studies have used cumulative measures (e.g., the number of hours above
21 selected concentrations). None of these statistics completely characterizes the relationships
22 among O3 concentration, exposure duration, interval between exposures, and plant response.
23
24 The use of a mean concentration with long averaging times (1) implies that all
25 concentrations of O3 are equally effective in causing plant responses, and (2) minimizes the
26 contributions of the peak concentrations to the response. Present evidence suggests that
27 higher concentrations, episodic peak occurrences, and duration of exposure have a relatively
28 greater role in producing plant effects than mean concentrations; therefore, an index that
29 cumulates hourly concentrations during the season and gives greater weight to higher
30 concentrations appears to be a more appropriate index for relating ambient exposures to
31 growth or yield effects. From the lexicological perspective, it is the peak occurrences or
32 concentrations above an unidentified effect level that are most likely to have an impact.
33 Effects on vegetation appear when the amount of pollutant that has entered a plant exceeds its
34 ability to repair or compensate for the impact.
35
36 An index of ambient exposure that relates well to plant response should directly or
37 indirectly incorporate both environmental influences, (e.g., temperature, humidity, and
38 soil-moisture status) and exposure dynamics.
39
40 No experimental studies have been designed specifically to evaluate the adequacy of the
41 various peak-weighted indices that have been proposed. In retrospective analyses when O3 is
42 the primary source of variation in response, year-to-year variations in plant response are
43 minimized by peak-weighted, cumulative exposure indices. However, a number of different
44 forms of peak-weighted, cumulative indices have been examined for their ability to properly
45 order yield responses from the large number of studies of the National Crop Loss Assessment
46 Network (NCLAN) program. These exposure indices (i.e., SUMOO, SUM06, SIGMOID,
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1 and W126) all performed equally well, and it is not possible to distinguish between them on
2 the basis of statistical fits of the data.
3
4 Exposure-Response of Plant Species
5
6 The number of crop species/cultivars for which information regarding O3 exposure
7 responses are available encompasses a mere fraction of the total of cultivated crops and even
8 a smaller fraction of native plants. The emphasis of experimental studies has usually been on
9 the more economically important crop plants and tree species, as seedlings.
10
11 Crop species usually are monocultures that are fertilized and in many cases watered.
12 Therefore, because crop plants are usually grown under optimal conditions, their sensitivity
13 to O3 exposures undoubtedly varies from that of native trees, shrubs, and herbaceous
14 vegetation.
15
16 The concept of limiting values was used in both the 1978 and 1986 criteria documents
17 to summarize visible foliar injury. Limiting values are defined as concentrations and
18 durations of exposure below which visible injury does not occur. The limit for visible injury
19 indicating reduced plant performance was an O3 exposure of 0.05 ppm for several hours per
20 day for greater than 16 days. When the exposure period was decreased to 10 days, the
21 O3 concentration required to cause injury was increased to 0.1 ppm. A short, 6-day
22 exposure further increased the concentration to 0.30 ppm. The exposure and concentration
23 periods apply today for those crops where appearance or aesthetic value (e.g, spinach,
24 cabbage, lettuce) is considered important. Limiting values for foliar injury to trees and
25 shrubs range from 0.06 to 0.1 ppm for 4 h.
26
27 Several conclusions were drawn in the 1986 criteria document from the various
28 experimental approaches used to estimate crop yield loss.
29
30 1. Ambient O3 concentrations are sufficiently elevated in several regions of the country to
31 impair growth and yield of plants. This is clearly indicated by comparison of data
32 obtained from crop yield in charcoal-filtered and unfiltered (ambient) exposures. These
33 elevated levels are further supported by data from studies using chemical protectants.
34 These response data make possible extrapolation to plants not studied experimentally.
35 Both approaches mentioned above indicate that effects occur with only a few exposures
36 above 0.08 ppm.
37
38 2. Several plant species exhibited growth and yield effects when the mean O3 concentration
39 exceeded 0.05 ppm for 4 to 6 h/day for at least 2 weeks.
40
41 3. Data from regression studies conducted to develop an exposure-response function for
42 estimating yield loss indicated that at least 50% of the species/cultivars tested could be
43 predicted to exhibit a 10% yield loss at 7-h seasonal mean O3 concentrations of 0.05 ppm
44 or less.
45
46 Based on research published since the 1986 criteria document, the following
47 conclusions can be drawn.
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1 1. Monitoring data from 80 to 200 nonurban sites for a period of 10 years were analyzed to
2 determine the ambient 7-h growing-season average O3 concentrations. For periods of
3 3 and 5 mo, concentrations ranged from 0.05 to 0.06 ppm and 0.047 to 0.054 ppm,
4 respectively.
5
6 2. Open-top chamber studies comparing yields at ambient O3 exposures with those in
7 filtered air, and retrospective analyses of crop data, indicate that current ambient
8 O3 concentrations at some sites in the United States are sufficient to reduce the yield of
9 major crops. These results also indicate that visible injury that reduces the market value
10 of certain crops and ornamentals (spinach, petunia, geranium, for example) occurs at
11 O3 concentrations ranging from 0.04 to 0.10 ppm for 4 h.
12
13 3. A growing season SUMO6 exposure of 26.4 ppm-h, corresponding to a 7-h growing
14 season mean of 0.049 ppm, is estimated to prevent a 10% yield loss from O3 in 50% of
15 the 54 experimental cases analyzed within this document. It is estimated that a
16 12-h growing season mean of 0.045 ppm would restrict yield losses to 10% in major crop
17 species.
18
19 Effects on Natural Ecosystems
20
21 Most of the information dealing with the possible responses of ecosystems to O3 stress
22 is based on the studies in the San Bernardino Forest ecosystem. This mixed conifer forest
23 ecosystem in southern California has been studied more than any other ecosystem in the
24 United States, over 20 years. Chronic O3 exposures for a period of 50 or more years have
25 been associated with major changes hi the ecosystem.
26
27 Data from an inventory conducted from 1968 through 1972 indicated that for 5 mo of
28 the year, trees were exposed to O3 concentrations greater than 0.08 ppm for more than
29 1,300 h. Concentrations rarely decreased below 0.05 ppm at night near the crest of the
30 mountain slope, approximately 5,500 ft. In addition, during the years 1973 to 1978, average
31 24-h O3 concentrations ranged from a background of 0.03 to 0.04 ppm in the eastern part of
32 the San Bernardino Mountains to a maximum of 0.10 to 0.12 ppm in the western part during
33 May through September. Although PAN and NO2 were present in these studies, symptoms
34 of PAN injury on forest herb-layer plant species could not be distinguished from those
35 caused by O3, and NO2 concentrations were too low to cause injury.
36
37 Ecosystem responses to stress are hierachial. They begin with the response of the
38 most sensitive individuals of a population. Stresses, whose primary effects occur at the
39 molecular level (within the leaves), must be propagated progressively up through more
40 integrated levels of organ physiology (e.g., leaf, branch, root) to whole plant physiology, to
41 populations within the stand (community), and then to the landscape level to produce
42 ecosystem effects.
43
44 Therefore, to understand the effects of a stress, one must utilize a framework of
45 hierarchical scales. This is particularly true of low-level stresses because only a small
46 fraction of stresses at the molecular level become disturbances at the tree, stand, or landscape
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1 level. Insect defoliation, for example, may severely reduce the growth of one or several
2 branches, whereas growth of the tree appears not to be affected. The time required for a
3 stress to be propagated from one level to the next determines how soon the effects of the
4 stress can be observed or measured.
5
6 Foliar injury is usually the first visible indication of O3 exposure in plants. In the San
7 Bernardino forest, injury was first observed on ponderosa pine, with Jeffrey pine, white fir,
8 black oak, incense cedar, and sugar pine following in decreasing order of sensitivity. Foliar
9 injury on sensitive ponderosa and Jeffrey pine was observed when 24-h-average
10 O3 concentrations were 0.05 to 0.06 ppm.
11
12 The biochemical changes within the leaves were expressed as (1) visible foliar injury;
13 (2) premature needle senescence; (3) a reduction in photosynthesis; (4) a reduction in
14 carbohydrate production; (5) altered carbohydrate allocation, reduced plant vigor; and (6) a
15 reduction in growth and reproduction.
16
17 Tree growth is the culmination of biochemical and physiological processes, during
18 which plants use, accumulate, and store carbon compounds (energy) to build and maintain
19 their structure. Within the leaves during the process of photosynthesis, carbon dioxide
20 absorbed from the atmosphere is converted to carbohydrates. The water and minerals
21 necessary for growth are absorbed from the soil through the roots. Growth and seed
22 formation depend not only on photosynthesis and the uptake of water and mineral nutrients,
23 but also on subsequent metabolic processes and the allocation of carbohydrates to the rest of
24 the plant. Impairment of any of these processes can decrease plant vigor and affect plant
25 growth and reproduction.
26
27 Trees each year require energy to grow new leaves and needles, to produce new fine
28 roots, and to increase radial growth. Factors that inhibit photosynthesis and limit
29 carbohydrate formation shift carbohydrate allocation to new leaves, whereas factors that limit
30 nitrogen or water availability will shift allocation to the roots. Increased carbohydrate
31 allocation to new needles and to repair foliage injured by O3 can place a drain on
32 carbohydrate reserves. Reduced tree vigor, the result of altered carbohydrate allocation,
33 increases susceptibility of trees to insect pests and fungal pathogens and reduces the
34 formation of mycorrhizae required for water and nutrient uptake.
35
36 Premature needle senescence, as observed in ponderosa and Jeffrey pine, not only
37 decreases the amount of foliage available to carry on photosynthesis, but alters
38 microorganismal succession on conifer needles, thus altering the detritis-forming process and
39 subsequent nutrient cycling.
40
41 The primary effect on the more susceptible members of the San Bernardino forest
42 community (e.g., ponderosa and Jeffrey pine) was that they were no longer able to compete
43 effectively for essential nutrients, water, light, and space. As a consequence of altered
44 competitive conditions in the community, there was a decline in the sensitive species,
45 permitting the enhanced growth of more tolerant species. In addition, changes in the
46 dominant individuals in the ecosystem altered the processes of energy flow and nutrient
47 cycling. These changes that began with the biochemical changes within the leaves of the
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1 sensitive conifers were ultimately transferred upward to the whole ecosystem, from the
2 individual, to the population, to the community, and finally, to the ecosystem.
3
4 Functional ecosystem changes associated with the deaths in the conifer populations
5 altered the processes of carbohydrate (energy) flow, mineral nutrient cycling, and water
6 movement. The altered processes also changed, either directly or indirectly, the functioning
7 of other living ecosystem components and ultimately changed the vegetational community
8 patterns. The continuum of changes beginning with injury to the individual trees resulted in
9 ecosystem breakdown and a shift in dominance from ponderosa and Jeffrey pine to
10 O3-tolerant shrub and oak species.
11
12 The effects that a stress at one level of organization will have on a higher level are
13 determined by variability and compensation. Variability in response to stress can mean that
14 not all trees are equally susceptible to O3, as was observed, in the San Bernardino Forest, in
15 the Appalachian Mountains, and the Cumberland Plateau of eastern Tennessee. Individuals
16 of Ponderosa, Jeffrey, and eastern white pine were designated as being sensitive,
17 intermediate or tolerant, based on their responses to O3 exposure. Compensation means that
18 plants tolerant to the stress are able either to detoxify or metabolize O3 entering the leaves or
19 to repair the injury.
20
21 Variability and compensation can also occur at the population level and, all populations
22 do not respond equally. Plant populations can respond in four different ways: (1) no
23 response, the individuals are tolerant to the stress; (2) mortality of all individuals and local
24 extinction of the extremely sensitive population, the most severe response; (3) physiological
25 accomodation, resulting hi growth and reproductive success of tolerant individuals; and
26 (4) differential response, some individuals of the population exhibit better growth and
27 reproductive success due to genetically determined traits.
28
29 The properties of variability and compensation at the individual level determine (1) the
30 severity of the response, (2) whether the effect will be propagated to the next level, and
31 (3) the length of tune required for the effect to be expressed functionally and structurally. In
32 most instances, the tune required for response at the individual level is a period of at least
33 3 to 5 years. Variability and compensation at the population level determine whether there
34 will be an ecosystem response. These properties help to explain the differences in responses
35 between the San Bernardino Forest and the forest ecosystems in the eastern United States.
36
37 Forest stands differ greatly in age, species composition, stability, and capacity to
38 recover from disturbance. In addition, the position in the stand or community of the most
39 sensitive species is extremely important. Ponderosa and Jeffrey pine are controller species.
40 Their removal altered energy flow, nutrient cycling, and water movement in the San
41 Bernardino forest ecosystem and changed the ecosystem. The removal of the eastern white
42 pine, on the other hand, did not alter the functional ecosystem processes sufficiently to bring
43 about a recognizable change within the ecosystems. For this reason, data dealing with the
44 responses of one forest type (e.g., San Bernardino) may not be applicable to other forest
45 types such as those found in the Appalachian Mountains.
46
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1 Individual eastern white pine trees varied in sensitivity to O3, and, because of
2 physiological accommodation and compensation, effects at the population level were not
3 reported in the forest stands in the Appalachian Mountains. Plantation plantings of eastern
4 white pine (a monoculture) on the Cumberland Plateau, however, did exhibit overall growth
5 reductions.
6
7 Mycorrhizae (fungus roots) function in the uptake of water and minerals (e.g., nitrogen,
8 phosphorus) and are required for optimal growth by most plants. Nitrogen is a critical
9 element in the process of photosynthesis and is usually the element in shortest supply in both
10 agricultural and natural ecosystems. Increased carbohydrate allocation to new needles and to
11 foliage repair limits allocation to the roots and reduces formation of the mycorrhizae needed
12 to take up water, nitrogen, and other nutrients. Mycorrhizae can also protect plants from
13 attack by root pathogens.
14
15 Effects on Materials
16
17 Over four decades of research show that O3 damages certain materials such as
18 elastomers, textile fibers, and dyes. The amount of damage to actual in-use materials and
19 the economic consequences of that damage are poorly characterized.
20
21 Natural rubber and synthetic polymers of butadiene, isoprene, and styrene, used in
22 products like automobile tires and protective outdoor electrical coverings, account for most
23 of the elastomer production in the United States. The action of 03 on these compounds is
24 well known, and concentration-response relationships have been established and corroborated
25 by several studies. These relationships, however, must be correlated with adequate exposure
26 information based on product use. For these and other economically important materials,
27 protective measures have been formulated to reduce the rate of oxidative damage. When
28 antioxidants and other protective measures are incorporated in elastomer production, the
29 O3-induced damage is reduced considerably, although the extent of reduction differs widely
30 according to the material and the type and amount of protective measures used.
31
32 Both the type of dye and the material in which it is incorporated are important factors
33 in the resistance of a fabric to O3. Some dyed fabrics, such as royal blue rayon-acetate, red
34 rayon-acetate, and plum cotton, are resistant to O3. On the other hand, anthraquinone dyes
35 on nylon fibers are sensitive to fading from O3. Field studies and laboratory work show a
36 positive association between O3 levels and dye fading of nylon materials. At present, the
37 available research is insufficient to quantify the amount of damaged materials attributable to
38 O3 alone.
39
40 The degradation of fibers from exposure to O3 is poorly characterized. In general,
41 most synthetic fibers like modacrylic and polyester are relatively resistant, whereas cotton,
42 nylon, and acrylic fibers have greater but varying sensitivities to O3. Ozone reduces the
43 breaking strength of these fibers, and the degree of reduction depends on the amount of
44 moisture present. The limited research in this area indicates that O3 in ambient air may have
45 a minimal effect on textile fibers, but additional research is needed to verify this conclusion.
46
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1 A number of artists' pigments and dyes are sensitive to O3 and other oxidants. Many
2 organic pigments in particular are subject to fading or other color changes when exposed to
3 O3. Although most, but not all, modern fine arts paints are more O3 resistant, many older
4 works of art are at risk of permanent damage due to O3-induced fading.
5
6 A great deal of work remains to be done to develop quantitative estimates of the
7 economic damage to materials from photochemical oxidants. Most of the available studies
8 are now outdated in terms of the O3 concentrations, technologies, and supply-demand
9 relationships that prevailed when the studies were conducted. Additionally, little is known
10 about the physical damage functions, so cost estimates have been simplified to the point of
11 not properly recognizing many of the scientific complexities of the impact of O$.
12
13
14 1.6 TOXICOLOGICAL EFFECTS OF OZONE
15
16 Respiratory Tract Effects of Ozone
17
18 Biochemical Targets of Ozone Interaction
19
20 Knowledge of molecular targets provides a basis for understanding mechanisms of
21 effects and strengthening animal-to-human extrapolations. Ozone reacts with polyunsaturated
22 fatty acids and sulfhydryl, amino, and some electron-rich compounds. These elements are
23 shared across species. Several types of reactions are involved, and free radicals may be
24 created. Based on this knowledge, it has been hypothesized that the O3 molecule is unlikely
25 to penetrate the liquid linings of the respiratory tract to reach the tissue, raising the
26 possibility that reaction products exert effects.
27
28 Lung Inflammation and Permeability Changes
29
30 Ozone disrupts the barrier function of the lung, resulting in (1) the entry of compounds
31 in the airspaces into the blood and (2) the entry of serum components (e.g., protein) and
32 white blood cells (especially polymorphonuclear leukocytes) into the airspaces and lung
33 tissue. This latter impact reflects the initial stage of inflammation. These cells can release
34 biologically active mediators that are capable of a number of actions, including damage to
35 other cells in the lung. In lung tissue, this inflammation can also increase the thickness of
36 the air-blood barrier.
37
38 Increases in permeability and inflammation have been observed at levels as low as
39 0.1 ppm (2 h/day, 6 days; rabbits). After acute exposures, the influence of the time of
40 exposure (from 2 h to several hours) increases as the concentration of O3 increases.
41 Long-term exposure effects are discussed under lung morphology.
42
43 The impacts of these changes are not fully understood. At higher O3 concentrations
44 (e.g., 0.7 ppm, 28 days), the diffusion of oxygen into the blood decreases, possibly because
45 the air-blood barrier is thicker; cellular death may result from the enzymes released by the
46 inflammatory cells; and host defense functions may be altered by mediators.
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1 Effects on Host Defense Mechanisms
2
3 Ozone exposure results in alterations of all defense mechanisms of the respiratory tract,
4 including mucociliary and alveolobronchiolar clearance, functional and biochemical activity
5 of the alveolar macrophage, and immunologic competence. These effects can cause
6 susceptibility to bacterial respiratory infections.
7
8 Mucociliary clearance, which removes particles and cellular debris from the conducting
9 airways, is slowed by acute, but not repeated exposures to O3. Ciliated epithelial cells that
10 move the mucous blanket are altered or destroyed by acute and chronic exposures. Neonatal
11 sheep exposed to O3 do not have normal development of the mucociliary system. Such
12 effects could prolong the retention of unwanted substances (e.g., inhaled particles) in the
13 lungs, allowing them to exert their toxic potential for a longer period of time.
14
15 Alveolar clearance mechanisms, which center on the functioning of alveolar
16 macrophages, are altered by O3. Short-term exposure to levels as low as 0.1 ppm (2 h/day,
17 1 to 4 days; rabbits) accelerates clearance, but longer exposures do not. Even so, after a
18 6-week exposure of rats to an urban pattern of O3, the retention of asbestos fibers in a region
19 protected by alveolar clearance is prolonged.
20
21 Alveolar macrophages engulf and kill microbes, as well as clear the deeper regions of
22 the lungs of nonviable particles. They also participate in immunological responses, but little
23 is known about the effects of O3 on this function. Acute exposures of rabbits to levels as
24 low as 0.1 ppm decrease the ability of alveolar macrophages to ingest particles. This effect
25 is displayed in decreases in the ability of the lung to kill bacteria after acute exposure of
26 mice to levels as low as 0.4 ppm.
27
28 Both the pulmonary and systemic immune system are affected by O3, but in a poorly
29 understood way. It appears that the part of the immune system dependent on T-cell function
30 is more affected than that part dependent on B-cell function.
31
32 Dysfunction of host defense systems results in enhanced susceptibility to bacterial lung
33 infections. For example, exposure as low as 0.08 ppm for 3 h can overcome the ability of
34 mice to resist infection with streptococcal bacteria, resulting in mortality. However,
35 prolonged exposures (weeks, months) do not cause greater effects on infectivity.
36
37 Effects on antiviral defenses are more complex and less well understood. Only high
38 concentrations (1.0 ppm, 3 h/day, 5 days; mice) increase viral-induced mortality.
39 Apparently, O3 does not impact antiviral clearance mechanisms. Although O3 does not affect
40 acute lung injury from influenza virus infection, it does enhance later phases of the course of
41 an infection (i.e., postinfluenzal alveolitis).
42
43 Morphological Effects
44
45 Ozone causes similar types of alterations in lung structure in all laboratory animal
46 species studied, from rats to monkeys. In the lungs, the most affected cells are the ciliated
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1 epithelial cells of the airways and Type 1 epithelial cells of the gas exchange region. In the
2 nasal cavity, ciliated cells are also affected.
3
4 The centriacinar region (the junction of the conducting airways and gas exchange
5 regions) is the primary target, possibly because this area is predicted to receive the greatest
6 dose of O3. The ciliated cells can be killed and are replaced by nonciliated cells (i.e., cells
7 not capable of clearance functions that also have increased ability to metabolize some foreign
8 compounds). Mucous-secreting cells are affected, but to a lesser degree. Type 1 cells,
9 across which gas exchange occurs, can be killed. They are replaced by Type 2 cells, which
10 are thicker and produce more lipids. An inflammatory response also occurs in the tissue.
11 The tissue is thickened further in later stages when collagen (a structural protein increased in
12 fibrosis) and other elements accumulate.
13
14 The distal airway is remodeled. More specifically, bronchiolar epithelium replaces the
15 cells present in alveolar ducts. Concurrent inflammation may play a role. This effect has
16 been observed at 0.25 ppm (8 h/day, 18 mo) in monkeys; at a higher concentration, this
17 remodeling persists after exposure stops.
18
19 The progression of effects during and after a chronic exposure is complex. Over the
20 first few days of exposure, inflammation peaks and then drops considerably, plateauing for
21 the remainder of exposure, after which it largely disappears. Epithelial hyperplasia increases
22 rapidly over the first few days and rises slowly or plateaus thereafter; when exposure ends, it
23 begins to return toward normal. In contrast, fibrotic changes in the tissue between the air
24 and blood increase very slowly over months of exposure, and after exposure ceases, the
25 change sometimes persists or increases further.
26
27 The pattern of exposure can make a major difference in effects. Monkeys exposed to
28 0.25 ppm O3 (8 h/day) every other month of an 18-mo period had equivalent changes in lung
29 structure, more fibrotic changes, and more of certain types of pulmonary function changes
30 than monkeys exposed every day over the 18 mo. From this work and rat studies, it appears
31 that natural seasonal patterns may be of more concern than more continuous exposures.
32 Thus, long-term animal studies with uninterrupted exposures may underestimate some of the
33 effects of O3.
34
35 There is no evidence that O3 causes emphysema.
36
37 Effects on Pulmonary Function
38
39 Pulmonary function changes in animals resemble those observed in humans after acute
40 exposure.
41
42 During acute exposure, the most commonly observed alteration is an increased
43 frequency of breathing and decreased tidal volume (i.e., rapid, shallow breathing). This has
44 been reported at exposures as low as 0.2 ppm for 3 h (rats). Typically, higher
45 concentrations (around 1 ppm) are required to affect breathing mechanics (compliance and
46 resistance). Extended characterizations of pulmonary function show types of changes
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1 generally seen in humans. For example, there are decreased lung volumes at levels
2 >0.5 ppm (a few hours; rats).
3
4 When rats are exposed to O3 for 2 h/day for 5 days, the pattern of attenuation of
5 pulmonary function responses is similar to that observed in humans. Other biochemical
6 indicators of lung injury did not return to control values by Day 5, and morphological
7 changes increased in severity over the period of exposure. Thus, attenuation did not result in
8 protection against all the effects of O3.
9
10 Long-term exposures have provided mixed results on pulmonary function, including no
11 or minimal effects, restrictive effects, or obstructive effects. When changes occurred and
12 postexposure examinations were performed, pulmonary function recovered.
13
14 Biochemical Effects
15
16 In acute and short-term exposure studies, a variety of lung lipid changes occur,
17 including an increase in arachidonic acid, the further metabolism of which produces a variety
18 of biologically active mediators that can affect host defenses, lung function, the immune
19 system, and other functions.
20
21 The level of lung antioxidant metabolism increases after O3 exposure, probably as a
22 result of the increase in the number of cells (Type 2 cells) rich in antioxidant enzymes.
23
24 Collagen (the structural protein involved in fibrosis) increases in O3-exposed lungs in a
25 manner that has been correlated to structural changes (e.g., increased thickness of the tissue
26 between the air and blood after prolonged exposure). Some, but not all, studies found that
27 the increased collagen persists after exposure ceases.
28
29 Generally, O3 enhances lung xenobiotic metabolism after both short- and long-term
30 exposure, possibly as a result of morphological changes (increased numbers of nonciliated
31 bronchiolar epithelial cells). The impact of this change is dependent on the xenobiotics
32 involved. For example, the metabolism of benzo[fl]pyrene to active metabolites was
33 enhanced by O3.
34
35 Genotoxictiy and Carcinogenicity of Ozone
36
37 The chemical reactivities of O3 give it the potential to be a genotoxic agent.
38
39 In vitro studies are difficult to interpret because the culture systems used allowed the
40 potential formation of artifacts, and often high or very high concentrations of O3 were used.
41 Generally, in these studies, O3 causes DNA strand breaks, sometimes is weakly mutagenic,
42 and causes cellular transformation and chromosomal breakage. The latter finding has been
43 investigated in vivo with mixed results hi animals. A well-designed human clinical study
44 found no such effect.
45
46 The few earlier long-term carcinogenic studies, with or without coexposure to known
47 carcinogens, are either negative or ambiguous.
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1 The National Toxicology Program (NTP) completed chronic rat and mouse cancer
2 bioassays using commonly accepted experimental approaches and designs. Both males and
3 females were studied. Animals were exposed for 2 years (6 h/day, 5 days/week) to 0.12,
4 0.5, and 1.0 ppm O3 or for a lifetime to the same levels (except 0.12 ppm). Following their
5 standard procedures for determination of weight-of-evidence for carcinogenicity, the NTP
6 reported "no evidence" in rats, "equivocal evidence" in male mice, and "some evidence" in
7 female mice. The increases in adenomas and carcinomas were observed only in the lungs.
8 There was no concentration response. One of the reasons for the designation of "some
9 evidence" in female mice was that when the 2-year and lifetime exposure studies were
10 combined, there was a statistically significant increase in total tumors at 1.0 ppm. It is not
11 justified to extrapolate these mouse data to humans at the present time because rats were not
12 affected, only a high level of O3 (1.0 ppm) caused a limited degree of carcinogenic activity
13 in one strain of mice, there was no concentration response, and there is inadequate
14 information to provide a mechanistic support for the finding in mice.
15
16 In a companion NTP study, male rats were treated with a tobacco carcinogen and
17 exposed for 2 years to 0.5 ppm O3. Ozone did not affect the response and therefore had no
18 tumor promoting activity.
19
20 Systemic Effects of Ozone
21
22 Ozone causes a variety of effects on tissues/organs distant from the lung. Because
23 O3 itself is not thought to penetrate the lung, these systemic effects are either secondary to
24 lung alterations or result from reaction products of O3. Effects have been observed on
25 clinical chemistry, white blood cells, red blood cells, the circulatory system, the liver,
26 endocrine organ(s), and the central nervous system. Most of these effects cannot be
27 adequately interpreted at this time and have not been investigated in humans, but it is of
28 interest to note that O3 exposures causing effects on the respiratory tract of animals cause a
29 wide array of effects on other organs also.
30
31 Several behavior changes occur in response to O3. For example, 0.12 ppm (6 h, rats)
32 decreases wheel-running activity, and 0.5 ppm (1 min) causes mice to avoid exposure.
33 These effects are not fully understood, but they may be related to lung irritation or decreased
34 ability to exercise.
35
36 Although cardiovascular effects, such as slowed heart rate and decreased blood
37 pressure, occur in O3-exposed rats, some observed interactions with thermoregulation prevent
38 qualitative extrapolation of these effects to humans at this time.
39
40 Developmental toxicity studies in pregnant rats summarized in the 1986 O3 criteria
41 document showed that levels up to about 2.0 ppm did not cause birth defects. Rat pups from
42 females exposed to 1.0 ppm O3 during certain periods of gestation weighed less or had
43 delays in development of behaviors (e.g., righting, eye opening). No "classical"
44 reproductive assays with O3 were found.
45
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1 Other studies have indicated that O3 can affect some endocrine organs (i.e., pituitary-
2 thyroid-adrenal axis and parathyroid gland). It appears that the liver has less ability to
3 detoxify drugs after O3 exposure, but assays of liver enzymes involved in xenobiotic
4 metabolism are not consistent with each other.
5
6 Interactions of Ozone with Other Co-occurring Pollutants
7
8 Animals studies of the effects of O3 in combination with other air pollutants show that
9 antagonism, additivity, and synergism can result, depending upon the animal species,
10 exposure regimen, and health endpoint. Thus, they clearly demonstrate the major
11 complexities and potential importance of interactions, but do not provide a scientific basis for
12 predicting the results of interactions under untested ambient exposure scenarios.
13
14
15 1.7 HUMAN HEALTH EFFECTS OF OZONE AND RELATED
16 PHOTOCHEMICAL OXIDANTS
17
18 This section summarizes key health effects associated with exposure to O3, the major
19 component of photochemical oxidant air pollution that is clearly of most health concern to the
20 human population. Another, often co-occurring photochemical oxidant component of "smog"
21 is PAN, but this compound has been demonstrated to be primarily responsible for induction
22 of smog-related eye irritation (stinging of eyes). Limited pulmonary function studies have
23 shown no effects of PAN at concentrations below 0.13 to 0.30 ppm, which are much higher
24 than the generally encountered ambient air levels in most cities.
25
26 Controlled Human Studies of Acute Ozone Effects
27
28 Effects on Lung Function
29
30 Controlled studies in healthy adult subjects have demonstrated O3-induced decrements
31 in pulmonary function, characterized by alterations in lung volumes and flow, airway
32 resistance, and airway responsiveness. Respiratory symptoms, such as cough and pain on
33 deep inspiration, are associated with these changes in lung function.
34
35 Ozone-induced decreases in lung volume, specifically forced vital capacity (FVC) and
36 forced expiratory volume in 1 s (FEVj), can be largely attributed to decreases in inspiratory
37 capacity, or the ability to take a deep breath; although at higher exposure concentrations,
38 there is clearly an additional component that is not volume dependent. They recover to a
39 large extent within 2 to 6 h; normal baseline function is typically reestablished within 24 h,
40 but not fully with more severe exposures.
41
42 Ozone causes increased airway resistance and may cause reductions in expiratory flow
43 and the FEV^FVC ratio.
44
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1 Ozone causes an increase in airway responsiveness to nonallergenic stimuli (e.g.,
2 histamine or methacholine) in healthy and asthmatic subjects. There is no clear evidence of a
3 relationship between O3-induced lung volume changes and changes in airway responsiveness.
4
5 Inflammation and Host Defense Effects
6
1 Controlled studies in healthy adult subjects also indicate that O3 causes an inflammatory
8 response in the lungs characterized by elevated levels of neutrophils (a type of white blood
9 cell), increased epithelial permeability, and elevated levels of biologically active substances
10 (e.g., prostaglandins, proinflammatory mediators, and cytokines).
11
12 Inflammatory responses to O3 can be detected within 1 h after a single 1-h exposure
13 with exercise to concentrations >0.30 ppm; the increased levels of some inflammatory cells
14 and mediators persist for at least 18 h. The temporal response profile is not adequately
15 defined, although it is clear that the tune course of response varies for different mediators
16 and cells.
17
18 Lung function and respiratory symptom responses to O3 do not seem to be correlated
19 with airway inflammation.
20
21 Ozone also causes inflammatory responses in the nose, marked by increased numbers of
22 neutrophils (neutrophilia) and protein levels suggestive of increased permeability.
23
24 Alveolar macrophages removed from the lungs of human subjects after 6.6 h exposure
25 to 0.08 and 0.10 ppm O3 have a decreased ability to ingest microorganisms, indicating some
26 impairment of host defense capability.
27
28 Ozone Exposure-Response Relationships
29
30 Functional, symptomatic, and inflammatory responses to O3 increase with increasing
31 exposure dose of O3. The major determinants of the exposure dose are O3 concentration
32 (C), exposure duration (T), and the amount of ventilation (VE). Of these factors, C has
33 more influence on the response than T or VE.
34
35 Exercise increases response to O3 by increasing VE (greater mass delivered), tidal
36 volume, inspiratory flow (greater percentage delivery), and the intrapulmonary
37 O3 concentration.
38
39 Repeated daily exposures to relatively high levels of O$ doses (C x T x VE) causing
40 substantial reductions in FEVj (>20% decrement) typically cause exacerbation of the lung
41 function and respiratory symptom responses on the second exposure day. However,
42 attenuation of these responses occurs with continued exposures for a few days. Most
43 inflammatory responses also attenuate; for example, neutrophilia is absent after five
44 consecutive exposures.
45
46 Multihour exposures (e.g., for up to 7 h) to O3 concentrations as low as 0.08 ppm
47 cause small but significant (1) decrements in lung function, (2) increases in respiratory
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1 symptoms, and (3) increases in neutrophils and protein levels. Ozone C is a more important
2 factor than exercise VE or T in predicting responses to multihour low-level O3 exposure.
3 There is now clear evidence of a response plateau in terms of lung volume response to
4 prolonged O3 exposure. This evidence suggests that for a given combination of exercise and
5 O3 concentration (i.e., dose rate), there is a response plateau; continued exposure (i.e,
6 increased T) at that dose rate will not increase response. Therefore, quantitative
7 extrapolation of responses to longer exposure durations is not valid.
8
9 Mechanisms of Acute Pulmonary Responses
10
11 The mechanisms leading to the observed pulmonary responses induced by O3 are
12 beginning to be better understood. The available descriptive data suggest a number of
13 mechanisms leading to the alterations in lung function and respiratory symptoms, including
14 (1) O3 delivery to the tissue (i.e., the inhaled concentration, breathing pattern, and airway
15 geometry; (2) O3 reactions with the airway lining fluid and/or epithelial cell membranes;
16 (3) local tissue responses, including injury and inflammation; and (4) stimulation of neural
17 afferents (bronchial C fibers) and the resulting reflex responses and symptoms. The
18 cyclooxygenase inhibitors block production of prostaglandin £2 and interleukin-6 as well as
19 reduce lung volume responses; however, these drugs do not reduce neutrophilic inflammation
20 and levels of cell damage markers such as lactate dehydrogenase.
21
22 Effects on Exercise Performance
23
24 Maximal oxygen uptake, a measure of peak exercise performance capacity, is reduced
25 hi healthy young adults if preceded by O3 exposures sufficient to cause marked changes in
26 lung function (i.e., decreases of at least 20%) and increased subjective symptoms of
27 respiratory discomfort. Limitations in exercise performance may be related to increased
28 symptoms, especially those related to breathing discomfort.
29
30 Factors Modifying Responsiveness to Ozone
31
32 Many variables have the potential for influencing responsiveness to O3; most, however,
33 are inadequately addressed in the available clinical data to make definitive conclusions.
34
35 Active smokers are less responsive to O3 exposure, which may reverse following
36 smoking cessation, but these results should be interpreted with caution.
37
38 The possibility of age-related differences in response to O3 has been explored, although
39 young adults historically have provided the subject population for controlled human studies.
40 Children and adolescents have similar lung volume responses to O3 as young adults, but lack
41 respiratory symptoms at levels to which they have been exposed. Pulmonary function
42 responsiveness in adults appears to decrease with age, whereas symptom rates remain similar
43 to young adults. Group mean lung function responses of adults over 50 years of age are less
44 than those of children, adolescents, and young adults.
45
46 The available data have not conclusively demonstrated that men and women respond
47 differently to O3. Likewise, pulmonary function responses of women have been compared
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1 during different phases of the menstrual cycle, but the results are conflicting. If gender
2 differences exist for lung function responsiveness to O3, they are not based on hormonal
3 changes, differences in lung volume, or the ratio of FVC to VE.
4
5 There is no compelling evidence, to date, suggesting that any ethnic or racial groups
6 have a different distribution of responsiveness to O3.
7
8 Seasonal and ambient factors may vary responsiveness to O3, but further research is
9 needed to determine how they affect individual subjects. Individual sensitivity to O3 may
10 vary throughout the year, related to seasonal variations in ambient O3 concentrations.
11
12 The specific inhalation route appears to be of minor importance in exercising adults.
13 Exposure to O3 by oral breathing (i.e., mouthpiece) yields similar results as oronasal
14 breathing (i.e., chamber exposures).
15
16 Population Groups at Risk from Ozone Exposure
17
18 Population groups that have demonstrated responsiveness to ambient concentrations of
19 O3 consist of exercising healthy and asthmatic individuals, including children, adolescents,
20 and adults.
21
22 Available evidence from controlled human studies on subjects with preexisting disease
23 suggests that (1) mild asthmatics have similar lung volume responses, but greater airway
24 resistance responses to O3 than nonasthmatics; and (2) moderate asthmatics may have, in
25 addition, greater lung volume responses than nonasthmatics.
26
27 Of all the other population groups studied, those with preexisting limitations in
28 pulmonary function and exercise capacity (e.g., chronic obstructive pulmonary disease,
29 chronic bronchitis, ischemic heart disease) would be of primary concern in evaluating the
30 health effects of O3. Unfortunately, limitations of (1) subject selection, (2) standardized
31 methods of subject characterization, and (3) range of exposure hamper the ability to make
32 definitive conclusions regarding the relative responsiveness of most chronic disease subjects.
33
34 Effects of Ozone Mixed with Other Pollutants
35
36 No significant enhancement of respiratory effects has been consistently demonstrated
37 for simultaneous exposures of O3 mixed with SO2, NO2, sulfuric or nitric acid, paniculate
38 aerosols, or with multiple combinations of these pollutants. It is fairly well established that
39 simultaneous exposure of healthy adults and asthmatics to mixtures of O3 and other pollutants
40 for short periods of time (< 2 h) induces pulmonary function responses not significantly
41 different from those following O3 alone when studies are conducted at the same
42 O3 concentration. Exposure to PAN has been reported to induce greater pulmonary function
43 responses than exposure to O3 alone, but at PAN concentrations (>0.27 ppm) much higher
44 than ambient levels. Unfortunately, only a limited number of pollutant combinations and
45 exposure protocols have been investigated, and subject groups are small and are
46 representative of only small portions of the general population. Thus, much is unknown
47 about the relationships between O3 and the complex mix of pollutants found in the ambient air.
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1 Prior exposure to O3 in asthmatics may cause an increase in response to other pollutant
2 gases, especially SO2. Likewise, prior exposure to other pollutants can enhance responses to
3 O3 exposure.
4
5 Controlled Human Studies of Ambient Air Exposures
6
7 Mobile laboratory studies of lung function and respiratory symptoms in a local subject
8 population exposed to ambient photochemical oxidant pollution provide quantitative
9 information on exposure-response relationships for O3. A series of these studies from
10 Los Angeles, CA, have demonstrated pulmonary function decrements at O3 concentrations of
11 0.14 ppm in exercising healthy adolescents, and increased respiratory symptoms and
12 pulmonary function decrements at 0.15 ppm in heavily exercising athletes and at 0.17 ppm in
13 lightly exercising healthy and asthmatic subjects. Comparison of the observed effects in
14 exercising athletes with controlled chamber studies at comparable O3 concentrations showed
15 no significant differences in lung function and symptoms, suggesting that coexisting ambient
16 pollutants have a minimal contribution to the measured responses under typical summer
17 ambient conditions in Southern California.
18
19 Field and Epidemiology Studies of Ambient Air Exposures
20
21 Individual-level field studies and aggregate level time-series studies have addressed the
22 acute effects of O3 on lung function decrements and increased morbidity and mortality in
23 human populations exposed to real-world conditions of O3 exposure.
24
25 Camp and exercise studies of lung function provide quantitative information on
26 exposure-response relationships linking lung function declines with O3 exposure occurring in
27 ambient air. Combined statistical analysis of six recent camp studies in children yields an
28 average relationship between decrements in FEVl and previous-hour O3 concentration of
29 —0.64 mL/ppb. Two key studies of lung function measurements before and after well-
30 defined outdoor exercise events in adults have yielded exposure-response slopes of
31 -0.40 and -1.35 mL/ppb. The magnitude of pulmonary function declines with
32 O3 exposure is consistent with the results of controlled human studies.
33
34 Daily life studies support a consistent relationship between O3 exposure and acute
35 respiratory morbidity in the population. Respiratory symptoms (or exacerbation of asthma)
36 and decrements in peak expiratory flow rate are associated with increasing ambient O3,
37 particularly in asthmatic children; however, concurrent temperature, particles, acidity
38 (hydrogen ions), aeroallergens, and asthma severity or medication status may also contribute
39 as independent or modifying factors. Aggregate results show greater responses in asthmatic
40 individuals than in nonasthmatics, indicating that asthmatics constitute a sensitive group in
41 epidemiologic studies of oxidant air pollution.
42
43 Summertime daily hospital admissions for respiratory causes in various locations of
44 eastern North America have consistently shown a relationship with ambient levels of O3,
45 accounting for approximately one to three excess respiratory hospital admissions per hundred
46 ppb O3 per million persons. This association has been shown to remain even after
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1 statistically controlling for the possible confounding effects of temperature and copollutants
2 (e.g., hydrogen ions, sulfate, and particles less than 10 jwm), as well as when considering
3 only concentrations below 0.12 ppm O3.
4
5 Two recent time-series epidemiologic studies indicate a small but statistically significant
6 association between O3 and total daily mortality in Los Angeles, CA, and New York City,
7 NY, where peak 1-h maximum O3 reached concentrations greater than 0.2 ppm during the
8 study period. The results were significant even after controlling for the potentially
9 confounding effects of temperature and particles. A third study in regions with lower
10 (<0.15 ppm) maximum 1-h O3 concentrations (St. Louis, MO, and Kingston-Harriman, TN)
11 did not detect a significant O3 association with mortality.
12
13 Only suggestive epidemiologic evidence exists for health effects of chronic ambient
14 O3 exposure in the population. All of the available studies of chronic respiratory system
15 effects in exposed children and adults are limited by a simplistic assignment of exposure or
16 by their inability to isolate potential effects related to O3 from those of other pollutants,
17 especially particles.
18
19
20 1.8 EXTRAPOLATION OF ANIMAL TOXICOLOGICAL DATA TO
21 HUMANS
22
23 There have been significant advances in O3 dosimetry since 1986 that better enable
24 quantitative extrapolation with marked reductions in uncertainty. Experiments and models
25 describing the uptake efficiency and delivered dose of O3 in the respiratory tract (RT) of
26 animals and humans are beginning to present a clearer picture than has previously existed.
27
28 The total RT uptake efficiency of rats at rest is approximately 50%. Within the RT of
29 the rat, 50% of the O3 taken up by the RT is removed in the head, 7% in the larynx/trachea,
30 and 43% in the lungs.
31
32 In humans at rest, the total RT uptake efficiency is between 80 and 95%. Total RT
33 uptake efficiency falls as flow increases. As tidal volume increases, uptake efficiency
34 increases and flow dependence lessens. Pulmonary function response data and O3 uptake
35 efficiency data in humans generally indicate that the mode of breathing (oral versus nasal
36 versus oronasal) has little effect on upper RT or on total RT uptake efficiency, though one
37 study suggests that the nose has a higher uptake efficiency than the mouth.
38
39 When all of the animal and human in vivo O3 uptake efficiency data are compared,
40 there is a good degree of consistency across data sets. This agreement raises the level of
41 confidence with which these data sets can be used to support dosimetric model formulations.
42
43 Several mathematical dosimetry models have been developed since 1986. Generally,
44 the models predict that net O3 dose to lung lining fluid plus tissue gradually decreases
45 distally from the trachea toward the end of the tracheobronchial region, and then rapidly
46 decreases in the pulmonary region.
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1 When the dose of O3 to lung tissue is computed theoretically, it is found to be very low
2 in the trachea, to increase to a maximum in the terminal bronchioles of the first generation
3 pulmonary region, and then to decrease rapidly, moving further into the pulmonary region.
4 The increased tidal volume and flow, associated with exercise in humans, shifts O3 dose
5 further into the periphery of the lung and causes a disproportionate increase in distal lung
6 dose.
7
8 Preditions of delivered dose have been used to investigate O3 responses in the context
9 of intra- and interspecies comparisons. In the case of intraspecies comparisons, for example,
10 the distribution of predicted O3 tissue dose to a ventilatory unit in a rat as a function of
11 distance from the bronchoalveolar duct junction is very consistent with the distribution of
12 alveolar wall thickening. In the case of interspecies comparisons (using the delivered
13 O3 dose to the proximal alveolar regions), although the tachypneic responses (i.e., rapid,
14 shallow breathing) differ markedly between rats and humans, there is similarity of dose-
15 response patterns in inflammation among species, with humans and guinea pigs more
16 responsive than rats and rabbits. In other words, the quantitative relationship between animal
17 and human responses is dependent on the animal species and the endpoint.
18
19 In summary, there is an emerging consistency among a variety of O3 dosimetry data
20 sets and between the experimental data and theoretical predictions of O3 dose. The
21 convergence of experimental data with theoretical predictions lends a degree of confidence to
22 the use of theoretical models to predict total and regional O3 dose. The use of O3 dosimery
23 data and models is beginning to bear fruit in attempts to extrapolate effects between animals
24 and humans. The data and models have thus far helped demonstrate that humans may be
25 more responsive to O3 than rats with respect to inflammatory responses. Thus, chronic
26 effects data in rats may not accurately reflect the degree to which comparably exposed
27 humans would respond.
28
29
30 1.9 INTEGRATIVE SUMMARY OF OZONE HEALTH EFFECTS
31
32 This section summarizes the primary conclusions derived from an integration of the
33 known health effects of O3 provided by animal lexicological, human clinical, and
34 epidemiological studies.
35
36 1. What are the health effects of short-term (<8 h) exposures to ozone?
37
38 Acute O3 exposure of laboratory animals and humans causes changes hi pulmonary
39 function, including tachypnea (rapid, shallow breathing), decreased lung volumes and flows,
40 and increased airway responsiveness to nonspecific stimuli. Increased airway resistance
41 occurs in both humans and laboratory animals, but typically at higher exposure levels than
42 other functional endpoints. In addition, adult human subjects experience O3-induced
43 symptoms of airway irritation such as cough or pain on deep inspiration. The changes in
44 pulmonary function and respiratory symptoms occur as a function of exposure concentration,
45 duration, and level of exercise. Recovery of pulmonary function and the absence of
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1 O3-induced symptoms is usually complete within 24 h of the end of exposure, although other
2 responses may persist somewhat longer.
3
4 • Pulmonary function decrements are generally observed in healthy subjects
5 (8 to 45 years of age) after 1 to 3 h of exposure as a function of the level of
6 exercise performed and the O3 concentration inhaled during the exposure.
7 Group mean data from numerous controlled human exposure and field
8 studies indicate that, in general, statistically significant pulmonary function
9 decrements beyond the range of normal measurement variability (e.g., 3 to
10 5% for FEVi) occur
11
12 (1) at >0.5 ppm when at rest,
13 (2) at >0.37 ppm with light exercise (slow walking),
14 (3) at >0.30 ppm with moderate exercise (brisk walking),
15 (4) at >0.18 ppm with heavy exercise (easy jogging), and
16 (5) at >0.16 ppm with very heavy exercise (running).
17
18 For a number of studies, small group mean changes (e.g., <5%) in FEV1;
19 the medical significance of which is a matter of controversy, have been
20 observed at lower O3 concentrations than those listed above. For example,
21 data from one specific study indicate that FEVj decrements occur with very
22 heavy exercise in healthy adults at 0.15 to 0.16 ppm O3, and data from two
23 studies indicate that such effects may occur in healthy adults at levels as
24 low as 0.12 ppm. Also, pulmonary function decrements have been
25 observed in children and adolescents at concentrations of 0.12 and
26 0.14 ppm O3 with heavy exercise. Pulmonary function decrements were
27 observed at 0.12 ppm O3 in healthy young adults undergoing heavy exercise
28 in a recent study. Some individuals within a study may experience FEVj
29 decrements in excess of 15% under these exposure conditions, even when
30 the group mean decrement is less than 5 %.
31
32 • For exposures of healthy subjects performing moderate exercise during
33 longer duration exposures (6 to 8 h), 5% group mean decrements in FEV^
34 were observed at
35
36 (1) 0.08 ppm O3 after 5.6 h,
37 (2) 0.10 ppm O3 after 4.6 h, and
38 (3) 0.12 ppm O3 after 3 h.
39
40 For these same subjects, 10% group mean FEVj decrements were observed
41 at 0.12 ppm O3 after 5.6 and 6.6 h. As in the shorter duration studies,
42 some individuals experience changes larger than those represented by the
43 group mean changes.
44
45 • An increase in the incidence of cough has been reported at
46 O3 concentrations as low as 0.12 ppm in healthy adults during 1 to 3 h of
47 exposure with very heavy exercise. Other respiratory symptoms, such as
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1 pain on deep inspiration, shortness of breath, and lower respiratory scores
2 (a combination of several symptoms), have been observed at 0.16 to
3 0.18 ppm O3 with heavy and very heavy exercise. Respiratory symptoms
4 have also been observed following exposure to 0.08, 0.10, and 0.12 ppm
5 O3 for 6.6 h with moderate levels of exercise.
6
7 • Increases in nonspecific airway responsiveness have been observed after
8 1 to 3 h of exposure to 0.40 ppm, but not 0.20 ppm, O3 at rest, and have
9 been observed at concentrations as low as 0.18 ppm, but not to 0.12 ppm,
10 O3 during exposure with very heavy exercise. Increases in nonspecific
11 airway responsiveness during 6.6-h exposures with moderate levels of
12 exercise have been observed at 0.08, 0.10, and 0.12 ppm O3.
13
14 Acute O3 exposure of laboratory animals and humans disrupts the barrier function of
15 the lung epithelium, permitting materials in the airspaces to enter lung tissue, allowing cells
16 and serum proteins to enter the airspaces (inflammation), and setting off a cascade of
17 responses.
18
19 • Increased levels of neutrophils and protein in lung lavage fluid have been
20 observed following exposure of humans to 0.20, 0.30, and 0.40 ppm with
21 very heavy exercise and have not been studied at lower concentrations for
22 1- to 3-h exposures. Increases in protein and/or neutrophils have also been
23 observed at 0.08 and 0.10 ppm O3 during 6.6-h exposures with moderate
24 exercise; lower concentrations have not been tested.
25
26 Acute O3 exposure of laboratory animals and humans impairs alveolar macrophage
27 clearance of viable and nonviable particles from the lungs and decreases the effectiveness of
28 host defenses against bacterial lung infections in animals and perhaps humans. The ability of
29 alveolar macrophages to engulf microorganisms is decreased in humans exposed to 0.08 and
30 0.10 ppm for 6.6 h with moderate exercise.
31
32 2. What are the health effects of repeated, short-term exposures to ozone?
33
34 During repeated acute exposures, some of the O3-induced responses are partially or
35 completely attenuated. Over a 5-day exposure, pulmonary function changes are typically
36 greatest on the second day, but return to control levels by the fifth day of exposure. Most of
37 the inflammatory markers (e.g., neutrophil influx) also attenuate by the fifth day of exposure,
38 but markers of cell damage (e.g., lactate dehydrogenase enzyme activity) do not attenuate
39 and continue to increase. Attenuation of lung function decrements is reversed following 7 to
40 10 days without O3. Some inflammatory markers are also reversed during this time period,
41 but others still show attenuation even after 20 days without O3. The mechanisms and
42 impacts involved in attenuation are not known, although the underlying cell damage continues
43 throughout the attenuation process. In addition, attenuation may alter the normal distribution
44 of O3 within the lung, allowing more O3 to reach sensitive regions, possibly affecting normal
45 lung defenses (e.g., neutrophil influx in response to inhaled microorganisms).
46
47
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1 3. What are the health effects of long-term exposures to ozone
2
3 Exposure to O3 for months and years causes structural changes in several regions of the
4 respiratory tract, but effects may be of the greatest importance in the centriacinar regions
5 where the alveoli and conducting airways meet because this region is typically affected in
6 most chronic diseases of the human lung. This information on O3 effects in the distal lung is
7 derived from animal lexicological studies because, to date, such data are not available in
8 humans. Epidemiological studies attempting to associate chronic health effects in humans
9 with long-term O3 exposure have yet to provide unequivocal evidence that such a linkage
10 exists.
11
12 Chronic exposure of one strain of female mice to high 63 levels (1 ppm) caused a
13 small, but statistically significant increase hi lung tumors. There was no concentration-
14 response relationship and rats were not affected. Genotoxicity data are either negative or
15 weak. Given the nature of the database, the effects in one strain of mice cannot yet be
16 qualitatively extrapolated to humans. Ozone did not show tumor-promoting activity in a
17 chronic rat study (at 0.5 ppm O3).
18
19 4. What are the health effects of binary pollutant mixtures containing ozone?
20
21 Combined data from laboratory animal and controlled human exposure studies on
22 O3 support the hypothesis that coexposure to pollutants, each at low-effect levels, may result
23 in effects of significance. The data from human studies of O3 in combination with NO2,
24 SO2, sulfuric acid, nitric acid, or CO show no more than an additive response on lung
25 spirometry or respiratory symptoms. The larger number of laboratory animal studies with
26 O3 in mixture with NO2 and sulfuric acid show that effects can be additive, synergistic, or
27 even antagonistic, depending upon the exposure regimen and the endpoint studied. This issue
28 of exposure to copollutants remains poorly understood, especially with regard to chronic
29 effects.
30
31 5. What population groups are at-risk as a result of exposure to ozone?
32
33 Identification of population groups that may show increased susceptibility to O3 are
34 based on their (1) biological responses to O3; (2) physiological status (e.g., preexisting lung
35 disease); (3) activity patterns; (4) personal exposure history; and (5) personal factors (e.g.,
36 age, nutritional status).
37
38 The predominant information on the health effects of O3 noted above comes from
39 studies on healthy, nonsmoking, exercising subjects, 8 to 45 years of age. These studies
40 demonstrate that among this group, there is a large variation in sensitivity and responsiveness
41 to O3, with at least a 10-fold difference between the most and least responsive individuals.
42 Individual sensitivity to O3 may also vary throughout the year, related to seasonal variations
43 in ambient O3 exposure. The specific factors that contribute to this large intersubject
44 variability, however, remain undefined. Although differences may be due to the dosimetry
45 of O3 in the respiratory tract, available data show little effect on O3 deposition after
46 inhalation through the nose or mouth.
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1 Controlled studies on mild asthmatics suggest that they have similar lung volume
2 responses but greater airway resistance changes to O3 than nonasthmatics. Furthermore,
3 limited data from studies of moderate asthmatics suggest that they may have greater lung
4 volume responses than nonasthmatics. Daily life studies reporting an exacerbation of asthma
5 and decrease in peak expiratory flow rates, particularly in asthmatic children, appear to
6 support the controlled studies; however, those studies are confounded by concurrent
7 temperature, particle or aeroallergen exposure, and asthma severity of the subjects or their
8 medication use. In addition, field studies of summertime daily hospital admissions for
9 respiratory causes show a consistent relationship between asthma and ambient levels of O3 in
10 various locations in the northeastern United States, even after controlling for independent
11 contributing factors.
12
13 Other population groups with preexisting limitations in pulmonary function and exercise
14 capacity (e.g., chronic obstructive pulmonary disease, chronic bronchitis, ischemic heart
15 disease) would be of primary concern in evaluating the health effects of O^. Unfortunately,
16 not enough is known about the responses of these individuals to make definitive conclusions
17 regarding their relative responsiveness to O3. Indeed, functional effects in these individuals
18 with reduced lung function may have greater clinical significance than comparable changes in
19 healthy individuals.
20
21 Currently available data on personal factors or personal exposure history known or
22 suspected of influencing responses to O3 are the following.
23
24 • Human studies have identified a decrease in pulmonary function
25 responsiveness to O3 with increasing age, although symptom rates remain
26 similar. Toxicological studies are not easily interpreted but suggest that
27 young animals are not more responsive than adults.
28
29 • Available lexicological and human data have not conclusively demonstrated
30 that males and females respond differently to O3. If gender differences
31 exist for lung function responsiveness to O3, they are not based on
32 differences in baseline pulmonary function.
33
34 • There is no compelling evidence to date to suggest that any ethnic or racial
35 group has a different distribution of responsiveness to O3. However, data
36 are not adequate to rule out the possibility of such differences.
37
38 • Information derived from O3 exposure of smokers is limited. The general
39 trend is that smokers are less responsive than nonsmokers. This reduced
40 responsiveness may wane after smoking cessation.
41
42 • Although nutritional status (e.g., vitamin E deficiency) makes laboratory
43 rats more susceptible to O3-induced effects, it is not clear if vitamin E
44 supplementation has an effect in human populations. Such supplementation
45 has no or minimal effects in animals. The role of such antioxidant vitamins
46 in O3 responsiveness, especially their deficiency, has not been well studied.
47
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1 Based on information presented in this document, the population groups that have
2 demonstrated responsiveness to ambient concentrations of O3 consist of exercising healthy
3 and asthmatic individuals, including children, adolescents, and adults.
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i 9. INTEGRATTVE SUMMARY OF OZONE
2 HEALTH EFFECTS
3
4
5 9.1 INTRODUCTION
6 This chapter integrates the knowledge gained in animal toxicological, human clinical,
7 and epidemiological studies of ozone (O3) that were discussed in Chapters 6, 7, and 8
8 respectively, of the criteria document. Because each of these approaches has different
9 strengths and weaknesses, a combined evaluation can better describe the full array of health
10 effects that are known to occur with exposure to 03.
11 The chapter is organized according to the health effects of short- and long-term
12 exposures of O3 alone and exposures to binary mixtures with O3. The section on short-term
13 exposures (i.e., less than 8 h) begins with a discussion of the relationship between exposure
14 and dose, as this lays a foundation for inter- and intraspecies extrapolation. Effects on lung
15 function, exacerbation of existing disease, and cellular-biochemical responses are then
16 presented descriptively. Finally, quantitative exposure-response relationships for the effects
17 of O3 on pulmonary function (e.g., changes in lung volume) are summarized separately
18 because the large number of studies allows more complex evaluations and modeling. For the
19 other classes of effects, the exposure-response information is integrated with the description
20 of the effects. The section on long-term exposures encompasses repeated exposures (i.e.,
21 1 to 5 days), prolonged exposures (i.e., months), and genotoxicity and carcinogenicity.
22 Because the data base on binary exposure studies has little predictive value, the emphasis is
23 placed on the principles of interaction. The conclusions section is organized according to
24 key questions.
25 Because this chapter integrates the results of a large number of studies from the current
26 and earlier O3 criteria documents, it is not practical to provide experimental details or cite
27 specific references. Rather, emphasis is given to main findings which are supported by
28 theory or other confirmatory studies, unless noted otherwise. Comprehensive details and
29 references are provided in the previous chapters.
30
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1 9.2 HEALTH EFFECTS OF SHORT-TERM EXPOSURES
2 9.2.1 Exposure-Dose Relationships
3 Qualitative and quantitative health assessment requires, among other things, the ability
4 to relate exposure to dose and dose to effect. In the case of O^ health assessment, this
5 ability is necessary for two major reasons: (1) to develop unified predictive models of
6 human population responses based upon exposure; and (2) to enable extrapolation from
7 animals to humans for chronic effects. Physically and biologically based models of dose
8 simplify the methods of predicting population responses and in turn significantly reduce the
9 uncertainty of these predictions. For animal-to-human extrapolations, splitting the problem
10 of exposure and response into an exposure-dose problem and a dose-response problem
11 separates the issue of interspecies sensitivity from purely dosimetric considerations.
12 Responses in animals may be homologous with humans but follow different dose-response
13 curves. By measuring or computing delivered O3 dose to relevant tissues in animals and
14 humans, transfer functions can, in principle, be developed relating dose-response curves
15 among different species. This section discusses the understanding of exposure-dose
16 relationships and how they improve the ability to interpret and predict O3 responses.
17 Historically, the first step beyond describing responses solely in terms of exposure
18 concentration was the use of the product of concentration x time x minute ventilation
19 (C x T x VE), yielding what has been often referred to as an "effective dose". Response
20 modeling has examined the interaction of individual pairs of variables. However, no single
21 model has been able to simply unify any response in terms of the product C x T x VE.
22 This is due to the fact that C x T x VE is a metric of exposure dose and not delivered dose
23 and, furthermore, does not account for the mediation of responses in localized regions of the
24 lung that would be responding to local O3 doses. Advances in O3 dosimetry modeling and
25 experimental determinations of regional O3 dose in animals and humans have enabled
26 extensions beyond simple C x T X VE modeling to interpret responses.
27 Ozone dosimetry models provide predictions on the dose distribution of O3 in the
28 respiratory tract from the trachea to the alveolar spaces of the lung. These models utilize the
29 best available anatomical, physiological, and biochemical data available for animals and
30 humans. These data are incorporated into mathematical formulations of convection,
31 diffusion, and chemical reaction processes in the lung. The models predict that under resting
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1 ventilatory conditions, the O3 dose per airway generation to all respiratory tract constituents
2 (tissue plus fluid) slowly decreases from the trachea to the terminal and respiratory
3 bronchioles and then declines in the alveolated generations. When dose of O3 to tissue alone
4 is considered (taking account of reaction and diffusion kinetics in the liquid lining layer),
5 there is a three order of magnitude increase in tissue dose from the trachea to the proximal
6 alveolar regions, after which the tissue and total dose are virtually equal and fall rapidly in
7 the alveolated generations. Currently, relationships between delivered regional dose and
8 response are derived assuming that O3 is the active agent directly responsible for effects.
9 There is uncertainty, however, whether this assumption is correct. Reactive intermediates,
10 such as peroxides and aldehydes formed when O3 interacts with constituents of lung lining
11 fluid, may be the agents mediating responses. Thus, the dose of the reactive intermediates
12 may be more relevant than the dose of O3. Despite this suggestion, the histopathological
13 findings from chronic O3 exposures in animals match the predicted distribution of O3 dose
14 (i.e., the sites of the highest predicted O3 doses correspond with those regions of the lung
15 with the greatest tissue alterations).
16 Experimental studies in humans have revealed some important features needed for
17 health assessment. Among these is the observation that the dose of O3 delivered to the lower
18 respiratory tract is independent of the mode of breathing (i.e., oral versus nasal versus
19 oronasal). This observation simplifies health assessment by eliminating the need for precise
20 information on modes of breathing when considering population responses. Experimental
21 studies in humans have also shown that increasing VE with exercise (increasing both
22 breathing frequency and tidal volume) only causes a small decrease in O3 uptake efficiency
23 by the total respiratory tract. Based on models of O3 dose, it appears that the increased
24 VE in exercise, though having little effect on uptake efficiency by the total respiratory tract,
25 causes the distribution of delivered O3 dose to shift deeper into the respiratory tract. The
26 shift in O3 dose as a function of VE could help explain the complex relationships seen
27 between response and C, T, and VE. An important observation from the human
28 experimental dosimetry studies is the general agreement between O3 dosimetry models and
29 the measured data.
30 Experiments in laboratory animals (particularly rats) have been valuable in providing,
31 in conjunction with human experimental data and mathematical dosimetry models, the basis
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1 for dosimetric extrapolation. Whereas the human total respiratory tract has an O3 uptake
2 efficiency between 70 and 100%, the respiratory tract of the rat only takes up about 50% of
3 the inhaled O3. Unlike the case with humans, the dosimetry models overestimate the uptake
4 efficiency of the rat respiratory tract by approximately 25 to 50% (i.e., the predicted uptake
5 efficiency is between 65 and 75%), but the models are still highly valuable for extrapolation
6 purposes. An important finding has been that the models correctly relate the regional dose of
7 O3 to the increase in alveolar wall thickness, both of which decline with distance from the
8 junction of the conducting airways and the alveolar regions of the lung.
9 Experimental O3 dosimetry and predictive O3 dosunetry models are informative about
10 the feasibility of extrapolating animal responses to humans. Some responses to 03 can be
11 compared across species on a strict dose-response basis. For example, both animals and
12 humans respond to O3 in a dose-dependent manner by increasing breathing frequency and
13 decreasing tidal volume (tachypnea). A qualitative comparison between rat and human
14 tachypneic responses at a variety of O3 concentrations and exercise levels indicate that when
15 exercising, rats and humans have a similar response, but at rest rats are somewhat more
16 responsive. However, when dose to the proximal alveolar region of the lung (normalized to
17 body weight) is considered as the dose metric for tachypneic responses, rats appear to be
18 much more responsive than humans. Another example is influx of protein into the alveolar
19 spaces following O3 exposure as measured in bronchoalveolar lavage (BAL) fluid. When
20 BAL protein is plotted as a function of pulmonary tissue dose, the rat, guinea pig, rabbit,
21 and human all respond with a similar dose-response pattern, reflecting a common mechanism
22 of response. However, each curve is offset from the other, reflecting overall sensitivity
23 differences among the species, with the human and guinea pig being more responsive than
24 the rat and rabbit.
25
26 9.2.2 Physiological Responses to Ozone Exposure
27 Typical acute physiological responses to 03 exposure in humans include a reduction in
28 forced vital capacity (FVC), decreased expiratory flow rates, and increased respiratory
29 symptoms. The most common symptoms include cowjj|flairway irritation, and chest
I'V' X. I WiiaJ : irtJH |W]i) i i,li i.n V4HWI I I
30 discomfort associated with a deep inhalation. These responses are often accompanied by
31 increased airway resistance and tachypnea. The voluntary spirometry and symptom
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1 responses cannot be elicited from animals, but their tachypneic response is well documented.
2 Ozone exposure also increases airway responsiveness to nonallergenic airway stimuli (e.g.,
3 histamine) in humans and animals. There is a large range of responses among humans with
4 at least a 10-fold difference between the most and least responsive individuals.
5
6 9.2.2.1 Respiratory Symptom Responses
7 \ The principal symptoms associated with O3 exposure in humans include cough,
-.-$; , ' . .'-„..,.--;
8 : irritation of the airways (described as a scratchy throat or discomfort under the sternum), and
when Sati|ffa deep breath (described as chest ti^^inMrpaii% fie chest).
^-sometimesReported"as a symptom in field or epidemiological studies witti
11 ) to oxidant mixtures, is not associated with exposure to O^ alone. The receptors responsible
12 for cough may be unmyelinated C-fibers or rapidly adapting receptors located in the larynx
13 and the largest conducting airways. Thus, there appears to be a potential mechanistic linkage
14 to changes in spirometry. Field and epidemiological studies also indicate an association
15 fc*tjetween hourly or daily ambient 03 levels and the presence of symptoms, particularly
16 I Such associations may-lie most evident in aslhmatic children? ^Although symptoms"cahtiotTxT
17 elicited from animals, indirect measures of symptom responses in animals include behavioral
18 responses indicative of aversion to O3 exposure.
19 Symptom responses to O3 exposure follow a monotonic exposure-response relationship
20 that has a similar form to that for spirometry responses. Increasing exposure levels elicit
21 increasingly more severe symptoms that persist for longer periods. Symptom and spirometry
22 responses follow a similar time course during an acute exposure and the subsequent recovery
23 as well as over the course of several days in a repeated exposure study. Furthermore,
24 medication interventions that block or reduce spirometry responses have a similar effect on
25 symptom responses. Levels at which symptoms occur under various exposure conditions are
26 discussed in Section 9.2.5.1. As with spirometry responses, symptom responses vary
27 considerably among subjects, although the individual correlations between spirometry and
28 symptom responses are relatively low. In several heavy or severe exercise studies of athletes
29 exposed to O3, the discomfort associated with the respiratory symptoms caused by
O3 concentrations in excess of 0.18 ppm was of sufficient severity that the athletes reported^*
that they would have been unable to perform maximally, if the conditions of the exposure >
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1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
19
20
21
22
23
24
25
26
27
28
29
30
31
present during athletic competition. In workers or active people exposed to O3,
respiratory symptoms may cause reduced productivity or curb the desire to pursue leisure
activity.
Symptom responses have also been reported in asthmatics exposed-to-Qg- In contrast to
nonasthmatics, wheezing is a prevalent symptom in addition to cough, chest tightness, aa4'f:v;:
,-.-,- ' •'Hr-'i'iS
-' '-' ' " , :., " =3
shortness of breath that are reported by subjects without asthma.
9.2.2.2 Changes in Lung Volume
In humans, 0j exposure reduces FVC primarily by decreasing iaspiratory
This is believed to be the result of neurogenic inhibition of maximal inspiration, possibly
caused by stimulation off C-fibesr afferents. C-fibers are also thought to be the receptors
responsible for the cough reflex in humans. After exposure to O3, coughing is frequently
elicited during the deep inspiration prior to the forced expiratory maneuver used in dynamic
spirometry tests such as FVC, forced expiratory volume in 1 s (FEVj), and forced expiratory
flow at 25 to 75% of FVC (FEF25_75%). The observation that nonsteroidal antiinflammatory
drugs (e.g., indomethacin, ibuprofen) reduce or block spirometric responses to O3 exposure
17 and reduce levels of prostaglandin £2 (PGE2) within the lung suggest that mediators released
18 , by damaged epithelial cells .and/or alveolar macrophages may play
m^dmal inspiration. Although it seems clear that the reduction in total lung capacity (TLC)
is not attributable to reduced lung compliance (i.e., a stiffer lung ) or inspiratory muscle
weakness, the understanding of the mechanism(s) which cause this response remains
incomplete. The O3-induced tachypneic response, seen in many animal species and in
exercising humans, may be related to the decrease in vital capacity. The tachypneic response
hi humans may not be entirely involuntary because it has been reported that O3-exposed
subjects may consciously modify their breathing pattern to relieve discomfort.
The time course of the spirometry responses to O3 exposure depends on the exposure
conditions.
|8ppm), responses are induced slowly
of response depending upon the duration of the exposure. At higher levels of
(e.g., very heavy exercise andO? concentration >Q.25 ppmj, responses occur Hf
StHwwf%••/ r - . -,- . '•; - -"*-.. - •- - -- : •"* •, . .-.-,. f<--j/i:-: ^?i-*»*?**.-21s;
/ rapidly (within 15 min) and the largest portion of the response tends to occur early in
February 1994
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3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
mwtthta 1 i to 2 h- The exposure-response relationships are
discussed more extensively in Section 9.2.5.
9.2.2.3 Responses to Ambient Ozone Exposures
"is-av •*-»*#>
and adolescents exposed to
changes mspnometry similar to those
«rimeotal <)aaditiofes, il^re is a substantial range of
* f „„
"respcmselinTong individuals in camp studies arid "between various locations. However, the
average FEV^ was lower when ambient O3 was higher. Although direct comparisons cannot
be made because of incompatible differences in experimental design and analytical approach,
this range of response is comparable to the range of responses seen in chamber studies at low
O3 concentrations. The similarity of response between field and chamber studies leaves little
doubt as to the relevance of controlled human exposure studies.
9.2.2.4 Changes in Airway Resistance
airway resistance following O3 exposure are small relative to those
with an inhalation exposure to a bronchoconstricting drug (methacholine),
a specific antigen, or to sulfur dioxide (SO2). However, because the airways of healthy
nonallergic people are relatively nonresponsive to a number of stimuli, including allergens,
methacholine, and histaminej
.whose airways are much more sensitive, u3 aeenrrorcause
although the changes are clearly greater than in healthy young
subjects. In rats exposed to O3, changes in resistance also tend to be small. The observation
that changes in airway resistance are modest clearly indicates that reductions in maximum
expiratory flow are not caused primarily by narrowing of large airways. The increase in
airway resistance appears to be vagally mediated because it is sensitive to inhibition by
atropine.
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1 9.2.2.5 Changes in Breathing Pattern
2 k " ' "
M; 5 :•--•>•.
3 breathing
i»"*-'» . -, "" "^
4 ^fc^^^pjMal breaths.OT particulif IntereitToFBo^aring
5 interspecies responses is that the responses of rats and guinea pigs fall within the same range
6 as seen for humans from rest to heavy exercise.
7
8 9.2.2.6 Changes in Airway Responsiveness
9 Ozone exposure causes increased responsiveness of the pulmonary airways to
10 subsequent challenge with bronchoconstrictor drugs such as histamine or methacholine.
11 Although this phenomenon is seen even after regression of spirometric changes, it is typically
12 no longer present after 24 h. One animal study has demonstrated decreased antigen-induced
13 bronchoconstriction after O3 exposure, and one human study is suggestive of an increase in
14 such a response. An increased response to a specific antigen to which a human is sensitized
15 is a plausible outcome of O3 exposure but needs to be further investigated. Although
16 changes in airway responsiveness tend to resolve somewhat more slowly and appear to be
17 less likely to be attenuated with repeated exposure, the evidence for a persistent increase in
18 responsiveness from animal studies is inconsistent. Changes in airway responsiveness in rats
19 and guinea pigs tend to occur at higher O3 concentrations and, as in humans, tend to be most
20 pronounced shortly after the exposure and less so 24 h postexposure. Changes in airway
21 responsiveness appear to occur independently of changes in pulmonary function. This
22 response does not appear to be due to inflammation (at least PMNs) or to the release of
23 arachidonic acid metabolites, but may be due to epithelial damage and the consequent
24 increased access of these chemicals to smooth muscle in the airways or to the receptors in the
25 airways responsible for reflex bronchoconstriction. The clinical relevance of this observation
26 is that after O3 exposure, human airways may be more susceptible to a variety of stimuli,
27 including antigens, chemicals, and particles.
28
29 9.2.2.7 Small Airways Responses
30 There are several tests purported to be indicators of "small airways" function, although
31 the morphological correlate of these functional tests is not clearly established.
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1 Morphologically, the small airways of the centriacinar region of the lung, that segment
2 between the last conducting airway and the gas exchange region, is highly susceptible to
3 damage by O3 and is the site of epithelial cell necrosis and remodelling of respiratory
4 bronchioles. Numerous pulmonary function tests reputed to measure responses in small
5 airways (e.g., closing volume, aerosol bolus) have been used in O3 studies. Responses have
6 been demonstrated, but it is not clear that these tests correlate with the morphological lesion
7 observed in animals, which is presumed to occur but has not been demonstrated in humans.
8 In dogs whose peripheral airways are directly exposed to O3 through a wedged
9 bronchoscope, the collateral resistance to airflow through nonairway channels is increased
10 almost immediately.
11
12 9.2.2.8 Effects on Exercise Performance
13 A large number of studies show that O3 exposure can interfere with exercise
14 performance, either by reducing maximal sustainable levels of activity or reducing the
15 duration of activity which can be tolerated at a particular work level. Such effects can be
16 seen with very heavy exercise at O3 concentrations of 0.18 ppm and above. Although there
17 are a large number of factors which can alter maximal or submaximal exercise performance,
18 many investigators have implicated the respiratory symptoms caused by O3 exposure. Small
19 changes in airway resistance have no effect on maximal or submaximal exercise
20 performance, and even modest mechanical restriction of total lung capacity will not induce a
21 respiratory limitation to maximal or submaximal exercise. Animals studies indicate
22 decreased wheel running activity and decreased activity associated with obtaining food.
23 Decreased worker productivity has also been associated with elevated O3 levels.
24
25 9.2.3 Exacerbation of Existing Disease
26 9.2.3.1 Responses of Asthmatics to Controlled Ozone Exposure
27 Asthmatics have qualitatively similar responses to O3 exposure as nonasthmatics.
28 Although symptom and volume related responses (i.e., decreased FVC) tend to be similar,
29 airway resistance increases relatively more, from an already higher baseline, hi asthmatics
30 exposed to O3. Altered responsiveness to bronchoconstrictor drugs shows similar changes in
31 asthmatics and nonasthmatics. There is no evidence at this time that O3 induces a persistent
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1 increase in airway responsiveness or that O3-exposed asthmatics are more likely to have a
2 late phase response to specific antigen challenge.
3
4 9.2.3.2 Increased Hospital Admissions and Asthma Attacks
5 A number of epidemiological studies have shown a consistent relationship between
6 ambient oxidant exposure and acute respiratory morbidity in the population. Decreased lung
7 function and increased respiratory symptoms, including exacerbation of asthma, occur with
8 increasing ambient O3, especially in children. Modifying factors, such as ambient
9 temperature, aeroallergens, and other copollutants (e.g., particles) can also contribute to this
10 relationship. Ozone air pollution may at least account for a portion of summertime hospital
11 admissions for respiratory causes, because studies conducted in various locations in the
12 eastern United States have consistently shown a relationship with increased incidence of
13 admissions, even after controlling for modifying factors, as well as when considering only
14 concentrations below 0.12 ppm O3. It has been estimated from these studies that O3 may
15 account for roughly one to three excess respiratory hospital admissions per hundred parts per
16 billion O3, per million persons.
17 The association between elevated ambient O3 concentrations during the summer months
18 and increased hospital admissions has a plausible biologic basis in the physiologic,
19 symptomatic, and field study evidence discussed earlier. Specifically, increased airway
20 responsiveness, airway inflammation, increased airway permeability, and increased incidence
21 of asthma attacks suggest that ambient O3 exposure could be a cause of the increased hospital
22 admissions, particularly for asthmatics.
23
24 9.2.4 Cellular-Biochemical Responses
25 9.2.4.1 Inflammation and Cell Damage
26 Ozone-induced cell injury may lead to effects including inflammation, altered
27 permeability of the epithelial barrier, impaired host defense and particle clearance,
28 irreversible structural alterations in the lung, exacerbation of preexisting disease (e.g.,
29 asthma), and increased sensitivity to biocontaminants (e.g., allergens). Of these, O3-induced
30 inflammation of the respiratory tract has been best documented and occurs in all species that
31 have been studied. The mechanisms leading to the observed inflammatory responses induced
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1 by O3 are just beginning to be studied. Both animal morphological studies and in vitro
2 studies indicate that airway ciliated epithelial cells and Type 1 cells are the most O3-sensitive
3 cells, and are initial targets of O3. These cells are damaged by O3 and produce a number of
4 proinflammatory mediators (e.g., IL-6, JCL-8, PGI^) capable of initiating a cascade of events
5 leading to neutrophil influx into the lung, activation of alveolar macrophages, inflammation,
6 and increased permeability across the epithelial barrier.
7
8 Ozone-Induced Inflammation in the Lower Respiratory Tract
9 In general, inflammation can be considered as the host response to injury and the
10 induction of inflammation as evidence that injury has occurred. Inflammation induced by
11 exposure of humans to O3 can have several outcomes: (1) inflammation induced by a single
12 exposure (or several exposures over the course of a summer) can resolve entirely;
13 (2) continued acute inflammation can evolve into a chronic inflammatory state; (3) continued
14 inflammation can alter the structure and function of other pulmonary tissue, leading to
15 diseases such as fibrosis; (4) inflammation can alter the body's host defense response to
16 inhaled microorganisms, particularly in potentially vulnerable populations such as the very
17 young and old; and (5) inflammation can alter the lung's response to other agents such as
18 allergens or toxins. It is also possible that the profile of response can be altered in persons
19 with preexisting pulmonary disease (e.g., asthma or COPD) or smokers.
20 The recent use of BAL as a research tool in humans has afforded the opportunity to
21 sample the lung and lower airways of humans exposed to O3 and to ascertain the extent and
22 course of inflammation and its constitutive elements. Several studies have shown that
23 humans exposed acutely (1 to 3 h) to 0.2 to 0.6 ppm O3 had O3-induced inflammation, cell
24 damage, and altered permeability of epithelial cells lining the respiratory tract (allowing
25 components from plasma to enter the lung). The lowest concentration of O3 tested,
26 0.08 ppm for 6.6 h, also induced increases in these endpoints. Short-term (< 8 h) exposure
27 of animals to O3 also results in cell damage, inflammation, and altered permeability,
28 although, in general, higher O3 concentrations are required to elicit a response equivalent to
29 that of humans. Because humans were exposed to O3 while exercising and most animal
30 studies were done at rest, differences in ventilation likely play a significant role in the
31 different response of humans and rodents to the same O3 concentration. Studies in which
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1 animals were exposed at night (during their active period), or in which ventilation was
2 increased with CO2, tend to support this idea.
3 Studies utilizing BAL techniques sample only free or loosely adherent cells in the lung;
4 thus, it is possible that cellular changes have occurred in the interstitium that are not
5 reflected in BAL studies. However, morphometric analyses of inflammatory cells present in
6 lung and airway tissue sections of animals exposed to O3 are in general agreement with BAL
7 studies. Short-term O3 exposure (< 8 h) causes similar types of alterations in lung
8 morphology in all laboratory animal species studied. The most affected cells are the ciliated
9 epithelial cells of the airways and Type 1 cells in the alveolar region. The centriacinar
10 region (the junction of the conducting airways and gas exchange region) is a primary target,
11 possibly because it receives the greatest dose of O3 delivered to the lower respiratory tract.
12 Sloughing of ciliated epithelial and Type 1 cells occurs within 2 to 4 h of exposure of rats to
13 0.5 ppm O3.
14
15 Ozone-Induced Inflammation in the Upper Respiratory Tract
16 Ozone causes inflammatory changes throughout the respiratory tract, including the
17 nose. Humans and laboratory animals exposed to O3 develop inflammation and increased
18 permeability in the nasal passages. Thus O3-induced changes in the nasal passages may
19 reflect similar changes occurring in the lung. A recent study reported a positive correlation
20 between nasal inflammation in children and measured ambient O3 concentrations. Studies
21 with rats suggest a potential competing mechanism between the nose and lung, with
22 inflammation occurring preferentially in the nose at low O3 concentrations and shifting to the
23 lung at higher concentrations. It is unclear if this represents a specialization restricted to rats
24 or is a more general phenomenon.
25
26 Time Course of Ozone-Induced Inflammatory Response
27 Findings from human and animal studies agree that the O3-induced inflammatory
28 response occurs rapidly and persists for at least 24 h. Increased levels of neutrophils and
29 protein are observed in the BAL fluid within 1 h following a 2-h exposure of humans to
30 O3 and continue for at least 20 h. The kinetics of response during this time have not been
31 well studied in humans, although a single study shows that neutrophil levels are higher at
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1 6 h postexposure than at 1 or 20 h. Several animal studies suggest that neutrophil and BAL
2 protein levels peak 12 to 16 h after an acute O3 exposure, and begin to decline by 24 h,
3 although some studies report detectable BAL neutrophils even 36 h after exposure. It is also
4 clear that hi humans the pattern of response differs for different inflammatory mediators.
5 Mediators of acute inflammation, such as IL-6 and PGE^, are more elevated immediately
6 after exposure; whereas mediators that could potentially play a role in resolving
7 inflammation, such as fibronectin and plasminogen activator, are preferentially elevated
8 18 h after exposure. The rapidity with which cellular and biochemical mediators are induced
9 by O3 makes it conceivable that some of them may play a role in O3-induced changes in lung
10 function—indeed there is some evidence that BAL PGE2 levels are correlated with
11 decrements in FEV^, and anti-inflammatory medications that block PGE2 production also
12 reduce or block the spirometric responses to O3. Although earlier studies suggested that
13 O3-induced PMN influx might contribute to the observed increase in airway hyperreactivity,
14 animal studies show that when neutrophils are prevented from entering the lung, O3-induced
15 hyperreactivity or increases in many inflammatory mediators still occur. In addition, studies
16 hi which anti-inflammatory drags are used to block O3-induced lung function decrements,
17 still show increases in neutrophils and most other inflammatory mediators (although PGEj is
18 not increased).
19
20 Individuals and Populations Susceptible to Ozone
21 To date, there have been no studies that have examined the cellular/biochemical
22 response of potentially susceptible subpopulations, such as asthmatics, to O3; nor are there
23 any data in humans addressing whether age, gender, or racial differences can modify the
24 inflammatory response to O3. However, inflammation is not induced to the same extent in
25 all individuals. In moderately exercising humans exposed to 0.08 ppm O3 for 6.6 h, the
26 mean changes in inflammatory indices were low, but some individuals had increases
27 comparable to those reported hi heavily exercising subjects exposed to 0.4 ppm O3 for 2 h,
28 suggesting that some segments of the population may be more responsive to low levels of O3.
29 It has not yet been studied whether intersubject differences hi inflammatory response to
30 O3 are reproducible over time for the same subject, as has been shown for intersubject
31 differences in lung function. There seems to be no strong correlation between the various
February 1994 9-13 DRAFT-DO NOT QUOTE OR CITE
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1 mediators of inflammation, cell damage, and permeability (i.e., those individuals with the
2 greatest neutrophil response are not necessarily those with the greatest BAL protein, PGI^,
3 or IL-6 response). Furthermore, the magnitude of lung function decrements and respiratory
4 symptoms has not yet been shown to be correlated with mediators of inflammation, with the
5 possible exception of PGE^.
6 Animal studies also show large interspecies and interstrain differences hi response to
7 O3 and suggest that genetic factors may play a role in susceptibility to O3. Different rat
8 strains respond to O3 differently; for example, Wistar rats have the greatest neutrophil
9 influx, whereas Fisher rats demonstrate the most epithelial cell damage. In addition, limited
10 data suggest that dietary antioxidant levels may affect the response of rodents to O3 and that
11 very young rats produce more PGF^ in response to O3 than do older rats. Taken as a whole,
12 both the human and animal studies suggest that the inflammatory response to O3 is complex
13 and that determinants of susceptibility may occur at several different genetic loci.
14
15 9.2.4.2 Host Defense
16 The mammalian respiratory tract has a number of closely integrated defense
17 mechanisms that, when functioning normally, provide protection from the adverse effects of
18 a wide variety of inhaled particles and microbes. Impaired mucociliary clearance can result
19 in unwanted accumulation of cellular secretions and increased numbers of particles and
20 microorganisms in the lung, leading to increased infections and bronchitis.
21
22 Mucociliary Clearance of Inhaled Particles
23 Animal studies consistently show that clearance of inhaled insoluble particles is slowed
24 after acute exposure to O3. Ozone-induced damage to cilia and increased mucus secretion
25 likely contribute to a slowing of mucociliary transport rates. Interestingly, retarded
26 mucociliary clearance is not observed in animals exposed repeatedly to O3. The effects of
27 O3 on mucociliary clearance in humans has not been well studied, and the results are
28 somewhat conflicting; one study reports an O3-induced increase in particle clearance in
29 subjects exposed to 0.4 ppm O3 for 2 h, and another study reports no O3-induced change in
30 particle clearance with a similar exposure regimen.
31
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1 Alveolar Macrophage Function
2 Macrophages represent the first line of defense against inhaled microorganisms and
3 particles that reach the lower airways and alveoli. Studies in both humans and animals have
4 shown that there is an immediate decrease in the number of BAL macrophages following
5 O3 exposure. Alveolar macrophages also have been shown to be crucial to the clearance of
6 certain gram-positive bacteria from the lung. Several studies in both humans and laboratory
7 animals have also shown that O3 impairs the phagocytic capacity of alveolar macrophages,
8 and some studies suggest that mice may be more impaired than rats. The production of
9 superoxide anion (an oxygen radical used in bacterial killing) by alveolar macrophages also is
10 depressed in both humans and animals exposed to O3, and the ability of alveolar
11 macrophages to directly kill bacteria is impaired. Decrements in alveolar macrophage
12 function have been observed in moderately exercising humans exposed to the lowest
13 concentration tested, 0.08 ppm O3 for 6.6 h.
14
15 Interaction with Infectious Agents
16 Concern about the effect of O3 on susceptibility to respiratory infection derives
17 primarily from animal studies in which O3-exposed mice die following a subsequent
18 challenge with aerosolized bacteria. Mortality has been shown to be concentration-
19 dependent, and exposure to as little as 0.08 ppm O3 for 3 h can increase mortality of mice to
20 a subsequent challenge with Streptococcus bacteria. In addition, younger mice are more
21 susceptible to infection than older mice; this has been related to increased PGF^ production
22 in these animals, which likely decreases alveolar macrophage activity.
23 It has been suggested that impaired alveolar macrophage function is the mechanism
24 likely responsible for enhanced susceptibility to bacteria. However, mortality is not observed
25 with other rodent species, raising the question of whether this phenomenon is restricted to
26 mice. Although both mice and rats show impaired macrophage killing of inhaled bacteria
27 following O3 exposure; rats mount a faster neutrophil response to O3 to compensate for the
28 deficit in alveolar macrophage function. The resulting slower clearance time in mice allows
29 the Streptococcus strain to persist in lung tissue and subsequently elaborate a number of
30 virulence factors that evade secondary host defense and lead to bacterial multiplication and
31 death of the host. Mortality as an endpoint is not directly relevant to humans; however,
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1 humans and laboratory animals share many host defense mechanisms being measured by
2 mortality in the mouse model.
3 There is no compelling evidence from lexicological, human clinical, or epidemiological
4 studies that O3 increases the incidence of respiratory viral infection in humans. A study of
5 experimental rhinovirus infection in susceptible volunteers failed to show any effect of
6 5 consecutive days of O3 exposure (0.3 ppm, 8 h/day) on the clinical picture or on host
7 response. Studies in which O3-exposed mice were challenged with influenza virus report
8 conflicting results, with some studies showing increased mortality, some showing decreased
9 mortality, and still others showing no change at all. However, even when increased
10 mortality was demonstrated, there was no difference in viral tilers in the lung, suggesting
11 virus-specific immune functions were not altered.
12 Taken as a whole, Ihe data clearly indicate lhat an acute O3 exposure impairs Ihe host
13 defense capability of both humans and animals, primarily by depressing alveolar macrophage
14 function and perhaps also by decreasing mucociliary clearance of inhaled particles and
15 microorganisms. This suggesls lhal humans exposed to O3 are likely to be predisposed to
16 bacterial infections in Ihe lower respiratory iracl. The seriousness of such infections may
17 depend on how quickly bacteria develop virulence factors and how rapidly neutrophils are
18 mobilized to compensate for Ihe deficil in alveolar macrophage function.
19 Ozone also has been reported to suppress natural killer cell activity in the lung, to
20 suppress proliferative responses to bacterial antigen (Lisleria) in bolh spleen and bronchial
21 lymph nodes, and to induce delayed hypersensilivily responses lo Lisleria antigen. However,
22 these effects occur al higher exposure levels (0.75 lo 1.0 ppm O3) lhan those thai affecl
23 macrophage function.
24
25 9.2.5 Ozone Exposure-Response Relationships
26 A quantitative understanding of Ihe relationship between O3 exposure and subsequenl
27 response is useful bolh for a better understanding of Ihe processes underlying oulcomes of
28 interest and for purposes of prediction. Examples of Ihe ulilily of Ihe latter include
29 identification of exposures unlikely lo produce effecls, risk and benefils assessmenl, and
30 prediction of responses based on exposures for which empirical dala do nol exisl. Exposure-
31 response relationships exisl bolh for Ihe population as a whole and for individuals wilhin Ihe
February 1994 9-16 DRAFT-DO NOT QUOTE OR CITE
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1 population. The form of the exposure-response relationship can be different for populations
2 and individuals, and predicted magnitudes of effect for the population generally do not reflect
3 the experience of all individuals.
4 Exposure-response relationships can be described in terms of concentration of
5 O3, dose rate of exposure, total inhaled dose, or dose at the active site. Most of the
6 completed work to date has focused on describing the relationships between C, VE, and
7 T (as introduced in Section 9.2.1) for either pulmonary function or BAL outcomes. Parallel
8 work has been performed in both humans and in laboratory animals. While exposure-
9 response relationships for individuals have been examined to a limited degree and are likely
10 to be generally similar in form to those for populations, little work has focussed upon
11 understanding or quantifying individual exposure-response relationships.
12 No single exposure-response model form has been adequately tested and identified as
13 providing an accurate, precise description of the relationship between exposure and response
14 in both humans and laboratory animals for lung function and BAL endpoints. Rather, for a
15 given study, a particular model may have been selected a priori to describe the exposure-
16 response data, or may have been identified as providing the best fit among several competing
17 models. In many cases, models have been found to be deficient, but rarely has the
18 performance of a number of possible models been systematically compared. The limiting
19 factor in most of this work has been that no single study to date has included a wide enough
20 range of the three exposure variables of interest, (i.e., C, VE, and T) to choose between
21 models or to identify the appropriate method of describing exposure. From the individual
22 studies, however, have come a number of observations which are qualitatively true for
23 describing BAL and pulmonary function responses in both humans and laboratory animals
24 and which should be considered in the selection of a model to describe population response
25 as a function of exposure.
26
27 1. Response monotonically increases with increases in C, VE, and T.
28
29 2. C has generally been found to be a stronger predictor of response than
30 VE or T.
31
32 3. The relationship between response and T depends upon the level of C, and
33 by logical extension upon VE. For example, the effect of duration of
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1 exposure upon response will be different for high- and low-concentration
2 exposures.
3
4 4. The relationship between response and each of the exposure variables is
5 curvilinear over a wide range of exposure conditions, although it may
6 appear linear over certain narrow ranges of exposure.
7
8 5. With increasing duration of exposure (and possibly with increasing
9 concentration), the FEVj response may approach a plateau in humans.
10 Some evidence exists suggesting that the level of the time-dependent
11 response plateau is a function of C. Respiratory symptom responses may
12 behave similarly, but have not been adequately studied, and this plateau has
13 not been observed in animal studies or for BAL endpoints.
14
15 Models that meet these criteria to a greater or lesser degree and that have been utilized
16 for purposes of prediction include the following.
17
18 1. Polynomial models including linear or second order terms of C, T, or VE,
19 but not including crossproduct terms. These models describe linear or
20 curvilinear functions, with each exposure variable having a different
21 weight. They do not allow the level of C, however, to affect the
22 relationship between response and T, nor do they allow a plateau in
23 response. There is no simple biological interpretation of individual terms
24 in such a model.
25
26 2. Polynomial models utilizing linear or higher order terms of the variable
27 C x T x VE. The product C X T x VE is conceptually pleasing in that
28 it represents the total inhaled dose of 0$ for a given exposure and in the
29 past has been referred to as "effective dose". These models describe a
30 linear or curvilinear function in which the level of C affects the
31 relationship between response and T, but do not allow the individual
32 variables to be weighted differently. These models do not allow a plateau
33 in response.
34
35 3. Exponential model utilizing C XT ajs the exposure variable (model
36 previously tested only at constant Vg). This model describes a nonlinear
37 exposure-response relationship, with C and T having equal weight,
38 allowing the level of C to affect the relationship between response and T.
39 This model does not allow a plateau in response.
40
41 4. Cumulative normal probability model or logistic model utilizing Cy XT as
42 the exposure variable (models previously tested only at constant VE).
43 These models describe sigmoid-shaped exposure-response relationships with
44 C having a different weight than T (identified by the exponent y) and allow
45 the level of C to affect the relationship between response and T. These
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1 models do not allow the level of the plateau in response to be a function of
2 concentration.
3
4 5. Logistic model of CxT as the exposure variable, with C having a further
5 effect upon the level of the time-dependent plateau (model previously tested
6 only at constant VE). This model describes a sigmoid-shaped exposure-
7 response relationship which allows C to have a different weight than T and
8 allows the level of C to affect the relationship between response and T.
9 This model describes a concentration-dependent plateau in response.
10 A model of this form has recently been found to describe the relationship
11 between change in FEVj and C and T for heavily exercising humans over
12 a range of exposure conditions.
13
14 Each of the above models has been found under some circumstance to describe the
15 relationship between exposure and response for a particular data set. Most single data sets,
16 however, do not include a wide enough range of data to adequately test the performance of a
17 particular model across a wide range of exposure conditions or to identify an appropriate
18 exposure metric. In particular, recent efforts have focussed upon the relationship between
19 response and C and T at constant VE. No definitive work has addressed the modeling of
20 response and VE for a given endpoint or for consideration of VE changing as a function of
21 T. Because animal and human studies are often conducted at different relative levels of
22 VE and because techniques to mathematically adjust for these differences are only now being
23 developed, efforts to compare responses across species or to develop extrapolation models
24 have been hampered.
25 Evidence indicates that, for humans and animals, the exposure-response relationship of
26 BAL and pulmonary function outcomes may be modified by previous recent exposure to O3,
27 and the relationship for FEVj changes in humans may be modified by age. Previous
28 exposure to O3 has not been included in any exposure-response models. For young adults,
29 the modification of the exposure-response relationship by age has been modeled.
30 In summary, no single universal model form has been identified which accurately and
31 precisely describes the relationship between population exposure and response under all
32 circumstances. In general, the ability of a predictive model based on one study to predict
33 responses from an independent study has not been studied adequately. For purposes of
34 prediction or risk estimation, the adequacy of fit of a given model in a given data set and the
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1
2
3
4
5
6
7
8
9
10
11
12
size and representativeness of the sample should be assessed. Extrapolation beyond the range
of observed data introduces additional uncertainty into predictions or risk estimates.
9.2.5.1 Prediction and Summary of Mean Responses
A selection of reports in which models of mean FEV^ or BAL response have been
developed is listed below, along with figures summarizing examples of predicted exposure-
response relationships. Following this section on prediction of mean responses will be a
further section which describes the individual responses within the population.
1. Hazucha (1987) predict mean FEVj decrements in humans as a function of
C (0.0 to 0.75 ppm) for four levels of VE for 2-h exposures (Figure 9-1).
110
0.2 0.4 0.6
Ozone Concentration (ppm)
08
Figure 9-1. Mean predicted postexposure to preexposure changes in forced expiratory
volume in 1 s (xlOO%) following 2-h exposures to ozone with intermittent
exercise.
Source: Hazucha (1987).
1
2
3
2. McDonnell and Smith (1994) predict mean ¥EVl decrements in heavily
exercising humans as a function of C (0.0 to 0.4 ppm) and T (1.0 to
6.6 h) (Figure 9-2).
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-5
0.00 0.10 0.20 0.30 0.40 0.50
Ozone (ppm)
Time (hours)
Figure 9-2. Predicted mean decrements in forced expiratory volume in 1 s for 1- and
2-h exposures to ozone with intermittent heavy exercise (A) and 6.6-h
exposures with moderate prolonged exercise (B).
Source: McDonnell and Smith (1994).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
3. Highfill et al. (1992) predict the BAL responses of resting rats and guinea
pigs as a function of C (0.0 to 0.8 ppm) and T (2 to 8 h) (Figure 9-3).
4. Tepper et al. (1994) predict the FVC changes as a function of C (0.0 to
0.8 ppm) and T (2 to 7 h) for exposures conducted with rats breathing at
three times resting VE (Figure 9-4).
Other reports in which models are developed or that contain data potentially useful for
further development or testing of models are listed below.
5. Seal et al. (1993) present data which would allow modeling of
FEV^ decrements in humans as a function of C (0.0 to 0.4 ppm) for 2-h
exposures with moderate exercise.
6. Folinsbee et al. (1978) predict lung function changes in humans as a
function of C (0.0 to 0.50 ppm) and VE (10 to 65 L/min) for 2-h
exposures.
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Rats
Guinea Pigs
600-
500
400
300-
200-
100-
— o2h
— a4h
- —*8h
0 02 0.4 0.6
Ozone (ppm)
02 0.4 0.6
Ozone (ppm)
Figure 9-3. Derived means of BAL protein (BALP) denoted by symbols and the
exponential model shown by lines as time of exposure varies from 2 to 8 h.
Source: Highfill et al. (1992).
i Observed
i Predicted
Ozone (ppm)
Figure 9-4. Predicted mean forced vital capacity for rats exposed to ozone while
undergoing intermittent carbon dioxide-induced hyperpnea.
Source: Tepper et al. (1994).
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1 7. Adams et al. (1981) predict lung function changes in humans as a
2 function of the product of C x T X VE for C = 0 to 0.4 ppm, T = 30
3 to 80 min, and VE = 33 or 66 L/min.
4
5 8. Rombout et al. (1989) predict the concentration of protein in BAL fluid
6 of rats as a function of C (0.25 to 4.0 mg/m3) and T (0 to 12 h) for
7 daytime and nighttime exposures.
8
9 9. Highfill and Costa (1994) compare the fits of quadratic, exponential, and
10 sigmoid-shaped models to published human lung function data and
11 O3 laboratory animal BAL data.
12
13 The concentrations and durations of exposure which result in mean lung function and
14 airway reactivity changes and mean changes in BAL endpoints in humans can be summarized
15 as follows. The estimates are based directly upon studies that were performed at exposure
16 conditions of interest rather than upon mathematical models.
17 Pulmonary function decrements are generally observed in healthy subjects (8 to
18 45 years of age) after 1 to 3 h of exposure as a function of the level of exercise performed
19 and the O3 concentration inhaled during the exposure. Group mean data from numerous
20 controlled human exposure and field studies indicate that, in general, statistically significant
21 pulmonary function decrements beyond the range of normal measurement variability (e.g.,
22 > 3 to 5 % for FEV^ occur:
23 (1) at >0.5 ppm when at rest,
24 (2) at >0.37 ppm with light exercise (slow walking),
25 (3) at >0.30 ppm with moderate exercise (brisk walking),
26 (4) at >0.18 ppm with heavy exercise (jogging), and
27 (5) at >0.16 with very heavy exercise (running).
28
29 For a number of studies, small group mean changes (e.g., <5%) in FEVl5 the medical
30 significance of which is a matter of controversy, have been observed at lower
31 O3 concentrations than those listed above. For example, data from one specific study
32 indicate that FEV^ decrements occur with very heavy exercise in healthy adults at 0.15 to
33 0.16 ppm O3, and data from two studies indicate that such effects may occur in healthy
34 adults at levels as low as 0.12 ppm. Also, pulmonary function decrements have been
35 observed in children and adolescents at concentrations of 0.12 and 0.14 ppm O3 with heavy
36 exercise. Pulmonary function decrements were observed at 0.12 ppm O3 in healthy young
37 adults undergoing heavy exercise in a recent study. Some individuals may experience FEV1
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1 decrements in excess of 15% under these exposure conditions, even when the mean
2 decrement is less than 5 %.
3 An increase in the incidence of cough has been reported at levels as low as 0.12 ppm
4 O3 hi healthy adults during exposure with very heavy exercise and at levels as low as
5 0.18 ppm with heavy exercise. Other respiratory symptoms, such as pain on deep
6 inspiration, shortness of breath, and lower respiratory scores (a combination of several
7 symptoms), have been observed at 0.16 to 0.18 ppm O3 with heavy and very heavy exercise.
8 Increases in nonspecific airway responsiveness have been observed following exposure
9 to 0.40, but not 0.20 ppm O3 at rest, and have been observed at concentrations as low as
10 0.18 ppm but not to 0.12 ppm O3 during exposure with very heavy exercise.
11 Increases in BAL protein concentration and/or PMNs have been observed following
12 exposure to 0.20, 0.30, and 0.40 ppm with very heavy exercise and have not been studied at
13 lower concentrations for 1 to 3 h exposures.
14 For exposures of healthy subjects performing moderate exercise during longer duration
15 exposures (6 to 8 h), 5% group mean decrements hi FEVj were observed at:
16 (1) 0.08 ppm O3 after 5.6 h,
17 (2) 0.10 ppm O3 after 4.6 h, and
18 (3) 0.12 ppm O3 after 3 h.
19
20 For these same subjects, 10% mean FEVj decrements were observed at 0.12 ppm O3 after
21 5.6 and 6.6 h. As in the shorter duration studies some individuals experience changes larger
22 than those represented by the group mean changes.
23 Increases in the respiratory symptoms (i.e., cough, shortness of breath, and pain on
24 deep inspiration) and hi nonspecific airway responsiveness have been observed following
25 exposure to 0.08, 0.10, and 0.12 ppm O3 for 6.6 h with moderate levels of exercise.
26 Increases in nonspecific airway responsiveness have been observed at 0.08, 0.10, and
27 0.12 ppm O3 during 6.6 h exposures with moderate levels of exercise.
28 Increases in BAL protein and/ or PMN have also been observed following 6.6 h
29 exposure to 0.08 and 0.10 ppm O3. No 6- to 8-h exposure studies have been conducted
30 using O3 concentrations less than 0.08 ppm.
31
32
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1 9.2.5.2 Prediction and Summary of Individual Responses
2 It is well known that considerable inter-individual differences in the magnitude of
3 response to O3 exposure exist. The individual lung function and, to a lesser extent,
4 respiratory symptom responses to O3 have been demonstrated to be reproducible over a
5 period of time, indicating that some individuals are consistently more responsive to O3 than
6 are others. The basis for these differences are not known, with the exception that young
7 adults have been observed to be more responsive than older adults (see Figure 9-5).
8
1.0
-------
1
2
3
4
5
6
7
8
9
10
11
Calculation of group mean responses for a population that includes both more and less
responsive individuals is useful for making inferences regarding the probability that a
population effect is present or absent for a given exposure. Since the frequency distribution
of individual responses to O3 changes with changing exposure conditions, however,
knowledge of the mean and variance of population responses does not provide reliable
information on the distribution of individual responses for a given exposure, and hence, is
not particularly useful for estimating risks to members of the population. One method of
presenting individual data is illustrated in Figure 9-6 in which histograms are presented for
individual responses of subjects participating in four 6.6-h studies of low-levels 03 exposure.
Distribution of Percent Change in FEV,
•
^^™
N-87
AIR
:—
•
N-60
0.08
N-32
0.10
N = 49
0.12
Percent of Subjects
> 10% Drop
•HFEV,
26%
31%
46%
Figure 9-6. The distribution of response for 87 subjects exposed to clean air and at least
one of 0.08, 0.10, or 0.12 ppm O3 is shown here. The O3 exposures lasted
6.6 h, during which time the subjects exercised for 50 min of each hour
with a 35-min rest period at the end of the third hour. The abscissa
indicates the number of subjects. The bar labels on the ordinate indicate
decreases in FEVj, expressed as percent change from baseline. For
example, the bar labeled 10 indicates the number of subjects with a
decrease in FEV, of >5% but <10%; the bar labeled -5 indicates
improvement in FEVj of >0% but <5%. The rectangle across the bottom
of the graph indicates the percentage of subjects at each O3 concentration
with a decrease of FEVX in excess of 10%.
Source: Folinsbee et al. (1991).
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1 Another method that allows interpolation between observed data points involves
2 definition of the effect of interest (e.g., a 10% decrement in FEVj) and modeling of the
3 proportion of individuals who experience such an effect as a function of exposure conditions.
4 For example, Figure 9-7 shows the prediction of the proportion of individuals (humans)
5 experiencing 10% FEVj decrements and respiratory symptom responses (Figure 9-8) as a
6 function of C (0.0 to 0.4 ppm O3) for three studies conducted at either 1 or 2 h of exposure
7 with heavy exercise.
8
• Avoletal. (1984)
D Kulleetal. (1985)
A McDonnell etal. (1983)
0.0
o.o
0.1 0.2 0:3
Ozone Concentration (ppm)
04
Figure 9-7. Proportion of heavily exercising individuals predicted to experience a 10%
decrement in forced expiratory volume in 1 s following a 1- or 2-h exposure
to ozone.
Source: U.S. Environmental Protection Agency (1989).
1 Predictions of the proportion of individuals experiencing a 5, 10, or 15% FEVl
2 decrement as functions of C (0.0 to 0.12 ppm), T (1 to 6.6 h), and age (18 to 34 years) for
3 exposures with moderate exercise are shown in Figure 9-9.
4 As an example of differences between the mean and individual responses, it was stated
5 earlier that exposure for 5.6 h to 0.08 ppm was the shortest duration for which a 5 % mean
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a Kulleetal. (1985)
A McDonnell et al. (1983)
0.1 0.2 0.3
Ozone Concentration (ppm)
Figure 9-8. Proportion of heavily exercising individuals predicted to experience mild
cough following a 2-h ozone exposure.
Source: U.S. Environmental Protection Agency (1989).
•5
g
0.1
0.2 0.3 0.4 0.5 0.6 0.7
Dose (ppm x hours)
0.8 0.9 1.0
Figure 9-9. Proportion of moderately exercising individuals exposed to ozone for
6.6 h predicted to experience 5, 10, or 15% decrements in forced expiratory
volume in 1 s as a function of CxT for age = 24 years.
Source: McDonnell et al. (1994).
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1 decrement in FEVj was observed. For those same exposure conditions, 41, 17, and 10% of
2 the subjects studied experienced FEVl decrements larger than 5, 10, and 15%, respectively.
3 The clinical significance of individual responses to O3 exposure depends on the
4 magnitude of the changes in spirometry (e.g., FEVj, FVC) and airway responsiveness to
5 nonspecific stimuli, the severity of respiratory symptoms (e.g., cough and pain on deep
6 breath), and the duration of the response. In nonasthmatic individuals, O3-induced changes
7 in specific airway resistance (SR^), a measure of large airway narrowing, are small and of
8 minimal significance. Asthmatics, however, often have baseline airway narrowing and
9 experience larger changes in SR^ upon exposure to O3 than do nonasthmatics. Because of
10 these baseline differences, the clinical significance of increases in SR^ depends both upon
11 percent changes from baseline and absolute increases in SR^. Table 9-1 categorizes these
12 physiological responses to O3 exposure as normal (or none), mild, moderate, or severe.
13 Qualitative relationships among the categories provide an indication of the severity of the
14 response.
15
TABLE 9-1. GRADATION OF PHYSIOLOGICAL RESPONSES TO SHORT-TERM
OZONE EXPOSURE3
Response
Cough symptom
Pain on deep
breath symptom
FEV! (also FVC)
SRaw (asthmatics)
Airway
responsiveness
Duration of response
None/Normal
Infrequent cough
None
Within normal
range (±3%)
Within normal
range (±20%)
Within person's
normal range
None
Mild
Cough with deep
breath or FVC test
Discomfort just
noticeable on FVC
test
FEVi decreased
less than 10%
Increase less than
100%
Increase less than
100%
Less than 4 h
Moderate
Frequent
spontaneous cough
Marked discomfort
on exercise or
FVC test
FEVj decreased
more than 10%
but less than 20%
Increase up to
200% or up to
15 cm H2O/s
Increase up to
300%
Less than 24 h
Severe
Persistent
uncontrollable cough
Exercise or
breathing tests cause
chest pain; FVC
tests cannot be
performed properly
FEV1 decreased
more than 20%
Increase greater than
200% or more than
15 cm H2O/s
Increase greater than
300%
Longer than 24 h
See text for discussion.
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1 9.3 HEALTH EFFECTS OF LONG-TERM EXPOSURES
2 In both humans and test animals, the response to a single O3 exposure can nominally be
3 characterized by lung dysfunction, lung cell injury and inflammation, and leakage of plasma
4 proteins into the airspace lumen. However, when such an exposure is repeated for several
5 consecutive days, these effects appear to wane, suggesting adaptation or the development of
6 tolerance to the continued intermittent challenge. In spite of this apparent state of tolerance,
7 long-term O3 exposures have been linked to subtle pulmonary effects, some of which have
8 irreversible components, thereby enhancing concern about chronic effects. The following
9 section will provide an overview attempting to synthesize the current understanding of the
10 phenomenon of adaptation during brief repeated exposures and the evidence for potential
11 health impairments resulting from protracted exposures to this oxidant.
12
13 9.3.1 Repeated Exposures
14 It is well established that a brief exposure of laboratory rodents to a minimally toxic
15 concentration of O3 will protect the animals from a subsequent lethal challenge of O3 a week
16 later. This phenomenon, called tolerance, bears a similarity to the pattern of attenuated
17 nonlethal effects (sometimes referred to as "adaptation") observed in both human volunteers
18 and animals when exposed to episodic levels of O3 (<0.5 ppm) for 1 to 7 h/day over a
19 succession of 5 or more days. Generally, over a 5-day exposure period, the effects of Day 1
20 are accentuated on Day 2 and diminish thereafter. Attenuation of the functional effects
21 include spirometric deficits and associated symptoms as well as irritative alterations of
22 breathing; nonspecific airway responsiveness, however, does not revert to normal levels.
23 Measures of tissue effects which attenuate include inflammation and impaired phagocytic
24 capabilities of alveolar macrophages. However, some evidence from animal studies suggests
25 that tissue alterations persist, although the observed changes may be part of a transition to a
26 chronically affected state of the lung. Thus, in general, cell associated indicators of injury or
27 damage within the lung appear to diminish in spite of the continued O3 exposure.
28 A number of mechanisms have been shown to be involved in the evolution of this
29 "adapted" state. These mechanisms range from the replacement of sensitive cells in the
30 alveolar lining (epithelium) by more resistant cells (with or without a thickened fluid barrier
31 on the lumenal surface) to the enhancement of antioxidant metabolism providing cell
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1 resistance and more biochemical defenses at the lung surface. However, controlled human
2 studies show that after a one-week period without O3 exposure, subjects regain their
3 spirometric responsiveness to O3 challenge, although this abrupt transition between
4 unresponsiveness and responsiveness appears less distinct in field-related studies. For
5 example, studies of Southern Californians suggest that they are significantly less responsive
6 to the spirometric effects of an acute episodic-like controlled challenge with O3 when studied
7 for a period after the "high" O3 season than after the relatively "low" O3 season. Likewise,
8 there is some evidence that O3-exposed urban populations are also somewhat more resistant
9 to the oxidant than populations that receive minimal exposure. This would appear to be in
10 conflict with hospital admissions data suggesting the aggravation of respiratory diseases, like
11 asthma, within such populations. It remains to be shown whether these latter data reflect the
12 responsiveness of a sensitive subpopulation, perhaps less adapted or having less reserve
13 function.
14
15 9.3.2 Prolonged Exposures
16 Most long-term exposure studies in animals have evaluated structural and functional
17 changes. In the few investigations of the immune system or antibacterial host defenses,
18 prolonged exposures of animals either caused no effects or did not increase the magnitude of
19 effects observed after acute exposures. Thus, the following discussion centers on the larger
20 body of knowledge on other endpoints.
21 Epidemiologic studies attempting to associate chronic lung effects in humans with long-
22 term O3 exposure have yet to provide unequivocal evidence that such a linkage exists. Most
23 studies have been cross-sectional in design and have been compromised by incomplete
24 control of confounding variables and inadequate exposure information. Other studies have
25 attempted to follow variably exposed groups prospectively. Studies of such design have been
26 conducted in communities of the Southwest Air Basin as well as in Canada where
27 comparisons could be drawn between lung function changes over several years in populations
28 from high or low oxidant pollution. The findings suggest small, but consistent decrements in
29 lung function among inhabitants of the more highly polluted communities. However,
30 associations between O3 and other copollutants and, in some cases, problems with study
31 population loss undermine the confidence in the study conclusions. Likewise, recent
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1 associations found between O3 and the incidence/severity of asthma over a decade of study,
2 though derived from well-designed studies, also tend to be weakened by colinearity of O3
3 with other air pollutants. Nevertheless, in all of the studies assessing lung function, the
4 pattern of dysfunction associated with the long-term exposure has been consistent with the
5 small airway lesions seen in animal studies.
6 The advantage of animal studies is the ability to examine closely the distribution and
7 intensity of the O3-induced lesions throughout the respiratory tract. Indeed, cells of the nose
8 like the distal lung are clearly affected by 03. Perhaps of greater health concern would be
9 the lesions that occur in the centriacinar regions of the lung where the alveoli meet the end-
10 airways. Altered function of the distal airways, the proximal conduits of air to the gas-
11 exchange regions, can result in reduced communication of fresh air with the alveoli, air-
12 trapping, and reduced oxygenation of the blood. In fact, chronic O3 lesions as found in
13 animal studies are reminiscent of the earliest lesions found in autopsied cigarette smokers,
14 many of whom would have theoretically progressed to chronic obstructive lung diseases.
15 As shown in Figure 9-10, the temporal pattern of effects during and after a chronic
16 exposure is complex. During the early days of exposure, the end-airway lumenal and
17 interstitial inflammation peaks, and thereafter appears to subside at a lower plateau of activity
18 sometimes referred to as a "smoldering" lesion. Several cytokines remain elevated beyond
19 the apparent adaptation phase of the response and may be conceptually linked to the
20 development of chronic lesions in the distal lung. To date, however, a clear association of
21 these BAL-derived mediators and cells with long-term toxicity has not been demonstrated.
22 Some evidence of molecular changes within the matrix of the lung may also link to the
23 chronic effects, but these too remain poorly defined. When exposures to O3 continue for
24 weeks or months, the diminished O3-induced exudative response in the distal bronchoalveolar
25 areas is supplanted by hyperplastic epithelia hi the alveoli and end-airways. Damaged cells
26 in centriacinar alveoli are replaced by metabolically active progenitor cells that are more
27 resistant to oxidant challenge. Junctional areas between conducting and gas exchange
28 regions, where the O3 changes are typically most intense, also undergo epithelial hyperplasia,
29 giving the appearance that airway cells are extending into the mouth of the alveolus, hence
30 the term "bronchiolization". The functional result of this concentration-dependent process is
31 the effective elongation of distal bronchioles, which functionally may alter air distribution
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CD
CO
O
a.
-------
1 that similar end-airway lesions result from ambient O3 exposure in areas with high oxidant
2 exposures.
3 Studies of prolonged exposures in monkeys and rats reveal generally similar
4 morphologic responses, although it appears that the monkey exhibits somewhat more tissue
5 injury than does the rat under roughly similar exposure conditions. Although adequate
6 dosimetric data are not yet available for a direct comparison of interspecies sensitivity, the
7 monkey, with its similarity in distal airway structure relative to the human, provides data that
8 may best reflect the potential effects in humans. As such, monkeys exposed to O3 at
9 0.15 ppm for 8 h each day for 6 to 90 days exhibit significant distal airway remodeling. Rats
10 show similar but more modest changes at 0.25 ppm after exposures of longer duration, up to
11 18 mo and beyond in both species (near-lifetime in the case of the rat). The chronic distal
12 lung and airway alterations appear consistent with incipient peribronchiolar fibrogenesis
13 within the interstitium. Attempts to correlate functional deficits have been variable, perhaps
14 due in part to the degree and distribution of the lesions and the general insensitivity of most
15 measures of the distal lung function. The interstitial changes may progress, however.
16 Moreover, one recent primate study revealed evidence that intermittent challenge with a
17 pattern of O3 exposure more reflective of seasonal episodes, with extended periods of clean
18 air in between extended periods of O3, actually leads to greater injury. The reasons for this
19 are unclear, but may relate to the known loss of tolerance which occurs in both humans and
20 animal test species with removal of the oxidant burden.
21 In conclusion, the collective toxicologic data on chronic exposure to O3 garnered in
22 animal exposure and human population studies have some ambiguities. What is clear is that
23 the distribution of the O3 lesions is roughly similar across species, is, in part, concentration
24 dependent (and perhaps time or exposure pattern dependent), and, under certain conditions,
25 has irreversible structural attributes. What is unclear is whether ambient exposure scenarios
26 encountered by humans result in similar lesions and whether there are resultant functional or
27 unpaired health outcomes, particularly since the human exposure scenario may involve much
28 longer exposures than can be studied in the laboratory. The epidemiologic lung function data
29 generally parallel those of the animal studies, but they lack the confidence of O3 exposure
30 history and are frequently confounded by personal or copollutant variables.
31
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1 9.3.3 Genotoxicity and Carcinogenicity of Ozone
2 Numerous in vitro exposure studies suggest that O3 either has a weak or no potential to
3 cause mutagenic, cytogenetic, or cellular transformation effects. Most of these experiments
4 utilized high concentrations of O3 (>5.0 ppm). Because of the exposure systems used, there
5 are unknowns about the formation of artifacts and the dose of O3. Therefore, these studies
6 are not very useful in health assessment. Cytogenetic effects have been observed in some,
7 but not all, laboratory animal and human studies of short-term O3 exposure. However, well-
8 designed human clinical cytogenetic studies were negative.
9 Until recently, in vivo exposure studies of carcinogenicity, with and without
10 co-exposure to known carcinogens, were either negative or ambiguous. A well-designed
11 cancer bioassay study has recently been completed by the National Toxicology Program
12 (NTP) using male and female F344/N rats and B6C3FJ mice. Animals were exposed for
13 2 years to 0.12, 0.5, and 1.0 ppm O3 (6 h/day, 5 days/week). A similar lifetime exposure
14 was conducted, but 0.12 ppm was not used. The NTP evaluated the weight-of-evidence for
15 this study. They found "no evidence" of carcinogenicity in rats. They reported "equivocal
16 evidence" of carcinogenicity in O3-exposed male mice and "some evidence" of carcinogenic
17 activity in O3-exposed female mice. The increases in adenomas and carcinomas were only
18 observed in the lungs. There was no concentration response. In the male mice, the
19 incidence of neoplasms in the 2-year study was not significantly elevated by O3 and was
20 within the range of historical controls. Also, the lifetime exposure did not significantly
21 increase the incidence of neoplasms, even though the incidence of carcinomas was increased.
22 In the female mice, a 2-year (but not lifetime) exposure to 1.0 ppm only increased the
23 incidence of animals with neoplasms. When the female mouse data from the two exposure
24 regimens (at 1.0 ppm) were combined, there was a statistically significant increase (about a
25 doubling) in neoplasms. In a companion study, male rats were treated with a tobacco
26 carcinogen and exposed for 2 years to 0.5 ppm O3. Ozone did not affect the response and
27 therefore had no tumor promoting activity.
28 In summary, only chronic exposure to a high concentration of O3 (1.0 ppm) has been
29 shown to evoke a limited degree of carcinogenic activity in one strain of mice. Rats were
30 not affected. Furthermore, there was no concentration response, and there is inadequate
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1 information from other research to provide a mechanistic support for the finding in mice.
2 Thus, it is not justified to extrapolate these mouse data to humans at the present time.
3
4
5 9.4 COMBINED POLLUTANT EXPOSURES
6 In the ambient air, people are exposed to mixtures of pollutants, making it important to
7 understand interactions. Epidemiological studies, which inherently evaluate O3 as part of
8 complex mixtures, are discussed in other subsections dealing with classes of effects. In the
9 laboratory it becomes possible to sort out the role of O3 in simple mixtures. Complex
10 mixtures are typically not investigated in the laboratory because even if only six pollutants
11 were involved, the experimental design required to unequivocally sort out which pollutant or
12 pollutant interactions were responsible for the responses or portions of the responses could
13 require as many as 719 additional separate experiments, and this would be true only if the
14 concentrations of the six pollutants remained the same.
15 The summary will focus only on binary mixtures since these are by far the predominant
16 type of experiments. Responses to a binary pollutant mixture may represent the sum of the
17 independent responses to the two chemicals (i.e., an additive response). If there is some
18 interaction between either the two responses or the two pollutants, the resultant response
19 could be larger than additive (synergism) or smaller than additive (antagonism). Interaction
20 between pollutants could result in the production of a more or less toxic byproduct.
21 Alternatively, the response to one pollutant could magnify the response to the other pollutant
22 or could interfere with or block the action of the other pollutant. Binary mixture studies fall
23 into two categories, simultaneous and sequential exposures. In the simultaneous exposures,
24 both the responses and the pollutants can interact. In the sequential exposures, it is primarily
25 the responses that would interact.
26 In general, controlled human studies of O3 mixed with other pollutants show no more
27 than an additive response with symptoms or spirometry as an endpoint. This applies to O3 in
28 combination with NO2, SO2, H2SO4, HNO3, or CO. Indeed, at the levels of copollutants
29 used in human exposure studies, the responses can be attributed primarily to O3. In one
30 study, exposure to O3 increased airway responsiveness to SO2 in asthmatics. Similarly, other
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1 pollutants that may increase airway responsiveness could augment the effect of 03 on airway
2 responsiveness.
3 The relatively large number of animal studies of O3 in mixture with NO2 and
4 H2SO4 show that additivity, synergism, and antagonism can result, depending upon the
5 exposure regimen and the endpoint studied. The numerous observations of synergism are of
6 concern, but the interpretation of most of these studies relative to the real world is
7 confounded by unrealistic exposure designs. For example, often ambient concentrations of
8 O3 were combined with levels of copollutants substantially higher than ambient, creating the
9 possibility that mechanisms of toxicity unlikely in the real world contributed to the
10 experimental outcome. Nevertheless, the data support a hypothesis that coexposure to
11 pollutants, each at innocuous or low-effect levels, may result in effects of significance.
12
13
14 9.5 CONCLUSIONS
15 This section summarizes the primary conclusions derived from an integration of the
16 known health effects of O3 provided by animal lexicological, human clinical, and
17 epidemiological studies.
18
19 1. What are the health effects of short-term (<8 h) exposures to ozone?
20 Acute O3 exposure of laboratory animals and humans causes changes in pulmonary
21 function, including tachypnea (rapid, shallow breathing), decreased lung volumes and flows,
22 and increased airway responsiveness to nonspecific stimuli. Increased airway resistance
23 occurs in both humans and laboratory animals, but typically at higher exposure levels than
24 other functional endpoints. In addition, adult human subjects experience O3-induced
25 symptoms of airway irritation such as cough or pain on deep inspiration. The changes in
26 pulmonary function and respiratory symptoms occur as a function of exposure concentration,
27 duration, and level of exercise. Recovery of pulmonary function and the absence of
28 O3-induced symptoms is usually complete within 24 h of the end of exposure, although other
29 responses may persist somewhat longer.
30
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1 • Pulmonary function decrements are generally observed in healthy subjects
2 (8 to 45 years of age) after 1 to 3 h of exposure as a function of the level of
3 exercise performed and the O3 concentration inhaled during the exposure.
4 Group mean data from numerous controlled human exposure and field
5 studies indicate that, in general, statistically significant pulmonary function
6 decrements beyond the range of normal measurement variability (e.g., 3 to
7 5% forFEVi) occur
8
9 (1) at >0.5 ppm when at rest,
10 (2) at >0.37 ppm with light exercise (slow walking),
11 (3) at >0.30 ppm with moderate exercise (brisk walking),
12 (4) at >0.18 ppm with heavy exercise (easy jogging), and
13 (5) at >0.16 ppm with very heavy exercise (running).
14
15 For a number of studies, small group mean changes (e.g., <5%) in FEVl5
16 the medical significance of which is a matter of controversy, have been
17 observed at lower O3 concentrations than those listed above. For example,
18 data from one specific study indicate that FEVj decrements occur with very
19 heavy exercise in healthy adults at 0.15 to 0.16 ppm O3, and data from two
20 studies indicate that such effects may occur in healthy adults at levels as
21 low as 0.12 ppm. Also, pulmonary function decrements have been
22 observed in children and adolescents at concentrations of 0.12 and
23 0.14 ppm O3 with heavy exercise. Pulmonary function decrements were
24 observed at 0.12 ppm O3 in healthy young adults undergoing heavy exercise
25 in a recent study. Some individuals within a study may experience FEVj
26 decrements in excess of 15 % under these exposure conditions, even when
27 the group mean decrement is less than 5 %.
28
29 • For exposures of healthy subjects performing moderate exercise during
30 longer duration exposures (6 to 8 h), 5% group mean decrements hi FEVj
31 were observed at
32
33 (1) 0.08 ppm O3 after 5.6 h,
34 (2) 0.10 ppm O3 after 4.6 h, and
35 (3) 0.12 ppm O3 after 3 h.
36
37 For these same subjects, 10% group mean FEVl decrements were observed
38 at 0.12 ppm O3 after 5.6 and 6.6 h. As in the shorter duration studies,
39 some individuals experience changes larger than those represented by the
40 group mean changes.
41
42 • An increase in the incidence of cough has been reported at
43 O3 concentrations as low as 0.12 ppm hi healthy adults during 1 to 3 h of
44 exposure with very heavy exercise. Other respiratory symptoms, such as
45 pain on deep inspiration, shortness of breath, and lower respiratory scores
46 (a combination of several symptoms), have been observed at 0.16 to
47 0.18 ppm O3 with heavy and very heavy exercise. Respiratory symptoms
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1 have also been observed following exposure to 0.08, 0.10, and 0.12 ppm
2 O3 for 6.6 h with moderate levels of exercise.
3
4 • Increases in nonspecific airway responsiveness have been observed after
5 1 to 3 h of exposure to 0.40 ppm, but not 0.20 ppm, O3 at rest, and have
6 been observed at concentrations as low as 0.18 ppm, but not to 0.12 ppm,
7 O3 during exposure with very heavy exercise. Increases in nonspecific
8 airway responsiveness during 6.6-h exposures with moderate levels of
9 exercise have been observed at 0.08, 0.10, and 0.12 ppm O3.
10
11 Acute O3 exposure of laboratory animals and humans disrupts the barrier function of
12 the lung epithelium, permitting materials in the airspaces to enter lung tissue, allowing cells
13 and serum proteins to enter the airspaces (inflammation), and setting off a cascade of
14 responses.
15
16 • Increased levels of neutrophils and protein in lung lavage fluid have been
17 observed following exposure of humans to 0.20, 0.30, and 0.40 ppm with
18 very heavy exercise and have not been studied at lower concentrations for
19 1- to 3-h exposures. Increases in protein and/or neutrophils have also been
20 observed at 0.08 and 0.10 ppm O3 during 6.6-h exposures with moderate
21 exercise; lower concentrations have not been tested.
22
23 Acute O3 exposure of laboratory animals and humans impairs alveolar macrophage
24 clearance of viable and nonviable particles from the lungs and decreases the effectiveness of
25 host defenses against bacterial lung infections in animals and perhaps humans. The ability of
26 alveolar macrophages to engulf microorganisms is decreased in humans exposed to 0.08 and
27 0.10 ppm for 6.6 h with moderate exercise.
28
29 2. What are the health effects of repeated, short-term exposures to ozone?
30 During repeated acute exposures, some of the O3-induced responses are partially or
31 completely attenuated. Over a 5-day exposure, pulmonary function changes are typically
32 greatest on the second day, but return to control levels by the fifth day of exposure. Most of
33 the inflammatory markers (e.g., neutrophil influx) also attenuate by the fifth day of exposure,
34 but markers of cell damage (e.g., lactate dehydrogenase enzyme activity) do not attenuate
35 and continue to increase. Attenuation of lung function decrements is reversed following 7 to
36 10 days without O3. Some inflammatory markers are also reversed during this time period,
37 but others still show attenuation even after 20 days without O3. The mechanisms and
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1 impacts involved in attenuation are not known, although the underlying cell damage continues
2 throughout the attenuation process. In addition, attenuation may alter the normal distribution
3 of O3 within the lung, allowing more O3 to reach sensitive regions, possibly affecting normal
4 lung defenses (e.g., neutrophil influx in response to inhaled microorganisms).
5
6 3. What are the health effects of long-term exposures to ozone
7 Exposure to O3 for months and years causes structural changes in several regions of the
8 respiratory tract, but effects may be of the greatest importance in the centriacinar regions
9 where the alveoli and conducting airways meet because this region is typically affected in
10 most chronic diseases of the human lung. This information on O3 effects in the distal lung is
11 derived from animal lexicological studies because, to date, such data are not available in
12 humans. Epidemiological studies attempting to associate chronic health effects in humans
13 with long-term O3 exposure have yet to provide unequivocal evidence that such a linkage
14 exists.
15 Chronic exposure of one strain of female mice to high 0$ levels (1 ppm) caused a
16 small, but statistically significant increase in lung tumors. There was no concentration-
17 response relationship and rats were not affected. Genotoxicity data are either negative or
18 weak. Given the nature of the database, the effects in one strain of mice cannot yet be
19 qualitatively extrapolated to humans. Ozone did not show tumor-promoting activity in a
20 chronic rat study (at 0.5 ppm O3).
21
22 4. What are the health effects of binary pollutant mixtures containing ozone?
23 Combined data from laboratory animal and controlled human exposure studies on
24 O3 support the hypothesis that coexposure to pollutants, each at low-effect levels, may result
25 in effects of significance. The data from human studies of O3 in combination with NO2,
26 SO2, sulfuric acid, nitric acid, or CO show no more than an additive response on lung
27 spirometry or respiratory symptoms. The larger number of laboratory animal studies
28 with O3 in mixture with NO2 and sulfuric acid show that effects can be additive, synergistic,
29 or even antagonistic, depending upon the exposure regimen and the endpoint studied. This
30 issue of exposure to copollutants remains poorly understood, especially with regard to
31 chronic effects.
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1 5. What population groups are at-risk as a result of exposure to ozone?
2 Identification of population groups that may show increased susceptibility to O3 are
3 based on their (1) biological responses to O3; (2) physiological status (e.g., preexisting lung
4 disease); (3) activity patterns; (4) personal exposure history; and (5) personal factors (e.g.,
5 age, nutritional status).
6 The predominant information on the health effects of O3 noted above comes from
7 studies on healthy, nonsmoking, exercising subjects, 8 to 45 years of age. These studies
8 demonstrate that among this group, there is a large variation in sensitivity and responsiveness
9 to O3, with at least a 10-fold difference between the most and least responsive individuals.
10 Individual sensitivity to O3 may also vary throughout the year, related to seasonal variations
11 in ambient O3 exposure. The specific factors that contribute to this large intersubject
12 variability, however, remain undefined. Although differences may be due to the dosimetry
13 of O3 in the respiratory tract, available data show little effect on O3 deposition after
14 inhalation through the nose or mouth.
15 Controlled studies on mild asthmatics suggest that they have similar lung volume
16 responses but greater airway resistance changes to 0$ than nonasthmatics. Furthermore,
17 limited data from studies of moderate asthmatics suggest that they may have greater lung
18 volume responses than nonasthmatics. Daily life studies reporting an exacerbation of asthma
19 and decrease in peak expiratory flow rates, particularly in asthmatic children, appear to
20 support the controlled studies; however, those studies are confounded by concurrent
21 temperature, particle or aeroallergen exposure, and asthma severity of the subjects or their
22 medication use. In addition, field studies of summertime daily hospital admissions for
23 respiratory causes show a consistent relationship between asthma and ambient levels of O3 in
24 various locations in the northeastern United States, even after controlling for independent
25 contributing factors.
26 Other population groups with preexisting limitations in pulmonary function and exercise
27 capacity (e.g., chronic obstructive pulmonary disease, chronic bronchitis, ischemic heart
28 disease) would be of primary concern in evaluating the health effects of O^. Unfortunately,
29 not enough is known about the responses of these individuals to make definitive conclusions
30 regarding their relative responsiveness to O3. Indeed, functional effects in these individuals
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1 with reduced lung function may have greater clinical significance than comparable changes in
2 healthy individuals.
3 Currently available data on personal factors or personal exposure history known or
4 suspected of influencing responses to O3 are the following.
5
6 • Human studies have identified a decrease in pulmonary function
7 responsiveness to O3 with increasing age, although symptom rates remain
8 similar. Toxicological studies are not easily interpreted but suggest that
9 young animals are not more responsive than adults.
10
11 • Available lexicological and human data have not conclusively demonstrated
12 that males and females respond differently to O3. If gender differences
13 exist for lung function responsiveness to O3, they are not based on
14 differences in baseline pulmonary function.
15
16 • There is no compelling evidence to date to suggest that any ethnic or racial
17 group has a different distribution of responsiveness to O3. However, data
18 are not adequate to rule out the possibility of such differences.
19
20 • Information derived from O3 exposure of smokers is limited. The general
21 trend is that smokers are less responsive than nonsmokers. This reduced
22 responsiveness may wane after smoking cessation.
23
24 • Although nutritional status (e.g., vitamin E deficiency) makes laboratory
25 rats more susceptible to O3-induced effects, it is not clear if vitamin E
26 supplementation has an effect in human populations. Such supplementation
27 has no or minimal effects in animals. The role of such antioxidant vitamins
28 in O3 responsiveness, especially their deficiency, has not been well studied.
29
30
31 Based on information presented in this document, the population groups that have
32 demonstrated responsiveness to ambient concentrations of O3 consist of exercising healthy
33 and asthmatic individuals, including children, adolescents, and adults.
34
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